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| ethanol |
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| CHEBI:16236 |
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| A primary alcohol that is ethane in which one of the hydrogens is substituted by a hydroxy group. |
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This entity has been manually annotated by the ChEBI Team.
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CHEBI:44594, CHEBI:42377, CHEBI:4879, CHEBI:14222, CHEBI:23978, CHEBI:30878, CHEBI:30880
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| eMolecules:475123 |
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SDF
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more structures >>
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| Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula CH3CH2OH. It is an alcohol, with its formula also written as C2H5OH, C2H6O or EtOH, where Et stands for ethyl. Ethanol is a volatile, flammable, colorless liquid with a characteristic wine-like odor and pungent taste.
As a psychoactive depressant, it is the active ingredient in alcoholic beverages, and the second most consumed drug globally behind caffeine.
Ethanol is naturally produced by the fermentation process of sugars by yeasts or via petrochemical processes such as ethylene hydration. Historically it was used as a general anesthetic, and has modern medical applications as an antiseptic, disinfectant, solvent for some medications, and antidote for methanol poisoning and ethylene glycol poisoning. It is used as a chemical solvent and in the synthesis of organic compounds, and as a fuel source for lamps, stoves, and internal combustion engines. Ethanol also can be dehydrated to make ethylene, an important chemical feedstock. As of 2023, world production of ethanol fuel was 29,590,000,000 US gallons (112.0 gigalitres), coming mostly from the U.S. (51%) and Brazil (26%).
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Read full article at Wikipedia
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| InChI=1S/C2H6O/c1-2-3/h3H,2H2,1H3 |
| LFQSCWFLJHTTHZ-UHFFFAOYSA-N |
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Saccharomyces cerevisiae
(NCBI:txid4932)
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Source: yeast.sf.net
See:
PubMed
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Escherichia coli
(NCBI:txid562)
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See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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See:
DOI
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polar solvent
A solvent that is composed of polar molecules. Polar solvents can dissolve ionic compounds or ionisable covalent compounds.
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Escherichia coli metabolite
Any bacterial metabolite produced during a metabolic reaction in Escherichia coli.
human metabolite
Any mammalian metabolite produced during a metabolic reaction in humans (Homo sapiens).
Saccharomyces cerevisiae metabolite
Any fungal metabolite produced during a metabolic reaction in Baker's yeast (Saccharomyces cerevisiae ).
mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
disinfectant
An antimicrobial agent that is applied to non-living objects to destroy harmful microorganisms or to inhibit their activity.
teratogenic agent
A role played by a chemical compound in biological systems with adverse consequences in embryo developments, leading to birth defects, embryo death or altered development, growth retardation and functional defect.
NMDA receptor antagonist
Any substance that inhibits the action of N-methyl-D-aspartate (NMDA) receptors. They tend to induce a state known as dissociative anesthesia, marked by catalepsy, amnesia, and analgesia, while side effects can include hallucinations, nightmares, and confusion. Due to their psychotomimetic effects, many NMDA receptor antagonists are used as recreational drugs.
protein kinase C agonist
An agonist that selectively binds to and activates a protein kinase C receptor
neurotoxin
A poison that interferes with the functions of the nervous system.
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antiseptic drug
A substance used locally on humans and other animals to destroy harmful microorganisms or to inhibit their activity (cf. disinfectants, which destroy microorganisms found on non-living objects, and antibiotics, which can be transported through the lymphatic system to destroy bacteria within the body).
polar solvent
A solvent that is composed of polar molecules. Polar solvents can dissolve ionic compounds or ionisable covalent compounds.
central nervous system depressant
A loosely defined group of drugs that tend to reduce the activity of the central nervous system.
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View more via ChEBI Ontology
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1-hydroxyethane
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ChemIDplus
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[CH2Me(OH)]
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MolBase
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[OEtH]
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MolBase
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alcohol
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NIST Chemistry WebBook
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alcohol etílico
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ChEBI
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alcool éthylique
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ChemIDplus
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Alkohol
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ChemIDplus
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Äthanol
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ChemIDplus
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Äthylalkohol
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ChemIDplus
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C2H5OH
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ChEBI
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etanol
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ChEBI
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Ethanol
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KEGG COMPOUND
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ETHANOL
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PDBeChem
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ethanol
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UniProt
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éthanol
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ChEBI
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Ethyl alcohol
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KEGG COMPOUND
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EtOH
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ChemIDplus
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hydroxyethane
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ChemIDplus
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Methylcarbinol
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KEGG COMPOUND
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spiritus vini
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ChEBI
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Dehydrated ethanol
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KEGG DRUG
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1076
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DrugCentral
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1373
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PPDB
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858
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MolBase
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859
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MolBase
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C00019560
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KNApSAcK
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c0038
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UM-BBD
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C00469
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KEGG COMPOUND
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D00068
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KEGG DRUG
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D06542
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KEGG DRUG
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DB00898
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DrugBank
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EOH
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PDBeChem
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Ethanol
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Wikipedia
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ETOH
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MetaCyc
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HMDB0000108
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HMDB
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| View more database links |
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1718733
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Reaxys Registry Number
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Reaxys
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64-17-5
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CAS Registry Number
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KEGG COMPOUND
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64-17-5
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CAS Registry Number
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ChemIDplus
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64-17-5
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CAS Registry Number
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NIST Chemistry WebBook
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787
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Gmelin Registry Number
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Gmelin
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Prendergast MA, Mulholland PJ (2012)
Glucocorticoid and polyamine interactions in the plasticity of glutamatergic synapses that contribute to ethanol-associated dependence and neuronal injury.
Addiction biology 17, 209-223 [PubMed:21967628]
[show Abstract]
Stress contributes to the development of ethanol dependence and is also a consequence of dependence. However, the complexity of physiological interactions between activation of the hypothalamic-pituitary-adrenal (HPA) axis and ethanol itself is not well delineated. Emerging evidence derived from examination of corticotropin-releasing factor systems and glucocorticoid receptor systems in ethanol dependence suggests a role for pharmacological manipulation of the HPA axis in attenuating ethanol intake, though it is not clear how activation of the HPA axis may promote ethanol dependence or contribute to the neuroadaptative changes that accompany the development of dependence and the severity of ethanol withdrawal. This review examines the role that glucocorticoids, in particular, have in promoting ethanol-associated plasticity of glutamatergic synapses by influencing expression of endogenous linear polyamines and polyamine-sensitive polypeptide subunits of N-methyl-D-aspartate (NMDA)-type glutamate receptors. We provide evidence that interactions among glucocorticoid systems, polyamines and NMDA receptors are highly relevant to both the development of ethanol dependence and to behavioral and neuropathological sequelae associated with ethanol withdrawal. Examination of these issues is likely to be of critical importance not only in further elucidating the neurobiology of HPA axis dysregulation in ethanol dependence, but also with regard to identification of novel therapeutic targets that may be exploited in the treatment of ethanol dependence. | Wright TH, Ferslew KE (2012)
Biotransformation of ethanol to ethyl glucuronide in a rat model after a single high oral dosage.
Alcohol (Fayetteville, N.Y.) 46, 159-164 [PubMed:22019193]
[show Abstract]
Ethyl glucuronide (EtG) is a minor ethanol metabolite that confirms the absorption and metabolism of ethanol after oral or dermal exposure. Human data suggest that maximum blood EtG (BEtG) concentrations are reached between 3.5 and 5.5h after ethanol administration. This study was undertaken to determine if the Sprague-Dawley (SD) rat biotransforms ethanol to EtG after a single high oral dose of ethanol. SD rats (male, n=6) were gavaged with a single ethanol dose (4 g/kg), and urine was collected for 3 h in metabolic cages, followed by euthanization and collection of heart blood. Blood and urine were analyzed for ethanol and EtG by gas chromatography and enzyme immunoassay. Blood and urine ethanol concentrations were 195±23 and 218±19 mg/dL, whereas BEtG and urine EtG (UEtG) concentrations were 1,363±98 ng equivalents/mL and 210±0.29 mg equivalents/dL (X ± standard error of the mean [S.E.M.]). Sixty-six male SD rats were gavaged ethanol (4 g/kg) and placed in metabolic cages to determine the extent and duration of ethanol to EtG biotransformation and urinary excretion. Blood and urine were collected up to 24 h after administration for ethanol and EtG analysis. Maximum blood ethanol, urine ethanol, and UEtG were reached within 4 h, whereas maximum BEtG was reached 6 h after administration. Maximum concentrations were blood ethanol, 213±20 mg/dL; urine ethanol, 308±34 mg/dL; BEtG, 2,683±145 ng equivalents/mL; UEtG, 1.2±0.06 mg equivalents/mL (X±S.E.M.). Areas under the concentration-time curve were blood ethanol, 1,578 h*mg/dL; urine ethanol, 3,096 h*mg/dL; BEtG, 18,284 h*ng equivalents/mL; and UEtG, 850 h*mg equivalents/dL. Blood ethanol and BEtG levels were reduced to below limits of detection (LODs) within 12 and 18 h after ethanol administration. Urine ethanols were below LOD at 18 h, but UEtG was still detectable at 24h after administration. Our data prove that the SD rat biotransforms ethanol to EtG and excretes both in the urine and suggest that it is similar to that of the human. | Butler TR, Prendergast MA (2012)
Neuroadaptations in adenosine receptor signaling following long-term ethanol exposure and withdrawal.
Alcoholism, clinical and experimental research 36, 4-13 [PubMed:21762181]
[show Abstract]
Ethanol affects the function of neurotransmitter systems, resulting in neuroadaptations that alter neural excitability. Adenosine is one such receptor system that is changed by ethanol exposure. The current review is focused on the A(1) and the A(2A) receptor subtypes in the context of ethanol-related neuroadaptations and ethanol withdrawal because these subtypes (i) are activated by basal levels of adenosine, (ii) have been most well-studied for their role in neuroprotection and ethanol-related phenomena, and (iii) are the primary site of action for caffeine in the brain, a substance commonly ingested with ethanol. It is clear that alterations in adenosinergic signaling mediate many of the effects of acute ethanol administration, particularly with regard to motor function and sedation. Further, prolonged ethanol exposure has been shown to produce adaptations in the cell surface expression or function of both A(1) and the A(2A) receptor subtypes, effects that likely promote neuronal excitability during ethanol withdrawal. As a whole, these findings demonstrate a significant role for ethanol-induced adaptations in adenosine receptor signaling that likely influence neuronal function, viability, and relapse to ethanol intake following abstinence. | Griffin WC, Nguyen SA, Deleon CP, Middaugh LD (2012)
Effects of vigabatrin, an irreversible GABA transaminase inhibitor, on ethanol reinforcement and ethanol discriminative stimuli in mice.
Behavioural pharmacology 23, 178-190 [PubMed:22336593]
[show Abstract]
We tested the hypothesis that the irreversible γ-amino butyric acid transaminase inhibitor, γ-vinyl γ-amino butyric acid [vigabatrin (VGB)], would reduce ethanol reinforcement and enhance the discriminative-stimulus effect of ethanol, effectively reducing ethanol intake. The present studies used adult C57BL/6J (B6) mice in well-established operant, two-bottle choice consumption, locomotor activity, and ethanol discrimination procedures to comprehensively examine the effects of VGB on ethanol-supported behaviors. VGB dose-dependently reduced operant responding for ethanol and ethanol consumption for long periods of time. Importantly, a low dose (200 mg/kg) of VGB was selective for reducing ethanol responding without altering the intake of food or water reinforcement. Higher VGB doses (>200mg/kg) reduced ethanol intake, but also significantly increased water consumption and, more modestly, increased food consumption. Although not affecting locomotor activity on its own, VGB interacted with ethanol to reduce the stimulatory effects of ethanol on locomotion. Finally, VGB (200 mg/kg) significantly enhanced the discriminative-stimulus effects of ethanol as evidenced by significant leftward and upward shifts in ethanol generalization curves. Interestingly, VGB treatment was associated with slight increases in blood ethanol concentrations. The reduction in ethanol intake by VGB appears to be related to the ability of VGB to potentiate the pharmacological effects of ethanol. | Baliño P, Monferrer L, Pastor R, Aragon CM (2012)
Intracellular calcium chelation with BAPTA-AM modulates ethanol-induced behavioral effects in mice.
Experimental neurology 234, 446-453 [PubMed:22306018]
[show Abstract]
Calcium (Ca(2+)) has been characterized as one of the most ubiquitous, universal and versatile intracellular signaling molecules responsible for controlling numerous cellular processes. Ethanol-induced effects on Ca(2+) distribution and flux have been widely studied in vitro, showing that acute ethanol administration can modulate intracellular Ca(2+) concentrations in a dose dependent manner. In vivo, the relationship between Ca(2+) manipulation and the corresponding ethanol-induced behavioral effects have focused on Ca(2+) flux through voltage-gated Ca(2+) channels. The present study investigated the role of inward Ca(2+) currents in ethanol-induced psychomotor effects (stimulation and sedation) and ethanol intake. We studied the effects of the fast Ca(2+) chelator, BAPTA-AM, on ethanol-induced locomotor activity and the sedative effects of ethanol. Swiss (RjOrl) mice were pretreated with BAPTA-AM (0-10 mg/kg) 30 min before an ethanol (0-4 g/kg) challenge. Our results revealed that pretreatment with BAPTA-AM prevented locomotor stimulation produced by ethanol without altering basal locomotion. In contrast, BAPTA-AM reversed ethanol-induced hypnotic effects. In a second set of experiments, we investigated the effects of intracellular Ca(2+) chelation on ethanol intake. Following a drinking-in-the-dark methodology, male C57BL/6J mice were offered 20% v/v ethanol, tap water, or 0.1% sweetened water. The results of these experiments revealed that BAPTA-AM pretreatment (0-5 mg/kg) reduced ethanol consumption in a dose-dependent manner while leaving water and sweetened water intake unaffected. Our findings support the role of inward Ca(2+) currents in mediating different behavioral responses induced by ethanol. Our results are discussed together with data indicating that ethanol appears to be more sensitive to intracellular Ca(2+) manipulations than other psychoactive drugs. | Fernández-Mateos P, Jiménez-Ortega V, Cano Barquilla P, Cardinali DP, Esquifino AI (2012)
Discontinuous versus continuous drinking of ethanol in peripubertal rats: effect on 24-hour pattern of hypophyseal-gonadal axis activity and anterior pituitary oxidative stress.
Neuroendocrinology 96, 194-203 [PubMed:22286266]
[show Abstract]
AimsDiscontinuous (weekend) consumption of alcohol is common in adolescents and young adults. This study therefore assesses, in peripubertal male rats, the effect of discontinuous as compared to chronic feeding of ethanol or control liquid diet.MethodsAnimals received an ethanol liquid diet (6.2 % w/v) starting on day 35 of life. Every week for 5 weeks, the discontinuous ethanol group received the ethanol diet for 3 consecutive days and the control liquid diet for 4 days. At the 5th week, 24 h after the last ethanol administration to the discontinuously ethanol-treated animals, rats were killed at 4-hour intervals beginning at 09.00 h. Chronically administered rats received the ethanol diet until immediately before study.ResultsDisrupted 24-hour rhythmicity together with a significant nocturnal increase in plasma luteinizing hormone (LH), testosterone and prolactin (PRL) occurred in the discontinuous ethanol group. Plasma ethanol levels were undetectable at 24 h after the last ethanol treatment. In contrast, after chronic ethanol administration, plasma PRL was increased late in scotophase while LH and testosterone decreased; blood ethanol levels were 2-fold greater than those in discontinuously ethanol-administered rats killed immediately after ethanol withdrawal. Circulating testosterone positively correlated with LH levels in control rats only. Chronic administration of ethanol significantly augmented mean expression of pituitary nitric oxide synthase (NOS)-2, heme oxygenase (HO)-1, Per1 and Per2 genes and disrupted their diurnal rhythmicity. Decreased NOS-1 and NOS-2 expression during scotophase, together with suppression of the rhythm in Per1 and Per2 expression, were found in the discontinuous ethanol group.ConclusionsAbstinence after discontinuous drinking of alcohol in rats, as compared to chronic administration of ethanol, is accompanied by increases of plasma LH and testosterone, a greater PRL response and a less pronounced oxidative damage of the anterior pituitary. | Pautassi RM, Nizhnikov ME, Acevedo MB, Spear NE (2012)
Early role of the κ opioid receptor in ethanol-induced reinforcement.
Physiology & behavior 105, 1231-1241 [PubMed:22261437]
[show Abstract]
Effects of early ethanol exposure on later ethanol intake emphasize the importance of understanding the neurobiology of ethanol-induced reinforcement early in life. Infant rats exhibit ethanol-induced appetitive conditioning and ethanol-induced locomotor activation, which have been linked in theory and may have mechanisms in common. The appetitive effects of ethanol are significantly modulated by μ and δ opioid receptors, whereas μ but not δ receptors are involved in the motor stimulant effects of ethanol during early development. The involvement of the κ opioid receptor (KOR) system in the motivational effects of ethanol has been much less explored. The present study assessed, in preweanling (infant) rats, the modulatory role of the KOR system in several paradigms sensitive to ethanol-induced reinforcement. Kappa opioid activation and blockade were examined in second-order conditioned place preference with varied timing before conditioning and with varied ethanol doses. The role of KOR on ethanol-induced locomotion and ethanol-induced taste conditioning was also explored. The experiments were based on the assumption that ethanol concurrently induces appetitive and aversive effects and that the latter may be mediated by activation of kappa receptors. The main result was that blockade of kappa function facilitated the expression of appetitive ethanol reinforcement in terms of tactile and taste conditioning. The effects of kappa activation on ethanol conditioning seemed to be independent from ethanol's stimulant effects. Kappa opioid activation potentiated the motor depressing effects of ethanol but enhanced motor activity in control subjects. Overall, the results support the hypothesis that a reduced function of the KOR system in nondependent subjects should attenuate the aversive consequences of ethanol. | Quoilin C, Didone V, Tirelli E, Quertemont E (2012)
Developmental differences in ethanol-induced sensitization using postweanling, adolescent, and adult Swiss mice.
Psychopharmacology 219, 1165-1177 [PubMed:21881875]
[show Abstract]
RationaleThe maturing adolescent brain has been suggested to be more sensitive than the adult brain to ethanol-induced neuroadaptations. In animal studies, sensitization to the stimulant effects of ethanol is used to study the vulnerability to chronic ethanol-induced neurobehavioral alterations.ObjectivesThe aim of the present study was to systematically characterize age-dependent changes in the development and expression of the sensitization to the stimulant effects of a range of ethanol doses in female Swiss mice. Three ages were studied: 21-day-old mice (postweanlings), 35-day-old mice (adolescents), and 63-day-old mice (adults).MethodsPostweanling, adolescent, and adult mice were daily injected with saline or various ethanol doses (1.5 to 4 g/kg) for 7 days. They were then tested for acute and sensitized locomotor activity.ResultsPostweanling and adolescent mice were more sensitive than adult mice to the acute stimulant effects of ethanol. In adult mice, daily injections of ethanol at doses between 2.5 and 4 g/kg led to significant sensitization. Higher ethanol doses (3.5 and 4 g/kg) were required to induce sensitization in postweanling and adolescent mice. However, younger mice showed ethanol sensitization of higher magnitude.ConclusionsYoung mice develop very strong ethanol sensitization at doses that mimic binge drinking in humans. These results might explain why early ethanol drinking during adolescence is related to a higher prevalence of subsequent alcohol disorders. | Bahi A, Dreyer JL (2012)
Involvement of nucleus accumbens dopamine D1 receptors in ethanol drinking, ethanol-induced conditioned place preference, and ethanol-induced psychomotor sensitization in mice.
Psychopharmacology 222, 141-153 [PubMed:22222864]
[show Abstract]
RationaleDopamine D1 receptor (D1R) signaling has been associated to ethanol consumption and reward in laboratory animals.ObjectivesHere, we hypothesize that this receptor, which is located within the nucleus accumbens (NAc) neurons, modulates alcohol reward mechanisms.MethodsTo test this hypothesis, we measured alcohol consumption and ethanol-induced psychomotor sensitization and conditioned place preference (CPP) in mice that received bilateral microinjections of small interference RNA (siRNA)-expressing lentiviral vectors (LV-siD1R) producing D1R knock-down. The other group received control (LV-Mock) viral vectors into the NAc.ResultsThere were no differences in the total fluid consumed and also no differences in the amount of ethanol consumed between groups prior to surgery. However, after surgery, the LV-siD1R group consumed less ethanol than the control group. This difference was not associated to taste neophobia. In addition, results have shown that down-regulation of endogenous D1R using viral-mediated siRNA in the NAc significantly decreased ethanol-induced behavioral sensitization as well as acquisition, but not expression, of ethanol-induced place preference.ConclusionsWe conclude that decreased D1R expression into the NAc led to reduced ethanol rewarding properties, thereby leading to lower voluntary ethanol consumption. Together, these findings demonstrate that the D1 receptor pathway within the NAc controls ethanol reward and intake. | Xu M, Chen G, Fu W, Liao M, Frank JA, Bower KA, Fang S, Zhang Z, Shi X, Luo J (2012)
Ethanol disrupts vascular endothelial barrier: implication in cancer metastasis.
Toxicological sciences : an official journal of the Society of Toxicology 127, 42-53 [PubMed:22331491]
[show Abstract]
Both epidemiological and experimental studies indicate that ethanol exposure enhances tumor progression. Ethanol exposure promotes cancer cell invasion and is implicated in tumor metastasis. Metastasis consists of multiple processes involving intravasation and extravasation of cancer cells across the blood vessel walls. The integrity of the vascular endothelial barrier that lines the inner surface of blood vessels plays a critical role in cancer cell intravasation/extravasation. We examined the effects of ethanol on the endothelial integrity in vitro. Ethanol at physiologically relevant concentrations did not alter cell viability but disrupted the endothelial monolayer integrity, which was evident by a decrease in the electric resistance and the appearance of intercellular gaps in the endothelial monolayer. The effect of ethanol was reversible once ethanol was removed. The disruption of the endothelial monolayer integrity was associated with an increased invasion of cancer cells through the endothelial monolayer. Ethanol induced the formation of stress fibers; stabilization of actin filaments by jasplakinolide prevented ethanol-induced disruption of endothelial integrity and cancer cell invasion. VE-cadherin is a critical component of the adherens junctions, which regulates vascular endothelial integrity. Ethanol induced the endocytosis of VE-cadherin and the effect was blocked by jasplakinolide. Our results indicate that ethanol may facilitate cancer metastasis by disrupting the vascular endothelial barrier. | Geddes CC, Nieves IU, Ingram LO (2011)
Advances in ethanol production.
Current opinion in biotechnology 22, 312-319 [PubMed:21600756]
[show Abstract]
Barriers to the commercialization of lignocellulosic ethanol include the development of more robust biocatalysts, reduction of cellulase costs, and high capital cost associated with a complex process. Improvements have been made in all areas during the past two years. Oxidoreductases, transporters, and regulators have been identified that can increase the tolerance of biocatalysts to inhibitors formed during pretreatment. Biocatalysts are being developed that grow under conditions that are optimal for cellulase activity and others have been engineered to produce glycoside hydrolases. Ethanol yields resulting from most current process configurations are similar, approximately 0.21 g ethanol/g dry cellulosic feedstock. Potentially, this can be increased to at least 0.27 g ethanol/g biomass (83 gal/ton) using simpler processes. | Haycock PC (2009)
Fetal alcohol spectrum disorders: the epigenetic perspective.
Biology of reproduction 81, 607-617 [PubMed:19458312]
[show Abstract]
Ethanol is a classic teratogen capable of inducing a wide range of developmental abnormalities. Studies in animal models suggest that differences in timing and dosage underlie this variability, with three particularly important developmental periods: preconception, preimplantation, and gastrulation. These periods of teratogenesis correlate with peak periods of epigenetic reprogramming which, together with the evidence that ethanol interferes with one-carbon metabolism, DNA methylation, histone modifications, and noncoding RNA, suggests an important role for epigenetic mechanisms in the etiology of fetal alcohol spectrum disorders (FASDs). In addition to a number of testable hypotheses, an epigenetic model suggests that the concept of a "fetal alcohol spectrum" should be expanded to include "preconceptional effects." This proposal has important public health implications, highlighting the urgency of research into the epigenetic basis of FASDs. | Scarino A, Tardif R, Charbonneau M (2009)
Influence of ALDH2 polymorphism on ethanol kinetics and pulmonary effects in male and female rats exposed to ethanol vapors.
Inhalation toxicology 21, 193-199 [PubMed:18925476]
[show Abstract]
Ethanol is being added in various proportions to fuel in order to reduce greenhouse gas emissions. This is likely to result in involuntary exposure to ethanol vapors. Whether or not such exposure might cause health effects is still unknown. Acetaldehyde, an important metabolite of ethanol detoxified by aldehyde dehydrogenase (ALDH2) is more toxic that ethanol. This study assessed the impact of genetic ALDH2 polymorphism in male and female Sprague-Dawley rats on ethanol kinetics and pulmonary effects following sub-chronic exposure to ethanol vapors. Homozygote rats ALDH2(Q)/2(Q) (fast ALDH2 activity) and ALDH2(R)/2(R) (ALDH2 deficiency) were exposed to 1000 or 3000 ppm, 6 h/day, 5 days/week for 13 weeks. Blood ethanol concentrations (BEC) were measured at various post-exposure times. Cellularity in bronchoalveolar lavages (BAL) and lung histological evaluation were performed at week 13. Results showed that BEC in males were systematically lower than in females, e.g. BEC in ALDH2(Q)/2(Q) males (2 min, 1,000 ppm, day 1) was significantly (p < 0.05) lower (66.8 +/- 10.7 microM) compared to females (87.6 +/- 15.3 microM). BEC for ALDH2(Q)/2(Q) rats were different from ALDH2(R)/2(R) only for males exposed for more than 64 days. Repeated exposures resulted in a significant decrease of BEC, e.g. for ALDH2(Q)/2(Q) males (3,000 ppm) BEC on day 1 and day 85 were 324.6 +/- 102.6 microM and 187.5 +/- 32.1 microM, respectively. BAL and histological evaluation revealed no pulmonary toxicity for all groups. Overall, results showed that 3,000 ppm of ethanol vapors represents no observed adverse effect level (NOAEL) for pulmonary toxicity in the rat. | Louis ED, Benito-León J, Bermejo-Pareja F (2009)
Population-based study of baseline ethanol consumption and risk of incident essential tremor.
