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.
"The interaction of alcohol with the gamma-aminobutyric acid-ergic (GABAergic) neurotransmitter system is well known (Grant and Lovinger, 1995), and targeting GABAergic neurotransmission has been considered as a potential treatment strategy for alcohol dependence (Heilig and Egli, 2006; Johnson et al., 2005; Muzyk et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Background:
Baclofen is a GABA-B receptor agonist currently used in the treatment of spasticity. In recent years, baclofen has been used to reduce craving, voluntary alcohol intake and withdrawal syndrome of alcoholic patients. To date, there are no data available to estimate the relationship between baclofen exposure and the variation of craving. The first objective of this study was to investigate the variation of craving as a function of exposure, and the second was to explore the possible existence of baclofen responders and nonresponders.
Sixty-seven outpatients, 43 men/24 women (weight: 73 kg [42 to 128]; age: 49 years old [29 to 68]) followed in the addictology unit, were studied during 3 months after treatment initiation. Baclofen was administered by oral route. Therapeutic drug monitoring enabled the measurement of plasma concentrations. Craving level was assessed by the Obsessive-Compulsive Drinking Scale (OCDS). A population pharmacokinetic (PK)-pharmacodynamic analysis of the OCDS variation following baclofen administration was performed. Demographic data, biological data, and tobacco consumption were tested for their influence on the parameters.
Data were modeled with a 1-compartment model with first-order absorption and elimination. PK analysis confirms the results of our previous study. An Emax model best-described the exposure-OCDS relationship. None of the covariates tested was able to improve the fit or decrease intersubject variability. However, 2 subpopulations were defined for the exposure corresponding to half the maximal effect (BE50). The proportion of patients being classified as responders was 38% (95% confidence interval [CI] 7 to 76), the maximal decrease in OCDS (Emax ) was 72% (95% CI 25 to 85), and the BE50 was 12.6 (95% CI 0.02 to 74.3) or 4,390 (95% CI 20.4 to 31,800) h mg/l for responders and nonresponders, respectively.
We defined the relationship between baclofen exposure and craving in patients with alcohol use disorder. Baclofen treatment decreased craving in all patients. However, we drew up the hypothesis of 2 subpopulations of patients differentiated by their speed of response. A wide interindividual variability in response was depicted, making it currently impossible to predict which group a patient will belong to.
Alcoholism Clinical and Experimental Research 09/2015; DOI:10.1111/acer.12823 · 3.21 Impact Factor
"We found that ceftriaxone 200 mg/kg/day (but not 100 mg/ kg/day) administered during acute alcohol withdrawal almost completely abolished all measured withdrawal manifestations . Our findings are in agreement with the large body of evidence that supports the hypothesis that ethanol withdrawal results from a rebound hyperglutamatergic state unmasked by the abrupt termination of ethanol intake (Chandler et al, 2006; Crews et al, 1996; De Witte et al, 2003; Grant and Lovinger, 1995). Furthermore, our results are in agreement with previous reports showing that ceftriaxone administration displayed anti-seizure properties in an invertebrate assay (Rawls et al, 2010a), reduced the frequency of seizure in a mouse model of tuberous sclerosis complex (Zeng et al, 2010), and reduced cumulative posttraumatic seizure duration in rats (Goodrich et al, 2013). "
[Show abstract][Hide abstract] 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; 39(7). DOI:10.1038/npp.2014.14 · 7.05 Impact Factor
"Despite the enormous impact of this disease on society, there are only 3 medications (disulfiram , naltrexone, and acamprosate) currently approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of alcohol dependence, and given their limited efficacy, there is a need for additional pharmacotherapy for alcohol dependence. The interaction of alcohol with the gamma-aminobutyric acid GABAergic neurotransmitter system is well known (Grant and Lovinger, 1995), and targeting GABAergic neurotransmission has been considered as a potential treatment strategy for alcohol dependence (Heilig and Egli, 2006; Johnson et al., 2005; Muzyk et al., 2012). Baclofen, a GABA-B receptor agonist, which is usually used in the treatment of spasticity, has attracted considerable attention as a potential medication for alcoholism (Heilig and Egli, 2006; Johnson et al., 2005). "
[Show abstract][Hide abstract] 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 · 3.21 Impact Factor
Maarten L J Doornbos, Laura Pérez-Benito, Gary Tresadern, