Cellular and behavioral neurobiology of alcohol: Receptor-mediated neuronal processes
ABSTRACT Ethanol can be viewed as a receptor modulator, selectively altering neurochemical processes in discrete regions of the CNS. The actions of ethanol at two inotropic receptor systems, gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) glutamate receptors, are highlighted in this review. In addition, evidence is presented and discussed concerning the possible effects of ethanol that arise from interactions between these two receptor systems, the interactions of ethanol with phosphorylation states of receptor proteins and with metabotropic receptor systems.
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ABSTRACT: Alcohol Withdrawal Syndrome (AWS) is a potentially fatal outcome of severe alcohol dependence that presents a significant challenge to treatment. Although AWS is thought to be driven by a hyperglutamatergic brain state, benzodiazepines, which target the GABAergic system, comprise the first-line of treatment for AWS. Using a rat model of ethanol withdrawal, we tested whether ceftriaxone, a β-lactam antibiotic known to increase the expression and activity of glutamate uptake transporter EAAT2, reduces the occurrence or severity of ethanol withdrawal manifestations. After a two-week period of habituation to ethanol in two-bottle choice, alcohol-preferring (P) and Wistar rats received ethanol (4.0 g/kg) every 6 hours for 3-5 consecutive days via gavage. Rats were then deprived of ethanol for 48 h during which time they received ceftriaxone (50 mg or 100 mg/kg, I.P.) or saline twice a day starting 12 h after the last ethanol administration. Withdrawal manifestations were captured by continuous video recording and coded. The evolution of ethanol withdrawal was markedly different for P rats versus Wistar rats, with withdrawal manifestations occurring >12 h later in P rats than in Wistar rats. Ceftriaxone 100 mg/kg/injection twice per day (200 mg/kg/day) reduced or abolished all manifestations of ethanol withdrawal in both rat variants and prevented withdrawal-induced escalation of alcohol intake. Finally, ceftriaxone treatment was associated with lasting upregulation of ethanol withdrawal-induced downregulation of EAAT2 in the striatum. Our data support the role of ceftriaxone in alleviating alcohol withdrawal and open a novel pharmacologic avenue that requires clinical evaluation in patients with AWS.Neuropsychopharmacology accepted article preview online, 23 January 2014. doi:10.1038/npp.2014.14.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2014; DOI:10.1038/npp.2014.14 · 7.83 Impact Factor
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ABSTRACT: Baclofen is a GABA-B receptor agonist used in the treatment of spasticity. Recently, baclofen is used out of its label to decrease craving of alcoholic patients. Its optimal use in these patients requires further pharmacokinetic information. The objective of this study was to characterize the pharmacokinetics of baclofen in alcohol-dependent patients. Randomized clinical trials are ongoing to evaluate the efficacy for this new indication. Thirty-seven outpatients (weight: 74.0 kg [42.0 to 104.0]; age: 49 years [31 to 68]) followed in the addictology unit were studied. Total mean dose of 77.9 mg (30 to 240) per day was administered by oral route. Therapeutic drug monitoring allowed the measurement of 139 plasma concentrations. The following covariates were evaluated: demographic data (age, body weight, height, sex), biological data (creatinine, urea, AST, ALT, albumin, PR, VGM, PAL, CDT, GGT), and tobacco consumption (number of cigarettes and Fagerstrom test). Pharmacokinetic analysis was performed by using a nonlinear mixed-effect population model (NONMEM 7.2 software). Data were modeled with a 1-compartment pharmacokinetic model. The population typical mean (95% confidence interval [95% CI]) values for clearance (CL), apparent volume of distribution (V), and rate constant of absorption (Ka) were 9.9 l/h (9.0 to 11.1), 80.7 l (63.6 to 96.9), and 4.6/h (1.5 to 19.9), respectively. The interindividual variability of CL (95% CI) and V (95% CI), and residual variability (95% CI) were 56.0% (47.9 to 60.7), 68.3% (48.7 to 80.1), and 0.096 mg/l (0.079 to 0.107), respectively. Baclofen exhibited a linear pharmacokinetics with a proportional relationship from 30 to 240 mg per day, the dose range currently used in alcoholic patients. A wide interpatient variability was observed which could not be explained by the covariates. This high variation of baclofen exposure may explain the lack of response observed for some patients.Alcoholism Clinical and Experimental Research 08/2013; DOI:10.1111/acer.12235 · 3.31 Impact Factor
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ABSTRACT: Glutamate NMDA receptors mediate many molecular and behavioral effects of alcohol, and they play a key role in the development of excessive drinking. Uncompetitive NMDA receptor antagonists may, therefore, have therapeutic potential for alcoholism. The first aim was to compare the effects of the NMDA antagonists memantine and ketamine on ethanol and saccharin drinking in alcohol-preferring rats. The second aim was to determine whether the effects of the two NMDA receptor antagonists were mediated by the mammalian target of rapamycin (mTOR). TSRI Sardinian alcohol-preferring rats were allowed to self-administer either 10% w/v ethanol or 0.08% w/v saccharin, and water. Operant responding and motor activity were assessed following administration of either memantine (0-10mg/kg) or ketamine (0-20mg/kg). Finally, ethanol self-administration was assessed in rats administered with either memantine or ketamine but pretreated with the mTOR inhibitor rapamycin (2.5mg/kg). The uncompetitive NMDA receptor antagonists memantine and ketamine dose-dependently reduced ethanol drinking in alcohol-preferring rats; while memantine had a preferential effect on alcohol over saccharin, ketamine reduced responding for both solutions. Neither antagonist induced malaise, as shown by the lack of effect on water intake and motor activity. The mTOR inhibitor rapamycin blocked the effects of ketamine, but not those of memantine. Memantine and ketamine both reduce alcohol drinking in alcohol-preferring rats, but only memantine is selective for alcohol. The effects of ketamine, but not memantine, are mediated by mTOR. The results support the therapeutic potential of uncompetitive NMDA receptor antagonists, especially memantine, in alcohol addiction.Behavioural brain research 03/2013; DOI:10.1016/j.bbr.2013.02.030 · 3.39 Impact Factor