Journal of neurology, neurosurgery, and psychiatry 80, 494-497 [PubMed:19359288]
[show Abstract]
BackgroundRecent postmortem studies have demonstrated pathological changes, including Purkinje cell loss, in the cerebellum in essential tremor (ET). Toxic exposures that compromise cerebellar tissue could lower the threshold for developing ET. Ethanol is a well-established cerebellar toxin, resulting in Purkinje cell loss.ObjectiveTo test whether higher baseline ethanol consumption is a risk factor for the subsequent development of incident ET.MethodsLifetime ethanol consumption was assessed at baseline (1994-1995) in a prospective, population-based study in central Spain of 3285 elderly participants, 76 of whom developed incident ET by follow-up (1997-1998).ResultsIn a Cox proportional hazards model adjusting for cigarette pack-years, depressive symptoms and community, the baseline number of drink-years was marginally associated with a higher risk of incident ET (relative risk, RR = 1.003, p = 0.059). In an adjusted Cox model, the highest baseline drink-year quartile doubled the risk of incident ET (RR = 2.29, p = 0.018), while other quartiles were associated with more modest elevations in risk (RR(3rd quartile) = 1.82 (p = 0.10), RR(2nd quartile) = 1.75 (p = 0.10), RR(1st quartile) = 1.43 (p = 0.34) vs non-drinkers (RR = 1.00)). With each higher drink-year quartile, the risk of incident ET increased an average of 23% (p = 0.01, test for trend).ConclusionsHigher levels of chronic ethanol consumption increased the risk of developing ET. Ethanol is often used for symptomatic relief; studies should explore whether higher consumption levels are a continued source of underlying cerebellar neurotoxicity in patients who already manifest this disease. | Chen G, Bower KA, Xu M, Ding M, Shi X, Ke ZJ, Luo J (2009)
Cyanidin-3-glucoside reverses ethanol-induced inhibition of neurite outgrowth: role of glycogen synthase kinase 3 Beta.
Neurotoxicity research 15, 321-331 [PubMed:19384566]
[show Abstract]
Ethanol is a potent teratogen for the developing central nervous system (CNS), and fetal alcohol syndrome (FAS) is the most common nonhereditary cause of mental retardation. Ethanol disrupts neuronal differentiation and maturation. It is important to identify agents that provide neuroprotection against ethanol neurotoxicity. Using an in vitro neuronal model, mouse Neuro2a (N2a) neuroblastoma cells, we demonstrated that ethanol inhibited neurite outgrowth and the expression of neurofilament (NF) proteins. Glycogen synthase kinase 3beta (GSK3beta), a multifunctional serine/threonine kinase negatively regulated neurite outgrowth of N2a cells; inhibiting GSK3beta activity by retinoic acid (RA) and lithium induced neurite outgrowth, while over-expression of a constitutively active S9A GSK3beta mutant prevented neurite outgrowth. Ethanol inhibited neurite outgrowth by activating GSK3beta through the dephosphorylation of GSK3beta at serine 9. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family rich in many edible berries and other pigmented fruits, enhanced neurite outgrowth by promoting p-GSK3beta(Ser9). More importantly, C3G reversed ethanol-mediated activation of GSK3beta and inhibition of neurite outgrowth as well as the expression of NF proteins. C3G also blocked ethanol-induced intracellular accumulation of reactive oxygen species (ROS). However, the antioxidant effect of C3G appeared minimally involved in its protection. Our study provides a potential avenue for preventing or ameliorating ethanol-induced damage to the developing CNS. | Maravelias C, Stefanidou M, Dona A, Athanaselis S, Spiliopoulou C (2009)
Drug-facilitated sexual assault provoked by the victim's religious beliefs: a case report.
The American journal of forensic medicine and pathology 30, 384-385 [PubMed:19901811]
[show Abstract]
The number of drug-facilitated sexual assault incidents has lately been increased all over the world leading law enforcement agencies and hospital doctors to constant alert. The drugs involved may be benzodiazepines, hypnotics, other sedatives, anesthetics, drugs of abuse or ethanol. The detection of these agents in biologic fluids is difficult, since most of them are shortly acting, and provoke victim's amnesia which in turn leads the victim to report the allegation late. An unusual case-study of a 35-year-old, married woman who was admitted to the hospital with dizziness and loss of memory for a period of 10 days is here reported. The toxicological analysis of the victim's blood and urine for unknown sedative drugs, achieved by GC-MS, revealed the presence of zolpidem (Stilnox), a nonbenzodiazepine hypnotic. Concentration of zolpidem in blood, 11 hours after the last supposedly intake, was 47 microg/L. After family counseling at the hospital, the victim's husband confessed that he was replacing the contents of Losec capsules of his wife, with Stilnox tablets. This unjust act was committed by the husband in order for him to have sex with his wife, since she was not willing to participate in a sexual intercourse due to her religious restraints for a fasting period of 40 days. The aim of this article is 2-fold. First, to emphasize the fact that a sexual assault can take place not only between 2 strangers, but also within a happily married couple. Second, to remind doctors that any case of sexual assault must be examined toxicologically, for a better and thorough investigation. | Oyedele OO, Kramer B (2008)
Acute ethanol administration causes malformations but does not affect cranial morphometry in neonatal mice.
Alcohol (Fayetteville, N.Y.) 42, 21-27 [PubMed:18249266]
[show Abstract]
Ethanol is a known teratogen and has been implicated in the etiology of human fetal alcohol syndrome (FAS), which is characterized by distinct craniofacial abnormalities such as microcephaly, agnathia, and ocular aberrations. Attempts at quantifying the craniofacial anomalies arising from ethanol exposure have largely been limited to radiographic evaluation in postnatal rats. Such studies discount the role of the cranial soft tissue in the morphology of FAS. We present a study whose aim was to conduct measurements of the entire head including soft and hard tissue in full-term fetuses of mice by means of a digital analyzer, while at the same time comparing stained skeletal tissues in treated and untreated animals. Thirteen pregnant C57BL/6J mice were fed with 25% ethanol (vol/vol) on gestation days (E) 6, 7, and 8, whereas 10 pregnant mice received water only. Fetuses were retrieved from the animals just before delivery on E18, digitally photographed, measured, and assessed for abnormalities. Ethanol-exposed mice showed a number of abnormalities such as anophthalmia and agnathia, but these were not significantly increased over those from nontreated fetuses (P=.5). Birth weight (P=.5), crown-rump length (P=.8), and mandibular length (P=.9) were also not significantly reduced compared to control fetuses. However, defects in some cranial bones and degrees of ossification that trailed same-stage controls were observed in treated animals, at a nonstatistically significant level (P=.14). Acute maternal ingestion of alcohol in mice during pregnancy may not cause a significant increase in craniofacial or skeletal defects when evaluated at term. However, these effects may be latent, manifesting postnatally. The postnatal ability of mice for recovery from alcohol-induced birth defects deserves further investigation. | Ferreira MP, Willoughby D (2008)
Alcohol consumption: the good, the bad, and the indifferent.
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 33, 12-20 [PubMed:18347649]
[show Abstract]
Dietary ethanol (alcohol) is the most widely consumed drug worldwide. High levels of mortality, morbidity, and social malaise are associated with abuse of alcohol, and increasing numbers of women and youth are abusing alcohol. However, strong epidemiological data demonstrate a U- or J-shaped relationship between volume of alcohol consumed and all-cause mortality or disease burden. Moderate alcohol consumption is associated with a lower risk of all-cause mortality and disease burden than are abstinence and immoderate drinking. A brief review of the absorption, distribution, metabolism, and excretion of ethanol is provided with a discussion of the impact of gender differences. Potential mechanisms by which ethanol, ethanol metabolites, and (or) phytochemicals, as associated with different types of ethanol-containing beverages, are discussed in regards to the beneficial and detrimental impacts they may have on physiological system functioning and mortality or disease burden. Per capita consumption of ethanol-containing beverages varies across geo-political regions worldwide. A more recent research focus is the impact of consumption patterns on consumption volumes as they relate to disease and mortality. Certain drinking patterns moderate overall volume of ethanol consumption. Thus, an emerging approach to the study of alcohol consumption in populations is to consider both the volume and pattern of consumption as they relate to mortality and disease burden. Alcohol consumption patterns among athletes are discussed; physiological implications of alcohol abuse in this population are outlined. Current guidelines for the consumption of alcohol are reviewed. Alcohol consumption guidelines reflect the current scientific understanding of both the benefits of moderate alcohol consumption and the detriments of immoderate alcohol consumption. | Tafti BA, Hantash BM (2008)
Dual regulation of the cardiac L-type calcium channel in L6 cells by protein kinase C.
Cell calcium 44, 545-553 [PubMed:18456322]
[show Abstract]
The role of protein kinase C (PKC) in the regulation of cardiac L-type Ca(2+) channel activity (LCC) was investigated in L6 rat neonatal myoblasts. Depolarization of fura-2 loaded cells with 140mM KCl activated a Ba(2+) influx pathway that was blocked by nifedipine and stimulated by (-) Bay K 8644. At least two splice variants of the alpha(1C) subunit of the cardiac LCC were identified by PCR; the alpha(1S) subunit of the skeletal muscle LCC was not detected. Peptides that specifically inhibit translocation of the novel, Ca(2+)-independent delta and epsilon PKC isozymes reduced Ba(2+) influx by 27% and 19%, respectively, whereas a corresponding peptide directed against translocation of classical PKC alpha had no effect. Ingenol 3,20-dibenzoate, an agent reported to selectively activate novel PKCs, increased Ba(2+) uptake by 31% while ethanol, a PKC epsilon agonist, enhanced uptake by 38%. In contrast, selective activation of classical PKCs with thymeleatoxin or an agonist peptide reduced Ba(2+) influx by 23-33%. Ba(2+) influx was reduced by 30-40% when cells were treated with either a PKC inhibitor (Gö 6983, bisindolylmaleimide) or the PKC activator phorbol-12-myristate-13-acetate. We propose that novel, Ca(2+)-insensitive PKC(s) enhance cardiac Ca(2+) channel activity in L6 cells under basal conditions while activation of the classical, Ca(2+)-sensitive PKC(s) inhibits channel activity. These findings provide the first evidence that different PKC isozymes exert class-specific opposing effects on cardiac L-type Ca(2+) channel activity in L6 myoblasts. | Nicholas PC, Kim D, Crews FT, Macdonald JM (2008)
1H NMR-based metabolomic analysis of liver, serum, and brain following ethanol administration in rats.
Chemical research in toxicology 21, 408-420 [PubMed:18095657]
[show Abstract]
Ethanol is a widely used drug that is consumed in large amounts for pharmacologic effects. Elimination of ethanol alters metabolism in the liver and throughout an organism. Ethanol's effect on metabolites can influence the regulation of key pathways such as gluconeogenesis. We adopted a proton NMR-based metabolomic approach to study ethanol-induced metabolic changes in liver, blood, and brain tissue from rats exposed to either a single dose of ethanol or a chronic 4 day binge-ethanol protocol. Both acute and binge ethanol caused (i) decreased glucose, lactate, and alanine in liver and serum; (ii) increased acetate in liver and serum; and (iii) increased acetoacetate in serum. Binge-ethanol increased liver beta-hydroxybutyrate and decreased betaine. Pretreatment with the antioxidant butylated hydroxytoluene (BHT) increased betaine and reduced ethyl glucuronide (EtG) in livers of binge-ethanol animals, as compared to those not pretreated with BHT. We found no change in brain metabolites after a single dose of ethanol. Unsupervised principal component (PC) analysis of spectral data from liver and serum successfully discriminated treatment groups, based largely on the biochemical differences outlined above, confirming the results of manual analysis. To explain the observed lack of gluconeogenesis following ethanol treatment and to resolve apparently discordant results from previous studies, we propose a model in which decreased hepatic alanine removes inhibition on pyruvate kinase, thus permitting a futile cycle that diverts phosphoenolpyruvate away from gluconeogenesis. This is a new mechanism that biochemically elucidates the well-known, yet unexplained, "empty calorie" phenomenon of ethanol. Reduction of EtG by pretreatment with BHT suggests that BHT and perhaps other compounds may alter the pharmacokinetics of EtG so that EtG may not always be a sensitive marker for ethanol abuse. | Sánchez F, Korine C, Kotler BP, Pinshow B (2008)
Ethanol concentration in food and body condition affect foraging behavior in Egyptian fruit bats (Rousettus aegyptiacus).
Die Naturwissenschaften 95, 561-567 [PubMed:18320157]
[show Abstract]
Ethanol occurs in fleshy fruit as a result of sugar fermentation by both microorganisms and the plant itself; its concentration [EtOH] increases as fruit ripens. At low concentrations, ethanol is a nutrient, whereas at high concentrations, it is toxic. We hypothesized that the effects of ethanol on the foraging behavior of frugivorous vertebrates depend on its concentration in food and the body condition of the forager. We predicted that ethanol stimulates food consumption when its concentration is similar to that found in ripe fruit, whereas [EtOH] below or above that of ripe fruit has either no effect, or else deters foragers, respectively. Moreover, we expected that the amount of food ingested on a particular day of feeding influences the toxic effects of ethanol on a forager, and consequently shapes its feeding decisions on the following day. We therefore predicted that for a food-restricted forager, ethanol-rich food is of lower value than ethanol-free food. We used Egyptian fruit bats (Rousettus aegyptiacus) as a model to test our hypotheses, and found that ethanol did not increase the value of food for the bats. High [EtOH] reduced the value of food for well-fed bats. However, for food-restricted bats, there was no difference between the value of ethanol-rich and ethanol-free food. Thus, microorganisms, via their production of ethanol, may affect the patterns of feeding of seed-dispersing frugivores. However, these patterns could be modified by the body condition of the animals because they might trade-off the costs of intoxication against the value of nutrients acquired. | Jones AW, Kugelberg FC, Holmgren A, Ahlner J (2008)
Occurrence of ethanol and other drugs in blood and urine specimens from female victims of alleged sexual assault.
Forensic science international 181, 40-46 [PubMed:18922656]
[show Abstract]
Results of toxicological analysis of blood and urine specimens from 1806 female victims of alleged non-consensual sexual activity are reported. After making contact with the police authorities, the victims were examined by a physician for injuries and biological specimens were taken for forensic toxicology and other purposes (e.g. DNA). Urine if available or otherwise on an aliquot of blood after protein precipitation was screened for the presence of drugs by enzyme immunoassay methods (EMIT/CEDIA). All positive results from screening were verified by more specific methods, involving isotope dilution gas chromatography-mass spectrometry (GC-MS) for illicit drugs. A large number of prescription drugs were analyzed in blood by capillary column gas chromatography with a nitrogen-phosphorous (N-P) detector. Ethanol was determined in blood and urine by headspace gas chromatography and concentrations less than 0.1g/L were reported as negative. The number of reported cases of alleged sexual assault was highest during the warmer summer months and the mean age of victims was 24 years (median 20 years), with approximately 60% being between 15 and 25 years. In 559 cases (31%) ethanol and drugs were negative. In 772 cases (43% of total) ethanol was the only drug identified in blood or urine. In 215 cases (12%) ethanol occurred together with at least one other drug. The mean, median and highest concentrations of ethanol in blood (N=806) were 1.24 g/L, 1.19 g/L and 3.7 g/L, respectively. The age of victims and their blood-alcohol concentration (BAC) were positively correlated (r=0.365, p<0.001). Because BAC decreases at a rate of 0.10-0.25 g/(Lh), owing to metabolism the concentration in blood at time of sampling is often appreciably less than when the crime was committed several hours earlier. Licit or illicit drugs were identified in blood or urine in N=262 cases (15%). Amphetamine and tetrahydrocannabinol were the most common illicit drugs at mean (median) concentrations in blood of 0.22 mg/L (0.1mg/L) and 0.0012 mg/L (0.0006 mg/L), respectively. Among prescription drugs, sedative-hypnotics such as diazepam and zopiclone were common findings along with SSRI antidepressants and various opiate analgesics. Interpreting the analytical results in terms of voluntary vs. surreptitious administration of drugs and the degree of incapacitation in the victim as well as ability to give informed consent for sexual activity is fraught with difficulties. | Gulick D, Gould TJ (2008)
Varenicline ameliorates ethanol-induced deficits in learning in C57BL/6 mice.
Neurobiology of learning and memory 90, 230-236 [PubMed:18411066]
[show Abstract]
Ethanol is a frequently abused drug that impairs cognitive processes such as learning. Varenicline, an alpha4beta2 nicotinic receptor partial agonist and alpha7 nicotinic receptor full agonist prescribed for smoking cessation, has been shown to decrease ethanol consumption. The current study investigated whether varenicline could ameliorate ethanol-induced deficits in learning and whether varenicline alters blood alcohol concentration in C57BL/6 mice. Conditioning consisted of two auditory conditioned stimulus (CS; 30s, 85dB white noise)-foot shock unconditioned stimulus (US; 2s, 0.57mA) pairings. For all studies, saline or ethanol (1.0, 1.5, 2.0g/kg i.p.) was administered 15min before training, and saline or varenicline (0.05, 0.1, 0.2mg/kg i.p.) was administered 60min before either training or testing. For blood alcohol analysis, saline or varenicline (0.1mg/kg) was administered 60min before collection, and saline or ethanol (1.0, 1.5, 2.0g/kg) was administered 15min before collection. Varenicline dose-dependently ameliorated ethanol-induced conditioning deficits for all three doses of ethanol when administered before training but not when administered 24h later, before testing. In addition, varenicline did not alter blood alcohol concentration. The smoking cessation aid varenicline may have therapeutic uses for treating ethanol-associated disruptions in cognitive processes. | Kashem MA, Harper C, Matsumoto I (2008)
Differential protein expression in the corpus callosum (genu) of human alcoholics.
Neurochemistry international 53, 1-11 [PubMed:18513832]
[show Abstract]
Ethanol is an addictive drug that deteriorates different neuronal pathways in the CNS, leading to the induction of cognitive dysfunction. Neuroimaging analyses revealed that alcohol-induced brain damage appears to be region-specific and major dysmorphology has been observed in the prefrontal cortex and the white matter (WM) particularly in the corpus callosum (CC). Recent diffusion tensor imaging (DTI) analysis indicated that microstructural degradation was prominent in the genu followed by the body and the splenium of the CC. Molecular mechanisms underlying these structural changes are largely unknown. In this study, using 2D electrophoresis based proteomics approach, protein expression profiles in 25 genus samples (12 controls, 7 uncomplicated alcoholics and 6 complicated alcoholics with hepatic cirrhosis) were analysed and compared. Image analysis showed that 35 protein spots in the uncomplicated alcoholic and 56 in the complicated group were differentially altered compared to the control (P<0.05; ANOVA). In total of 91 spots, 25 spots were overlapped between two alcoholic groups. When protein expression profile of the genu was compared with those in other WMs [BA9 white matter (WM) and splenium] the highest number of region-specific proteins was identified in the genus indicating that genu might be the most sensitive and/or vulnerable region to chronic alcohol ingestion at least from the aspect of protein expression. Out of total 66 spots (identified as 50 different proteins), 31 spots (identified as 28 different proteins) were expressed only in the complicated group. This result indicates that alcohol-related liver dysfunction has synergetic effects on brain protein expression. It is also interesting to note that abnormality in thiamine-related cascade which was previously found in the BA9 WM was observed in the genu, but not in the splenium. It is therefore suggested that both hepatic and nutritious factors might be underlying the mechanisms of microstructural damage detected by DTI. | Verna G, Kefalas N, Boriani F, Carlucci S, Choc I, Bocchiotti MA (2008)
Launois-Bensaude Syndrome: an unusual localization of obesity disease.
Obesity surgery 18, 1313-1317 [PubMed:18408978]
[show Abstract]
BackgroundLaunois-Bensaude syndrome is a rare pathology consisting of adipose masses symmetrically distributed mainly in the superior part of the body. Men are especially affected between age of 30 and 60 as well as chronic alcohol abusers. Etiopathogenesis is attributable to mutations or deletions of mitochondrial DNA, and alcohol is a possible cofactor.MethodsThe current treatment of the disease is described based on the authors' experience. Four cases treated in our department are retrospectively reviewed regarding comorbidities and type of surgery performed.ResultsA relevant and long-lasting reduction of fat bulges has been obtained in all cases with no major complications except for a mild anemia.ConclusionLaunois-Bensaude syndrome causes a functional rather than esthetic concern due to the peculiar localization of fat bulges. Currently, the only effective therapy is surgery, through lipectomy or liposuction of adipose bulges. | Chiang CY, Yeh KY, Lin SF, Hsuchou H, Tai MY, Ho YJ, Tsai YF (2008)
Effects of alcohol on the mouse-killing behavior of olfactory bulbectomized rats.
The Chinese journal of physiology 51, 408-413 [PubMed:19280886]
[show Abstract]
The purpose of the current study was to evaluate the effects of chronic administration of alcohol on the olfactory bulbectomy (OBX)-induced mouse-killing behavior (MKB), an animal model for screening antidepressants. The rats were divided into three groups, which were given alcohol (0, 0.5, or 1 g/kg/day) orally for 28 days. MKB was analyzed before and at the end of each week of the alcohol treatment. The results showed that chronic alcohol treatment produced a significant increase in the latency of MKB, implying that alcohol may have an antidepressant-like activity. This suggests that alcohol dependence or abuse in depressed patients may result from "self-medication". Since it has been reported that OBX causes a decrease in the density of N-methyl-D-aspartate (NMDA) receptors in the brain and that alcohol is a potent and selective inhibitor of NMDA receptors, the possible role of NMDA receptors in this effect is discussed. | Sellman D (2008)
If alcohol was a new drug.
The New Zealand medical journal 122, 6-8 [PubMed:19851413] | Sanchis C, Aragón CM (2007)
[What we drink when we drink? The role of the acetaldehyde in the alcohol consumption].
Adicciones 19, 5-11 [PubMed:17687877]
[show Abstract]
Although ethyl alcohol (ethanol) is the most widely consumed drug in the Western society, ethanol mechanisms of action in the Central Nervous System (CNS) remain unknown. In consequence, the development of pharmacological strategies to treat excessive alcohol consumption and alcoholism has proven to be difficult. A major difficulty in those attempts arises from the molecular properties of ethanol, which do not allow a sterocomplementary binding to any known receptor. Therefore, over the last years, it has been proposed that a large number of effects observed alter ethanol administration/consumption might be actually mediated by its first metabolite, namely acetaldehyde, produced inside the CNS via catalase activity. Nowadays, a large number of evidences support this proposal, leading the possibility of new pharmacological strategies (i.e. pharmacological inactivation of acetaldehyde) in the management of alcohol excessive consumption. | Alcoceba Borràs E, Botey Faraudo E, Gaig Jané P, Bartolomé Zavala B (2007)
Alcohol-induced anaphylaxis to grapes.
Allergologia et immunopathologia 35, 159-161 [PubMed:17663926]
[show Abstract]
BackgroundAllergy to grape is uncommon, however allergic reactions to all different types of grape and wine have been described and exercise-induced allergy to grape has also been reported.Case reportAn 18-year-old woman who had presented several anaphylactic reactions on New Year's Eve. She remains asymptomatic if she eats the fruit alone but not if she associates the fruit with alcoholic drinks. Skin prick test with fresh grape and oral challenge with grapes and champagne together were positive. We performed an immunologic study using the patient's sera and the sera of two other patients with grape allergy not alcohol-induced in order to determine if the allergens implicated are different when alcohol is a cofactor: any differences were found. We use SDS-PAGE technique and Ig E immunobloting to identify the allergens.ConclusionWe report a case of alcohol- induced anaphylaxis to grape where no different allergens to grape were identified when alcohol is a cofactor. | Schäfer C, Ludwig Y, Shahin V, Kramer A, Carl P, Schillers H, Oberleithner H (2007)
Ethanol alters access to the cell nucleus.
Pflugers Archiv : European journal of physiology 453, 809-818 [PubMed:17043811]
[show Abstract]
Ethanol is the most frequently used drug among humans. We tested the hypothesis whether ethanol, at clinically relevant concentrations modifies, signaling across the nuclear envelope (NE). In cell nuclei isolated from Xenopus oocytes, we measured NE electrical resistance and NE macromolecule permeability 1 to 20 h after addition of ethanol (0.05 to 0.2%). Furthermore, with atomic force microscopy, nuclear pores of the NE were imaged after exposure to ethanol. We found that NE permeability decreased within hours of ethanol exposure. In parallel, nuclei swell and nuclear pores form clusters in the NE. Force measurements on individual nuclear pores indicate that pores found in clusters are stiffer than those found randomly distributed in the NE. Application of a transcription blocker (actinomycin D) or RNase treatment of isolated nuclei in vitro after ethanol exposure prevents the permeability changes. In conclusion, ethanol, at commonly used concentrations, changes NE structure by transcriptional processes in the cell nucleus. Within hours, the NE becomes less permeable for diffusible ions and macromolecules. This could explain altered signaling to and communication with the cell nucleus in the pathophysiology of alcohol abuse. | Conroy SK, Rodd Z, Chambers RA (2007)
Ethanol sensitization in a neurodevelopmental lesion model of schizophrenia in rats.
Pharmacology, biochemistry, and behavior 86, 386-394 [PubMed:16934862]
[show Abstract]
Substance use disorder comorbidity in schizophrenia may reflect dysfunctional cortical-striatal-limbic circuitry commonly involved in the addiction process and the pathogenesis of schizophrenia. Rats with neonatal ventral hippocampal lesions (NVHL) demonstrate post-adolescent onset of schizophrenia-like symptoms and increased addiction vulnerability in paradigms using cocaine in adulthood. Here, we investigated response profiles of young adult NVHL vs. SHAM rats to ethanol, an addictive drug with many psychopharmacological effects divergent from those of cocaine, in a locomotor sensitization paradigm. Over 15 days of daily injections of saline, low (0.15 g/kg) or high (1.0 g/kg) doses of ethanol, NVHL rats showed stimulatory effects at the low dose compared to saline and high-dose conditions, while SHAM rats showed expected patterns of dose-dependent suppression of locomotor activity. In a challenge session 2 weeks later in which a moderate dose (0.25 g/kg) of ethanol was given to all subjects, NVHL rats with history of prior ethanol exposure showed greater locomotor activity consistent with installment of alcohol-induced sensitization not present in SHAMs. These findings provide further evidence of enhanced short- and long-term responsivity to abused drugs in a neurodevelopmental model of schizophrenia, and may reflect potentiation of common mechanisms of addiction shared between pharmacologically diverse addictive drugs. | Salek RM, Maguire ML, Bentley E, Rubtsov DV, Hough T, Cheeseman M, Nunez D, Sweatman BC, Haselden JN, Cox RD, Connor SC, Griffin JL (2007)
A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human.
Physiological genomics 29, 99-108 [PubMed:17190852]
[show Abstract]
Type 2 diabetes mellitus is the result of a combination of impaired insulin secretion with reduced insulin sensitivity of target tissues. There are an estimated 150 million affected individuals worldwide, of whom a large proportion remains undiagnosed because of a lack of specific symptoms early in this disorder and inadequate diagnostics. In this study, NMR-based metabolomic analysis in conjunction with multivariate statistics was applied to examine the urinary metabolic changes in two rodent models of type 2 diabetes mellitus as well as unmedicated human sufferers. The db/db mouse and obese Zucker (fa/fa) rat have autosomal recessive defects in the leptin receptor gene, causing type 2 diabetes. 1H-NMR spectra of urine were used in conjunction with uni- and multivariate statistics to identify disease-related metabolic changes in these two animal models and human sufferers. This study demonstrates metabolic similarities between the three species examined, including metabolic responses associated with general systemic stress, changes in the TCA cycle, and perturbations in nucleotide metabolism and in methylamine metabolism. All three species demonstrated profound changes in nucleotide metabolism, including that of N-methylnicotinamide and N-methyl-2-pyridone-5-carboxamide, which may provide unique biomarkers for following type 2 diabetes mellitus progression. | Arjona A, Boyadjieva N, Kuhn P, Sarkar DK (2006)
Fetal ethanol exposure disrupts the daily rhythms of splenic granzyme B, IFN-gamma, and NK cell cytotoxicity in adulthood.
Alcoholism, clinical and experimental research 30, 1039-1044 [PubMed:16737463]
[show Abstract]
BackgroundCircadian (and daily) rhythms are physiological events that oscillate with a 24-hour period. Circadian disruptions may hamper the immune response against infection and cancer. Several immune mechanisms, such as natural killer (NK) cell function, follow a daily rhythm. Although ethanol is known to be a potent toxin for many systems in the developing fetus, including the immune system, the long-term effects of fetal ethanol exposure on circadian immune function have not been explored.MethodsDaily rhythms of cytotoxic factors (granzyme B and perforin), interferon-gamma (IFN-gamma), and NK cell cytotoxic activity were determined in the spleens of adult male rats obtained from mothers who were fed during pregnancy with chow food or an ethanol-containing liquid diet or pair-fed an isocaloric liquid diet.ResultsWe found that adult rats exposed to ethanol during their fetal life showed a significant alteration in the physiological rhythms of granzyme B and IFN-gamma that was associated with decreased NK cell cytotoxic activity.ConclusionThese data suggest that fetal ethanol exposure causes a permanent alteration of specific immune rhythms that may in part underlie the immune impairment observed in children prenatally exposed to alcohol. | Bezerra RM, Dias AA, Fraga I, Pereira AN (2006)
Simultaneous ethanol and cellobiose inhibition of cellulose hydrolysis studied with integrated equations assuming constant or variable substrate concentration.
Applied biochemistry and biotechnology 134, 27-38 [PubMed:16891664]
[show Abstract]
The integrated forms of the Michaelis-Menten equation assuming variable substrate (depletion) or constant substrate concentration were used to study the effect of the simultaneous presence of two exoglucanase Cel7A inhibitors (cellobiose and ethanol) on the kinetics of cellulose hydrolysis. The kinetic parameters obtained, assuming constant substrate (K(m) = 21 mM, Kic = 0.035 mM; K(icl) = 1.5 x 1,015 mM; k(cat) = 12 h-1) or assuming variable substrate (K(m) = 16 mM, Kic = 0.037 mM; K(icl) = 5.8 x 1,014 mM; k(cat) = 9 h-1), showed a good similarity between these two alternative methodologies and pointed out that both ethanol and cellobiose are competitive inhibitors. Nevertheless, ethanol is a very weak inhibitor, as shown by the large value estimated for the kinetic constant K(icl). In addition, assuming different concentrations of initial accessible substrate present in the reaction, both inhibition and velocity constants are at the same order of magnitude, which is consistent with the obtained values. The possibility of using this kind of methodology to determine kinetic constants in general kinetic studies is discussed, and several integrated equations of different Michaelis-Menten kinetic models are presented. Also examined is the possibility of determining inhibition constants without knowledge of the true accessible substrate concentration. | Yildiz HB, Toppare L (2006)
Biosensing approach for alcohol determination using immobilized alcohol oxidase.
Biosensors & bioelectronics 21, 2306-2310 [PubMed:16352430]
[show Abstract]
Alcohol oxidase (AOD) was immobilized in polypyrrole (PPy) and a random copolymer containing 3-methylthienyl methacrylate and p-vinylbenzyloxy poly(ethyleneoxide) matrices. Immobilization of enzyme was performed via entrapment in conducting polymers during electrochemical polymerization of pyrrole through the thiophene moiety of the copolymer. Three different alcohols, namely methanol, ethanol and n-propanol, were used as substrates. Maximum reaction rates, Michaelis-Menten constants, optimum temperature and pH values, operational stabilities and shelf life of the enzyme electrodes were investigated. | Miñambres R, Guasch RM, Perez-Aragó A, Guerri C (2006)
The RhoA/ROCK-I/MLC pathway is involved in the ethanol-induced apoptosis by anoikis in astrocytes.
Journal of cell science 119, 271-282 [PubMed:16390872]
[show Abstract]
Anoikis is a programmed cell death induced by loss of anchorage that is involved in tissue homeostasis and disease. Ethanol is an important teratogen that induces marked central nervous system (CNS) dysfunctions. Here we show that astrocytes exposed to ethanol undergo morphological changes associated with anoikis, including the peripheral reorganization of both focal adhesions and actin-myosin system, cell contraction, membrane blebbing and chromatin condensation. We found that either the small GTPase RhoA or its effector ROCK-I (Rho kinase), promotes membrane blebbing in astrocytes. Ethanol induces a ROCK-I activation that is mediated by RhoA, rather than by caspase-3 cleavage. Accordingly, the RhoA inhibitor C3, completely abolishes the ethanol-induced ROCK-I activation. Furthermore, inhibition of both RhoA and ROCK prevents the membrane blebbing induced by ethanol. Ethanol also promotes myosin light chain (MLC) phosphorylation, which might be involved in the actin-myosin contraction. All of these findings strongly support that ethanol-exposed astrocytes undergo apoptosis by anoikis and also that the RhoA/ROCK-I/MLC pathway participates in this process. | Porcu P, Grant KA, Green HL, Rogers LS, Morrow AL (2006)
Hypothalamic-pituitary-adrenal axis and ethanol modulation of deoxycorticosterone levels in cynomolgus monkeys.
Psychopharmacology 186, 293-301 [PubMed:16133132]
[show Abstract]
RationaleThe metabolites of deoxycorticosterone (DOC) and progesterone, allotetrahydrodeoxycorticosterone and allopregnanolone, are potent endogenous neuroactive steroids that are increased in rodent brain and plasma after hypothalamic-pituitary-adrenal (HPA) axis activation by acute stress or ethanol administration. However, little data are available for male nonhuman primates.ObjectiveTo determine DOC concentrations in plasma samples from 11 monkeys following challenge of the HPA axis with naloxone, corticotropin-releasing factor (CRF), dexamethasone, adrenocorticotropic hormone (ACTH) following dexamethasone pretreatment and ethanol.MethodsDOC levels were measured in monkey plasma by radioimmunoassay.ResultsDOC levels were increased after naloxone (125 microg/kg and 375 microg/kg, respectively) and CRF administration (1 microg/kg), and decreased following dexamethasone (130 microg/kg) administration. ACTH (10 ng/kg) challenge, 4-6 h after 0.5 mg/kg dexamethasone, and administration of ethanol (1.0 g/kg and 1.5 g/kg) had no effect on DOC concentrations. DOC levels were positively correlated with cortisol and ACTH levels after the naloxone (375 microg/kg), CRF, and ACTH challenges. Finally, the suppression of DOC levels measured after dexamethasone was negatively correlated with subsequent alcohol self-administration.ConclusionsThese results suggest that DOC levels in monkeys are regulated by the HPA axis and may contribute to physiological responses following activation. | Welch-Carre E (2005)
The neurodevelopmental consequences of prenatal alcohol exposure.
Advances in neonatal care : official journal of the National Association of Neonatal Nurses 5, 217-229 [PubMed:16084479]
[show Abstract]
During pregnancy, ingestion of alcohol, a known teratogen, can cause harm to the fetus. Prenatal alcohol exposure is one of the leading causes of birth defects, developmental disorders, and mental retardation in children. The fetal central nervous system is particularly vulnerable to alcohol; this vulnerability contributes to many of the long-term disabilities and disorders seen in individuals with prenatal alcohol exposure. Diagnoses associated with prenatal alcohol exposure include fetal alcohol syndrome (FAS), partial fetal alcohol syndrome, fetal alcohol effects, alcohol-related neurodevelopmental disorder, and alcohol-related birth defects. Once diagnosed, early intervention improves the long-term outcome of affected children. Without documentation of maternal alcohol use, a diagnosis, and consequently treatment, is often difficult to attain. It is imperative that nurses, physicians, and other healthcare providers become comfortable with obtaining a history of, and providing anticipatory guidance and counseling about, alcohol use. | Quintanilla ME, Tampier L, Sapag A, Israel Y (2005)
Polymorphisms in the mitochondrial aldehyde dehydrogenase gene (Aldh2) determine peak blood acetaldehyde levels and voluntary ethanol consumption in rats.
Pharmacogenetics and genomics 15, 427-431 [PubMed:15900217]
[show Abstract]
Dependence on alcohol, a most widely used drug, has a heritability of 50-60%. Wistar-derived rats selectively bred as low-alcohol consumers for many generations present an allele (Aldh2(2)) of mitochondrial aldehyde dehydrogenase that does not exist in high-alcohol consumers, which mostly carry the Aldh2(1) allele. The enzyme coded by Aldh2(2) has a four- to five-fold lower affinity for NAD than that coded by Aldh2(1). The present study was designed to determine whether these polymorphisms account for differences in voluntary ethanol intake and to investigate the biological mechanisms involved. Low-drinker F0 Aldh2(2)/Aldh2(2) rats were crossed with high-drinker F0 Aldh2(1)/Aldh2(1) rats to obtain an F1 generation, which was intercrossed to obtain an F2 generation that segregates the Aldh2 alleles from other genes that may have been coselected in the breeding for each phenotype. Data show that, with a mixed genetic background, F2 Aldh2(1)/Aldh2(1) rats voluntarily consume 65% more alcohol (P<0.01) than F2 Aldh2(2)/Aldh2(2) rats. A major phenotypic difference was a five-fold higher (P<0.0025) peak blood acetaldehyde level following ethanol administration in the lower drinker F2 Aldh2(2)/Aldh2(2) compared to the higher drinker F2 Aldh2(1)/Aldh2(1) animals, despite the existence of identical steady-state levels of blood acetaldehyde in animals of both genotypes. Polymorphisms in Aldh2 play an important role in: (i) determining peak blood acetaldehyde levels and (ii) modulating voluntary ethanol consumption. We postulate that the markedly higher peak of blood acetaldehyde generated in Aldh2(2)/Aldh2(2)(2) animals is aversive, leading to a reduced alcohol intake in Aldh2(2)/Aldh2(2) versus that in Aldh2(1)/Aldh2(1) animals. | Chen W, Tang Z, Fortina P, Patel P, Addya S, Surrey S, Acheampong EA, Mukhtar M, Pomerantz RJ (2005)
Ethanol potentiates HIV-1 gp120-induced apoptosis in human neurons via both the death receptor and NMDA receptor pathways.
Virology 334, 59-73 [PubMed:15749123]
[show Abstract]
Neuronal loss is a hallmark of AIDS dementia syndromes. Human immunodeficiency virus type I (HIV-1)-specific proteins may induce neuronal apoptosis, but the signal transduction of HIV-1 gp120-induced, direct neuronal apoptosis remains unclear. Ethanol (EtOH) is considered to be an environmental co-factor in AIDS development. However, whether EtOH abuse in patients with AIDS increases neuronal dysfunction is still uncertain. Using pure, differentiated, and post-mitotic NT2.N-derived human neurons, we investigated the mechanisms of HIV-1 and/or EtOH-related direct neuronal injury and the molecular interactions between HIV-1-specific proteins and EtOH. It was demonstrated that NT2.N neurons were susceptible to HIV-1 Bal (R5-tropic strain) gp120-induced direct cell death. Of importance, EtOH induced cell death in human neurons in a clinically-relevant dose range and EtOH strongly potentiated HIV-1 gp120-induced neuronal injury at low and moderate concentrations. Furthermore, this potentiation of neurotoxicity could be blocked by N-methyl-D-aspartate (NMDA) receptor subunit 2B (NR2B) antagonists. We analyzed human genomic profiles in these human neurons, using Affymetrix genomics technology, to elucidate the apoptotic pathways involved in HIV-1- and EtOH-related neurodegeneration. Our findings indicated significant over-expression of selected apoptosis functional genes. Significant up-regulation of TRAF5 gene expression may play an essential role in triggering potentiation by EtOH of HIV-1 gp120-induced neuronal apoptosis at early stages of interaction. These studies suggested that two primary apoptotic pathways, death receptor (extrinsic) and NMDA receptor (intrinsic)-related programmed cell-death pathways, are both involved in the potentiation by EtOH of HIV-1 gp120-induced direct human neuronal death. Thus, these data suggest rationally-designed, molecular targets for potential anti-HIV-1 neuroprotection. | Larsson A, Jerlhag E, Svensson L, Söderpalm B, Engel JA (2004)
Is an alpha-conotoxin MII-sensitive mechanism involved in the neurochemical, stimulatory, and rewarding effects of ethanol?
Alcohol (Fayetteville, N.Y.) 34, 239-250 [PubMed:15902919]
[show Abstract]
Ethanol and nicotine are the most commonly abused drugs among human beings, and a large body of evidence, from both epidemiologic and preclinical studies, indicates that there is a positive correlation between intake of both drugs. Findings of studies from our research group have demonstrated that nicotinic acetylcholine receptors, especially those located in the ventral tegmental area, are important for the stimulatory, rewarding, and dopamine-enhancing effects of ethanol. Furthermore, results of recent work indicate that the alpha4beta2* and the alpha7* receptor subunits of the nicotinic acetylcholine receptors do not seem to be involved in the neurochemical and behavioral effects of ethanol in rodents. The aim of the current study was to investigate further the role of different nicotinic acetylcholine receptor subunits in the stimulatory, dopamine-enhancing, and rewarding effects of ethanol in rodents by using the peptide alpha-conotoxin MII (5 nmol; an antagonist of the alpha3beta2*, beta3*, and alpha6* subunits of the nicotinic acetylcholine receptor) administered locally into the ventral tegmental area. A significant reduction of ethanol-induced accumbal dopamine overflow, measured by means of in vivo microdialysis, and of locomotor stimulation was observed in mice. Furthermore, alpha-conotoxin MII was demonstrated to reduce voluntary ethanol intake significantly in both rats and mice. These results indicate that alpha-conotoxin MU-sensitive receptors may be important in mediating the stimulatory, dopamine-enhancing, and rewarding effects of ethanol, and that alpha-conotoxin MII-sensitive receptors may constitute targets for development of new adjuvant for treatment of ethanol dependence. | Salaspuro V, Salaspuro M (2004)
Synergistic effect of alcohol drinking and smoking on in vivo acetaldehyde concentration in saliva.
International journal of cancer 111, 480-483 [PubMed:15239123]
[show Abstract]
Alcohol drinking and smoking are independent risk factors for upper digestive tract cancers. Furthermore, their combined use interacts in a multiplicative way on cancer risk. There is convincing evidence that acetaldehyde, the first metabolite of ethanol and a constituent of tobacco smoke, is a local carcinogen in humans. Therefore, we examined the combined effect of alcohol drinking and tobacco smoking on in vivo acetaldehyde concentration in saliva. Seven smokers and 6 nonsmokers participated in the study. First, to measure the effect of alcohol on salivary acetaldehyde, all volunteers ingested 0.8 g/kg body weight of ethanol and saliva samples were collected every 20 min for 160 min thereafter. After a 3-day washout period, smokers ingested again the same amount of ethanol and smoked one cigarette every 20 min and saliva samples were collected at 10 min intervals for 160 min. Acetaldehyde and ethanol concentrations were analyzed by headspace gas chromatograph. Firstly, smokers without concomitant smoking during ethanol challenge had 2 times higher in vivo salivary acetaldehyde concentrations than nonsmokers after ethanol ingestion (AUC 114.8 +/- 11.5 vs. 54.2 +/- 8.7 microM x hr, respectively; p = 0.002). Secondly, smokers with active smoking during ethanol challenge had 7 times higher in vivo salivary acetaldehyde levels than nonsmokers (AUC 369.5 +/- 12.2 vs. 54.2 +/- 8.7 microM x hr, respectively; p < 0.001). We conclude that this markedly increased exposure of upper digestive tract mucosa to carcinogenic salivary acetaldehyde of smoking and drinking subjects may explain the synergistic and multiplicative risk effect of alcohol drinking and tobacco smoking on upper gastrointestinal tract carcinogenesis. | Matthews DB, Silvers JR (2004)
The use of acute ethanol administration as a tool to investigate multiple memory systems.
Neurobiology of learning and memory 82, 299-308 [PubMed:15464411]
[show Abstract]
The discovery of multiple memory systems supported by discrete brain regions has been one of the most important advances in behavioral neuroscience. A wealth of studies have investigated the role of the hippocampus and related structures in supporting various types of memory classifications. While the exact classification that best describes hippocampal function is often debated, a specific subset of cognitive function that is focused on the use of spatial information to form hippocampal cognitive maps has received extensive investigation. These studies frequently employ a variety of experimental manipulations including brain lesions, temporary neural blockade due to cooling or discrete injections of specific drugs. While these studies have provided important insights into the function of the hippocampus, they are limited due to the invasive nature of the manipulation. Ethanol is a drug that is easily administered in a non-invasive fashion, is rapidly absorbed and produces effects only in specific brain regions. The hippocampus is one brain region affected by acute ethanol administration. The following review summarizes research from the last 20 years investigating the effects of acute ethanol administration on one specific type of hippocampal cognitive function, namely spatial memory. It is proposed that among its many effects, one specific action of acute ethanol administration is to produce similar cognitive and neurophysiological effects as lesions of the hippocampus. Based on these similarities and the ease of its use, it is concluded that acute ethanol administration is a valuable tool in studying hippocampal function and multiple memory systems. | Larsson A, Engel JA (2004)
Neurochemical and behavioral studies on ethanol and nicotine interactions.
Neuroscience and biobehavioral reviews 27, 713-720 [PubMed:15019421]
[show Abstract]
The most commonly abused drugs, alcohol and nicotine, are likely also the most costly drugs in terms of health and societal costs. A large body of evidence from epidemiological studies indicate that smoking and alcohol-intake are positively correlated. The mesocorticolimbic dopamine system has been implicated in mediating some of the reinforcing effects of ethanol, however, the mechanism(s) of action remains to be elucidated; consideration as to ethanol's ability to interact with ligand-gated ion channels should be considered. Accumulating evidence from electrophysiological, pharmacological and neurochemical studies suggest that ethanol may interact with the nicotinic acetylcholine receptor (nAChR). Thus, it has been shown that the ethanol-induced stimulation of the mesolimbic dopamine system and of locomotor activity as well as ethanol intake and preference in rodents may involve central nicotinic acetylcholine receptors. Additionally, data has been presented that nAChRs located in the ventral tegmental area may be of particular importance for these effects of ethanol. Studies aimed at defining the nAChR subpopulation(s) involved in mediating ethanol-induced locomotor stimulation and accumbal dopamine overflow as well as ethanol-intake have revealed that alpha(3)beta(2) or alpha(6) (using alpha-Conotoxin MII) but not alpha(4)beta(2) (using dihydro-beta-erythroidine) or alpha(7) (using methyllycaconitine), could represent targets for developing new drugs in the treatment of alcoholism. These results do not allow any conclusion as to whether the involvement nAChRs in mediating the effects of ethanol is direct and/or indirect. With regard to an indirect effect, evidence has accumulated indicating that the cholinergic excitatory input to the dopaminergic neurons in the ventral tegmental area may be an important part of the neuronal circuits mediating natural as well as drug-rewarded behavior. The possibility may thus be considered that ethanol activates the cholinergic afferents causing a release of acetylcholine in the ventral tegemental area leading to a stimulation of nAChRs and thereby excite the mesocorticolimbic dopamine system. | Petrakis IL, Limoncelli D, Gueorguieva R, Jatlow P, Boutros NN, Trevisan L, Gelernter J, Krystal JH (2004)
Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism.
The American journal of psychiatry 161, 1776-1782 [PubMed:15465973]
[show Abstract]
ObjectiveA family history of alcoholism is a risk factor for the development of ethanol dependence. Ethanol is an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor, and alterations in NMDA receptor function are thought to be involved in ethanol abuse and dependence. The purpose of this study was to determine in healthy individuals with no ethanol dependence whether response to the NMDA receptor antagonist ketamine would differentiate those with a family history of ethanol dependence from those without such a family history.MethodHealthy subjects between the ages of 21 and 30 received 40-minute intravenous infusions of saline, low-dose ketamine (0.1 mg/kg), and high-dose ketamine (0.5 mg/kg) on three separate test days in a randomized order under double-blind conditions. The healthy individuals with at least one first-degree relative and another first- or second-degree relative with ethanol dependence (N=16) were compared with those who had no family history of ethanol dependence in any first- or second-degree relative (N=29). Outcome measures included the Brief Psychiatric Rating Scale, Clinician-Administered Dissociative States Scale, verbal fluency, Hopkins Verbal Learning Test, a biphasic alcohol effects scale, visual analog scales of mood states, and ketamine levels.ResultsDuring ketamine infusion, individuals with a family history of ethanol dependence showed an attenuated response in terms of perceptual alterations and dysphoric mood relative to those without such a family history.ConclusionsThese data suggest that alterations in NMDA receptor function may contribute to subjective response to ethanol and therefore also to the risk of developing alcoholism. | Patki KC, Greenblatt DJ, von Moltke LL (2004)
Ethanol inhibits in-vitro metabolism of nifedipine, triazolam and testosterone in human liver microsomes.
The Journal of pharmacy and pharmacology 56, 963-966 [PubMed:15285839]
[show Abstract]
Although extended exposure to ethanol induces CYP3A metabolism in-vivo, the acute effects of ethanol on CYP3A metabolism have not been fully evaluated in-vitro. We assessed the effect of ethanol on CYP3A-mediated biotransformation using human liver microsomes in-vitro with three prototypic CYP3A-mediated reactions: nifedipine to oxidized nifedipine, triazolam to its 1-hydroxy (1-OH TRZ) and 4-hydroxy (4-OH TRZ) metabolites, and testosterone to 6beta-hydroxytestosterone (6beta-OH TST). Ethanol inhibited metabolism of nifedipine (oxidized nifedipine IC50 3 mg dL(-1), where the IC50 value is the inhibitor concentration corresponding to a 50% reduction in metabolite formation velocity), triazolam (1-OH TRZ IC50 1.1 mg dL(-1), 4-OH TRZ IC50 2.7 mg dL(-1)) and testosterone (6beta-OH TST IC50 2.4 mg dL(-1)). The inhibitory potency of ethanol was similar for the three substrates representing the three hypothetical CYP3A substrate categories. The IC50 values obtained were lower than clinically relevant blood alcohol concentrations. In conclusion, ethanol is an inhibitor of human CYP3A metabolism and may contribute to clinically important interactions. | Gould TJ, Lommock JA (2003)
Nicotine enhances contextual fear conditioning and ameliorates ethanol-induced deficits in contextual fear conditioning.
Behavioral neuroscience 117, 1276-1282 [PubMed:14674846]
[show Abstract]
Nicotine and ethanol are 2 commonly used and abused drugs that have divergent effects on learning. The present study examined the effects of acute nicotine (0.25 mg/kg), ethanol (1.0 g/kg), and ethanol-nicotine coadministration on fear conditioning in C57BL/6 mice. Mice were assessed for contextual and cued fear conditioning at 1 day and 1 week posttraining. Ethanol disrupted acquisition but not consolidation of contextual fear conditioning; nicotine enhanced contextual fear conditioning and ameliorated ethanol-associated deficits in contextual fear conditioning. Mecamylamine antagonized this effect. Fear conditioning was reassessed 1 week after initial testing with no drug administered. At the 1-week retest, mice previously treated with nicotine continued to show enhanced contextual fear, and mice previously treated with ethanol continued to show contextual fear deficits. Thus, nicotine both produces a long-lasting enhancement of contextual fear conditioning and protects against ethanol-associated deficits. | Ferrani-Kile K, Randall PK, Leslie SW (2003)
Acute ethanol affects phosphorylation state of the NMDA receptor complex: implication of tyrosine phosphatases and protein kinase A.
Brain research. Molecular brain research 115, 78-86 [PubMed:12824058]
[show Abstract]
Phosphorylation has been shown to regulate N-methyl-D-aspartic acid receptor (NMDAR) function. The inhibitory effect of ethanol on NMDAR function could be due, at least in part, to a change in NMDAR phosphorylation states. In order to investigate the effect of ethanol on phosphorylation of NR1 and NR2 subunits, NMDAR complexes were immunoprecipitated from cortical slices pre-exposed to ethanol. Acute ethanol, 100 and 200 mM, significantly decreased the tyrosine phosphorylation of NR2 subunits (Tyr-NR2). Treatment with a tyrosine phosphatase inhibitor reduced the inhibition of Tyr-NR2 phosphorylation caused by 100 mM ethanol. This suggests an involvement of tyrosine phosphatases in ethanol-induced inhibition of Tyr-NR2 phosphorylation. Slices pre-exposed to 100 and 200 mM ethanol exhibited a significant increase in the phosphorylation of NR1 by PKA at serine 897 (Ser897-NR1), which was blocked by a PKA inhibitor. Moreover, at 200 mM, ethanol produced a significant increase in PKA activity. Together, these results indicate that ethanol may increase Ser897-NR1 phosphorylation by activating PKA. However, ethanol did not affect phosphorylation of NR1 subunits by PKC at serine 896. We conclude that ethanol has the ability to modulate phosphorylation of both NR2 and NR1 subunits and these effects appear to implicate tyrosine phosphatases and PKA, respectively. | Krystal JH, Petrakis IL, Limoncelli D, Webb E, Gueorgueva R, D'Souza DC, Boutros NN, Trevisan L, Charney DS (2003)
Altered NMDA glutamate receptor antagonist response in recovering ethanol-dependent patients.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 28, 2020-2028 [PubMed:12888778]
[show Abstract]
Ethanol is an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. Ethanol dependence upregulates NMDA receptors and contributes to crosstolerance with selective NMDA receptor antagonists in animals. This study evaluated whether recovering ethanol-dependent patients show evidence of a reduced level of response to the effects of the NMDA receptor antagonist, ketamine. In this double-blind study, 34 recently detoxified alcohol-dependent patients and 26 healthy comparison subjects completed 3 test days involving a 40-min infusion of saline, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg in a randomized order. Recovering ethanol-dependent patients showed reduced perceptual alterations, dysphoric mood, and impairments in executive cognitive functions during ketamine infusion relative to the healthy comparison group. No attenuation of ketamine-induced amnestic effects, euphoria, or activation was observed. The alterations in NMDA receptor function observed in recovering ethanol-dependent patients may have important implications for ethanol tolerance, ethanol dependence, and the treatment of alcoholism. | Sultana R, Babu PP (2003)
Ethanol-induced alteration in N-methyl-D-aspartate receptor 2A C-terminus and protein kinase C activity in rat brain.
Neuroscience letters 349, 45-48 [PubMed:12946583]
[show Abstract]
Ethanol is a potent inhibitor of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. In the present study, expression of NR2A and its phosphorylation status were investigated in adult rat cerebral cortex and cerebellum, using an experimental paradigm of in vivo chronic ethanol exposure. In addition, PKC activity was measured in both cytosol and membrane fraction of cerebral cortex and cerebellum using Histone III S as substrate. Western blot analysis using NR2A antibody showed an increased immunoreactivity in cerebral cortex and no immunoreactivity in cerebellum of alcohol-treated rats. Furthermore, PKC activity was increased in both membrane and cytosolic fraction of alcohol-treated rat cerebellum, whereas PKC activity in cerebral cortex was found to be decreased in membrane fraction with no appreciable change in cytosolic fraction. In vitro phosphorylation study showed hypophosphorylation in ethanol-treated cerebral cortex and cerebellum. Our current findings imply that the truncation of NR2A subunit upon alcohol administration in cerebellum probably contributes to altered NMDA receptor function and cerebellar atrophy and motor incoordination in alcoholic rats. | Brown G, Stephens DN (2002)
Effects of cocaine on responding for ethanol or sucrose under a progressive ratio schedule.
Behavioural pharmacology 13, 157-162 [PubMed:11981228]
[show Abstract]
Progressive ratio (PR) schedules have been increasingly used to study motivation for self-administered drugs of abuse, such as psychostimulants and ethanol. In these and other studies, the breaking point (BP) is thought to be a measure of the motivation of the animal to work for a particular reward. Ethanol, a highly abused drug, maintains only low BPs. The present experiment was designed to examine if the low BP achieved by animals working for ethanol could be increased by the administration of a psychostimulant. A group working for a sucrose reinforcer was included for comparison. Rats previously trained to lever press under a PR schedule for 0.1 ml aliquots of 10% ethanol or 5% sucrose reinforcers were dosed once a week with cocaine (0, 5 and 15 mg/kg intraperitoneally) 30 min prior to their daily operant session using a Latin square design. Vehicle and 5 mg/kg cocaine had no effect on BP for any reinforcer, but 15 mg/kg cocaine produced a significantly higher BP (P<0.05) for animals working for either ethanol or sucrose. The same doses of cocaine decreased consumption of, and preference for, a 5% sucrose solution. These results indicate that, although cocaine administration does not increase sucrose preference, it may increase BP values in PR schedules. It is therefore unlikely that the increases in BP reflect cocaine-induced increased motivation, and they may be due to cocaine's stimulant or other properties. These data reinforce opinions that PR schedules may be unsuitable for assessing the effects of experimental manipulations on motivation for drugs with stimulant actions. | Czapski GA, Sun GY, Strosznajder JB (2002)
Inhibition of N-methyl-D-aspartic acid-nitric oxide synthase in rat hippocampal slices by ethanol. Evidence for the involvement of tetrahydrobiopterin but not lipid peroxidation.
Journal of biomedical science 9, 3-9 [PubMed:11810019]
[show Abstract]
The ionotropic glutamatergic receptor system, especially the subtype mediated by N-methyl-D-aspartic acid (NMDA), is known to exhibit special sensitivity to the effect of ethanol. This is due partly to the ability of ethanol to modulate the production of nitric oxide through the NMDA-nitric oxide synthase (NOS) pathway. In this study, we examined the effects of ethanol on basal and NMDA-stimulated NOS activity in rat hippocampal slices by measuring the conversion of [(14)C]-arginine into [(14)C]-citrulline in an incubation system containing the necessary cofactors. Stimulation of hippocampal slices with NMDA (100 microM) enhanced NOS activity by 43% (n = 12). Although ethanol did not alter NOS activity when added to the incubation system during NMDA stimulation, it dose-dependently inhibited NMDA-NOS activity when added to the slices during the 90-min preincubation period. Further assay of NOS activity with brain cytosolic fraction indicated an inhibitory effect of ethanol (200 mM) when the assay was carried out in the absence of exogenous tetrahydrobiopterin (BH4), a redox-active cofactor for NOS. Incubation of brain homogenates resulted in a time-dependent increase in the levels of lipid peroxidation products, but ethanol did not further enhance these products. Taken together, these results provide evidence for the role of BH4 but not oxidative stress in the inhibitory effect of ethanol on NMDA-NOS activity in rat hippocampal slices. | Li Q, Wilson WA, Swartzwelder HS (2002)
Differential effect of ethanol on NMDA EPSCs in pyramidal cells in the posterior cingulate cortex of juvenile and adult rats.
Journal of neurophysiology 87, 705-711 [PubMed:11826039]
[show Abstract]
Ethanol (EtOH) is a potent inhibitor of N-methyl-D-aspartate (NMDA) receptor-mediated activity in a number of brain areas, and recent studies have indicated that this inhibitory effect of ethanol is more powerful in the juvenile brain compared with the adult brain. However, previous direct developmental comparisons have been limited to studies of extracellular responses in the hippocampus. To begin an assessment of the mechanisms underlying this developmental sensitivity, we assessed the inhibitory effect of EtOH on NMDA receptor-mediated synaptic transmission in neocortical slices from adult (95-135 days old) and juvenile (28-32 days old) rats using the whole cell patch-clamp recording technique. In the presence of 6,7-dinitroquinoxaline-2,3-dione (20 microM) and bicuculline methiodine (20 microM), NMDA receptor-mediated excitatory postsynaptic currents were isolated from pyramidal cells of the posterior cingulate cortex (PCC). In slices from juvenile rats 5, 10, 30, and 60 mM EtOH reduced the mean amplitude of NMDA receptor-mediated EPSCs by 11, 22, 35, and 46%, respectively. However, the same concentrations of EtOH inhibited the mean amplitude of EPSCs by only 4, 8, 15, and 31% in slices from adult rats. This developmental difference in the potency of EtOH against NMDA receptor-mediated EPSCs was also observed when the holding potential of the neurons was increased to +30 mV, although the inhibitory effect of ethanol on adult neurons was diminished at that voltage. These results provide a cellular analysis of the enhanced potency of ethanol against NMDA receptor-mediated EPSCs in neocortical cells from juvenile animals compared with adults. | Guerri C (2002)
Mechanisms involved in central nervous system dysfunctions induced by prenatal ethanol exposure.
Neurotoxicity research 4, 327-335 [PubMed:12829422]
[show Abstract]
Clinical and experimental evidence has demonstrated that ethanol is a teratogen, and that its consumption during pregnancy induces harmful effects on the developing foetus that leads to foetal alcohol syndrome (FAS). Central nervous system dysfunctions are the most severe and permanent consequence of maternal alcohol intake and can occur in absence of gross morphological defects associated with FAS. Mental retardation and long-term cognitive and behavioural deficits are some of the problems commonly found in children of women who were moderate or heavy drinkers during pregnancy. Experimental evidence demonstrates that alcohol interferes with many molecular, neurochemical and cellular events occurring during the normal development of the brain. Some brain areas are more affected than others and, even within a given region, some cell populations are more vulnerable than others. The neocortex, hippocampus and cerebellum are especially susceptible to alcohol and have been associated with the behavioural deficits. For example, alcohol exposure during the development of neocortex increases natural apoptosis and induces cell necrosis. These effects may be associated with ethanol-induced alterations in both neurotrophic support, and the expression of cell adhesion molecules, which may affect cell-cell interactions and cell survival. Experimental evidence also shows that alcohol disrupts radial glial and astroglial development which may lead to alterations in cell migration and neuronal survival and differentiation. Impairment of several neurotransmitter systems and/or their receptors, as well as changes in the endocrine environment during brain development, are also important factors involved in the neurodevelopmental liabilities observed after in utero alcohol exposure. | Rush CR (2001)
Pretreatment with hydromorphone, a mu-opioid agonist, does not alter the acute behavioral and physiological effects of ethanol in humans.
Alcoholism, clinical and experimental research 25, 9-17 [PubMed:11198720]
[show Abstract]
BackgroundEndogenous opioid systems are thought to mediate at least some of the behavioral effects of ethanol. Opioid antagonists, like naloxone and naltrexone, decrease ethanol self-administration under a variety of conditions in different species of laboratory animals (e.g., rodents and nonhuman primates). Opioid agonists, like morphine, also alter ethanol consumption. However, the dose-response functions for opioid agonists are complex in that low doses increase ethanol self-administration, whereas moderate to high doses decrease ethanol self-administration. The results of prospective human laboratory studies that assessed the behavioral effects of ethanol after pretreatment with an opioid antagonist are mixed. The aim of the present study was to assess the acute subject-rated effects of ethanol (0, 0.5, and 1 g/kg) after pretreatment with hydromorphone, a mu-opioid agonist.MethodsIn the present experiment, the acute subject-rated, performance-impairing, and physiological effects of ethanol (0, 0.5, and 1 g/kg) were examined after pretreatment with hydromorphone (0, 1, and 2 mg), a mu-opioid agonist, in nine healthy volunteers. Volunteers received one of the nine possible ethanolhydromorphone combinations during each of nine experimental sessions.ResultsEthanol produced prototypical subject-rated drug effects (e.g., dose dependently increased ratings of "high"), impaired performance, and increased heart rate. Hydromorphone pretreatment generally did not significantly alter the subject-rated, performance-impairing, or physiological effects of ethanol.ConclusionsThe results of the present experiment suggest that hydromorphone pretreatment does not significantly affect the subject-rated effects of ethanol. Future human laboratory studies should test higher doses of hydromorphone. Future studies also might use more sophisticated behavioral procedures like self-administration, or perhaps drug discrimination, to determine if opioid agonists can modulate the behavioral effects of ethanol in humans. | Miles DR, Svikis DS, Kulstad And JL, Haug NA (2001)
Psychopathology in pregnant drug-dependent women with and without comorbid alcohol dependence.
Alcoholism, clinical and experimental research 25, 1012-1017 [PubMed:11505026]
[show Abstract]
BackgroundIndividuals with comorbid alcohol and drug use disorders are at particularly high risk for a variety of problems, including other psychiatric disorders. In general, patients with comorbid alcohol and drug dependence tend to have more severe dependence problems and often have poorer treatment outcomes than individuals with single disorders. For treatment-seeking pregnant women, psychiatric comorbidity can lead to relapse and premature treatment dropout, with adverse consequences to mother and infant.MethodsPsychopathology, as measured by the Minnesota Multiphasic Personality Inventory-Revised (MMPI-2), was examined in 170 pregnant women admitted to a comprehensive treatment program for cocaine or opiate dependence. Most were single (75%) and African American (80%), with a mean age of 29 years. Thirty-six met DSM-III-R criteria for both alcohol and drug dependence (alcohol positive), whereas 134 were drug dependent only (alcohol negative).ResultsAlcohol-positive women had higher levels of psychopathology than alcohol-negative women, with higher scores on scales 2 (Depression), 4 (Psychopathic Deviance), 8 (Schizophrenia), and 0 (Social Introversion; p < 0.05). The mean MMPI-2 profile for alcohol-positive women was 2-4-8 (Depression-Psychopathic Deviance-Schizophrenia; all T-scores > 65), whereas alcohol-negative women had only a scale 4 increase.ConclusionsResults suggest that pregnant, drug-dependent women with comorbid alcohol dependence present for treatment with greater psychopathology and thus may require more intense interventions than pregnant, drug-dependent women without comorbid alcohol dependence. Alcohol use by pregnant women is particularly important to address in treatment, because alcohol is a known teratogen associated with mental retardation and behavioral problems. | López JR, Antolín N, Barceló MV, Pérez M, Ballesteros AM, García AL (2001)
[Alcohol consumption among students of a health area. Habits and beliefs].
Atencion primaria 27, 159-165 [PubMed:11262320]
[show Abstract]
Objectives1. To describe the habits and conduct of school students (13-17 years old) around alcohol in the Cartagena Health Area. 2. To discover the factors underlying consumption. 3. To analyse beliefs and behaviour about consumption.DesignCross-sectional descriptive study.SettingHealth area.Participants16,657 school students. Sample population (n = 1004). Large-group sampling (sampling unit: class-room), accuracy = 3%, CI = 95%, p = q = 50%, stratified by school and geographical area.Measurements and main resultsAnonymous, self-filled questionnaire (33 open and closed questions).Selection criteriaattendance at class on the day of the questionnaire.Variablessocial, economic and cultural data on parents and students, course, type of family, alcohol consumption (starting age, access, individual habits, friends and family), beliefs about consumption, study profile of consumer.Statistical analysisdescription of variables, chi-squared test, t test, logistical regression. 99.2% filled in the questionnaire. Students' average age was 15.84 (SD, 1.21). 89.96% lived with their parents. 83.4% had consumed alcohol on some occasion, with no relationship to current consumption (p > 0.05). Starting age was 13.77 (SD, 1.78), 48.5% in discos/bars and 19% at home (p > 0.05). 47.5% had got drunk on some occasion (p > 0.05). 88.2% customarily drank alcohol mixed with other drinks (p > 0.05). 51.8% drank at week-ends (2.4% every day) (p > 0.05). 63.3% thought it easy to acquire drinks: 48.9% in supermarkets, 26.4% at petrol stations (p = 0.038). 71% of consumers agreed that "alcohol is a drug" (p = 0.005). 13% believed "it does not cause dependency" (p = 0.00001). 23.3% thought that it is not true to say "the person who does sport is healthier and does not take alcohol".ConclusionsThe pattern of consumption is similar to that found in other autonomous communities, although in greater quantity and without differences in kind. Mean age of consumer: 15 years old. They usually drink alcohol mixed with other soft drinks, normally at week-ends. They are very ignorant of the effects of consumption. | Chang YC, Okeke BC, Hatsu M, Takamizawa K (2001)
In vitro dehalogenation of tetrachloroethylene (PCE) by cell-free extracts of Clostridium bifermentans DPH-1.
Bioresource technology 78, 141-147 [PubMed:11333032]
[show Abstract]
Cell-free extracts of Clostridium bifermentans DPH-1 catalyzed tetrachloroethylene (PCE) dechlorination. PCE degradation was stimulated by addition of a variety of electron donors. Ethanol (0.61 mM) was the most effective electron donor for PCE dechlorination. Maximum activity was recorded at 30 degrees C and pH 7.5. Addition of NADH as a cofactor stimulated enzymatic activity but the activity was not stimulated by addition of metal ions. When the cell-free enzyme extract was incubated in the presence of titanium citrate as a reducing agent, the dehalogenase was rapidly inactivated by propyl iodide (0.5 mM). The activity of propyliodide-reacted enzyme was restored by illumination with a 250 W lamp. The dehalogenase activity was also inhibited by cyanide. The substrate spectrum of activity included trichloroethylene (TCE), cis-1,2-dichloroethylene (cDCE), trans-dichloroethylene, 1,1-dichloroethylene, 1,2-dichloroethane, and 1,1,2-trichloroethane. The highest rate of degradation of the chlorinated aliphatic compounds was achieved with PCE, and PCE was principally degraded via TCE to cDCE. Results indicate that the dehalogenase could play a vital role in the breakdown of PCE as well as a variety of other chlorinated aliphatic compounds. | da Silva GE, Morato GS, Takahashi RN (2001)
Rapid tolerance to Delta(9)-tetrahydrocannabinol and cross-tolerance between ethanol and Delta(9)-tetrahydrocannabinol in mice.
European journal of pharmacology 431, 201-207 [PubMed:11728426]
[show Abstract]
Motor incoordination in the rota-rod test was used to assess the development of rapid tolerance to Delta(9)-tetrahydrocannabinol and rapid cross-tolerance between ethanol and Delta(9)-tetrahydrocannabinol in mice. Further, the influence of the cannabinoid receptor antagonist SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide) on the motor impairment induced by both drugs was examined. Mice were injected on day 1 with equipotent doses of Delta(9)-tetrahydrocannabinol (28 mg/kg, i.p.) and ethanol (2.25 g/kg, i.p.) and tested at 30, 60 and 90 min after the injections. On day 2, control groups received ethanol or Delta(9)-tetrahydrocannabinol, some groups received the same treatment as the day before, while the remaining groups switched the treatment. All groups were tested to evaluate tolerance. The development of rapid tolerance to Delta(9)-tetrahydrocannabinol was observed and pretreatment with ethanol resulted in rapid cross-tolerance to Delta(9)-tetrahydrocannabinol. SR 141716A (2 mg/kg, i.p.) failed to block the development of rapid tolerance to both drugs, ethanol and Delta(9)-tetrahydrocannabinol. These results suggest that Delta(9)-tetrahydrocannabinol, similarly to ethanol, can induce rapid tolerance to motor incoordination in mice. They also support the use of the 2-day protocol as an effective procedure to reduce the length of drug exposure necessary to induce tolerance. | Gianoulakis C (2001)
Influence of the endogenous opioid system on high alcohol consumption and genetic predisposition to alcoholism.
Journal of psychiatry & neuroscience : JPN 26, 304-318 [PubMed:11590970]
[show Abstract]
There is increasing evidence supporting a link between the endogenous opioid system and excessive alcohol consumption. Acute or light alcohol consumption stimulates the release of opioid peptides in brain regions that are associated with reward and reinforcement and that mediate, at least in part, the reinforcing effects of ethanol. However, chronic heavy alcohol consumption induces a central opioid deficiency, which may be perceived as opioid withdrawal and may promote alcohol consumption through the mechanisms of negative reinforcement. The role of genetic factors in alcohol dependency is well recognized, and there is evidence that the activity of the endogenous opioid system under basal conditions and in response to ethanol may play a role in determining an individual's predisposition to alcoholism. The effectiveness of opioid receptor antagonists in decreasing alcohol consumption in people with an alcohol dependency and in animal models lends further support to the view that the opioid system may regulate, either directly or through interactions with other neurotransmitters, alcohol consumption. A better understanding of the complex interactions between ethanol, the endogenous opioids and other neurotransmitter systems will help to delineate the neurochemical mechanisms leading to alcoholism and may lead to the development of novel treatments. | Olney JW, Wozniak DF, Jevtovic-Todorovic V, Ikonomidou C (2001)
Glutamate signaling and the fetal alcohol syndrome.
Mental retardation and developmental disabilities research reviews 7, 267-275 [PubMed:11754521]
[show Abstract]
It has been known for three decades that ethanol, the most widely abused drug in the world, has deleterious effects on the developing human brain, but progress has been slow in developing animal models that are optimal for studying this problem, and the underlying mechanisms have remained elusive. Recently, we have shown that during the synaptogenesis period, also known as the brain growth spurt period, ethanol has the potential to trigger widespread neuronal suicide (apoptosis), deleting many millions of neurons from the in vivo mammalian brain. It appears that ethanol triggers apoptotic neurodegeneration by a dual mechanism (blockade of NMDA glutamate receptors and excessive activation of GABA(A) receptors), in that ethanol has both NMDA antagonist and GABAmimetic properties; we have shown that other drugs which have either of these properties trigger apoptotic neurodegeneration in the developing brain. The brain growth spurt period in humans spans the last trimester of pregnancy and the first several years after birth. Thus, our findings provide a likely explanation for the reduced brain mass and neurobehavioral disturbances associated with the human fetal alcohol syndrome. Furthermore, since NMDA antagonist and GABAmimetic drugs are sometimes abused by pregnant women and also are used as anticonvulsants, sedatives, or anesthetics in pediatric medicine, our findings suggest the possibility that exposure of the developing brain to these various drugs either pre or postnatally could contribute to mental disability syndromes that have heretofore been attributed to unknown causes. In addition, the observation that ethanol and related drugs trigger massive neuronal apoptosis in the developing brain provides an unprecedented opportunity to study both neuropathological aspects and molecular mechanisms of apoptotic neurodegeneration in the in vivo mammalian brain. | Krupitsky EM, Burakov AM, Romanova TN, Grinenko NI, Grinenko AY, Fletcher J, Petrakis IL, Krystal JH (2001)
Attenuation of ketamine effects by nimodipine pretreatment in recovering ethanol dependent men: psychopharmacologic implications of the interaction of NMDA and L-type calcium channel antagonists.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 25, 936-947 [PubMed:11750186]
[show Abstract]
Ketamine blocks the calcium channel associated with N-methyl-D-aspartate (NMDA) glutamate receptors. It has transient behavioral effects in healthy humans that resemble aspects of schizophrenia, dissociative disorders, and ethanol intoxication. Ethanol is an antagonist of both NMDA receptors and L-type voltage-sensitive calcium channels (VSCC) and it has minimal psychotogenic activity in humans. A double-blind placebo-controlled study was conducted that evaluated whether pretreatment with the L-type VSCC antagonist, nimodipine, 90 mg D, modulated ketamine response (bolus 0.26 mg/kg, infusion of 0.65 mg/kg/hr) in 26 ethanol-dependent inpatients who were sober for at least one month prior to testing. This study found that nimodipine reduced the capacity of ketamine to induce psychosis, negative symptoms, altered perception, dysphoria, verbal fluency impairment, and learning deficits. Nimodipine improved memory function, but had no other intrinsic behavioral activity in this patient group. Nimodipine pretreatment attenuated the perceived similarity of ketamine effects to ethanol as well as ketamine-induced euphoria and sedation. However, nimodipine did not reduce the stimulant effects of ketamine. These data suggest that antagonism of L-type VSCCs attenuates the behavioral effects of NMDA antagonists in humans. They support the continued evaluation of nimodipine in the treatment of neuropsychiatric disorders. They also suggest that drugs, such as ethanol, that combine NMDA and L-type VSCC antagonism may have enhanced tolerability without attenuation of their stimulant effects. | Olney JW, Ishimaru MJ, Bittigau P, Ikonomidou C (2000)
Ethanol-induced apoptotic neurodegeneration in the developing brain.
Apoptosis : an international journal on programmed cell death 5, 515-521 [PubMed:11303910]
[show Abstract]
It has been known for three decades that ethanol, the most widely abused drug in the world, has deleterious effects on the developing human brain, but progress has been slow in developing animal models for studying this problem, and the underlying mechanisms have remained elusive. Recently, we have shown that during the synaptogenesis period, also known as the brain growth spurt period, ethanol has the potential to trigger massive neuronal suicide in the in vivo mammalian brain. The brain growth spurt period in humans spans the last trimester of pregnancy and first several years after birth. The NMDA antagonist and GABAmimetic properties of ethanol may be responsible for its apoptogenic action, in that other drugs with either NMDA antagonist or GABAmimetic actions also trigger apoptotic neurodegeneration in the developing brain. Our findings provide a likely explanation for the reduced brain mass and neurobehavioral disturbances associated with the human fetal alcohol syndrome. Furthermore, since NMDA antagonist and GABAmimetic drugs are sometimes abused by pregnant women and also are used as anticonvulsants, sedatives or anesthetics in pediatric medicine, our findings raise several complex drug safety issues. In addition, the observation that ethanol and several other drugs trigger massive neuronal apoptosis in the developing brain provides an unprecedented opportunity to study both neuropathological aspects and molecular mechanisms of apoptotic neurodegeneration in the in vivo mammalian brain. | Li C, Xiong K, Weight FF (2000)
Ethanol inhibition of adenosine 5'-triphosphate-activated current in freshly isolated adult rat hippocampal CA1 neurons.
Neuroscience letters 295, 77-80 [PubMed:11090978]
[show Abstract]
The effect of ethanol on current activated by extracellular adenosine 5'-triphosphate (ATP) was studied in freshly isolated adult rat hippocampal CA1 neurons using whole-cell patch-clamp recording. ATP activated an inward current with an EC(50) value of 18 microM. The inward current was also activated by 2-methylthio ATP (2-MeSATP) and alpha,beta-methylene ATP (alpha,beta-MeATP), inhibited by pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), and potentiated by Zn(2+). Ethanol inhibited current activated by 10 microM ATP with an IC(50) value of 83 mM in a voltage-independent manner. Ethanol, 100 mM, shifted the ATP concentration-response curve to the right, increasing the EC(50) value for ATP from 18 to 33 microM, but did not reduce the maximal response to ATP. The results suggest that ethanol can inhibit the function of P2X receptors in adult rat hippocampal neurons by decreasing the apparent affinity of the binding site for ATP. | Kolarzyk E, Pach J (2000)
[Comparison of respiratory regulation in alcohol and opiate abusers].
Pneumonologia i alergologia polska 68, 312-318 [PubMed:11200745]
[show Abstract]
Opioid drugs and alcohol, both central nervous system depressants, may also have a depressive action on the brain stem centre responsible for breathing control. Disorders of breathing regulation are reflected in respiratory efficiency. The aim of this study was to evaluate the regulation of breathing by measuring the respiratory pattern and occlusion pressure of abusers of opiates and alcohol. There were 180 persons under examination: 84 alcohol abusers (group I), 36 opiates abusers (group II) and 40 healthy persons (control group). Both groups of dependent persons were treated in the Detoxication Unit of the Department of Clinical Toxicology CMUJ. Respiratory regulation was evaluated "on line" by means of synchronous measurements of the respiratory pattern (according to Milic-Emili assumptions) and occlusion pressure P 0.1 (according to Whitlaw assumptions). The central respiratory drive (VT/Tin) and the timing component of the breathing cycle (Tin/Ttot) were simillar in both groups of abusers. In comparison to the control group, in the group of opiates abusers, values of VT/Tin were higher during examination performed after treatment, and values of Tin/Ttot were elevated (in group I--only before treatment; in group II--before and after treatment). Examination of respiratory pattern and occlusion pressure is based on recording spontaneous breathing, which this can be performed even in unconscious patients in very early stage of poisoning. | Rowlands JC, Wang H, Hakkak R, Ronis MJ, Strobel HW, Badger TM (2000)
Chronic intragastric infusion of ethanol-containing diets induces CYP3A9 while decreasing CYP3A2 in male rats.
The Journal of pharmacology and experimental therapeutics 295, 747-752 [PubMed:11046114]
[show Abstract]
The CYP3A subfamily is the most abundant of the human hepatic cytochrome P450 enzymes. They mediate the biotransformation of many drugs, including a number of psychotropic, cardiac, analgesic, hormonal, immunosuppressant, antineoplastic, and antihistaminic agents. We studied diet/ethanol interactions using total enteral nutrition in adult male Sprague-Dawley rats with diets containing 16% protein, ethanol (13 g/kg), corn oil (fat; 25-45%), and carbohydrate (CHO; 1-21%). Using this model, chronic ethanol feeding decreased CYP3A activity (testosterone 6 beta-hydroxylation) and apoprotein levels (Western blot) (P <.05) and these effects were independent of the dietary CHO/fat ratio. The CYP3A2 mRNA levels decreased (P <.05) in the rats fed ethanol-containing diets by 73 to 83% compared with rats fed control diets, regardless of the CHO/fat ratio. In contrast, ethanol induced CYP3A9 mRNA levels (P <.05) and this effect was greater (P <.05) in the high-CHO/low-fat group (11.3-fold) than in the low-CHO/high-fat group (2.6-fold). Purified recombinant rat P450 3A9 had a chlorzoxazone 6-hydroxylase activity with a turnover number 1.3 nmol/min/nmol of P450. These results indicate that 1) ethanol differentially affects the expression of CYP3A gene family and this regulation appears to be modulated by dietary CHO/fat ratio; 2) the decrease in testosterone 6 beta-hydroxylase activity and CYP3A apoprotein levels are most likely due to the ethanol-induced decrease in CYP3A2 mRNA levels; and 3) CYP3A9 is induced by ethanol and is a low-affinity, high-K(m) chlorzoxazone hydroxylase. |
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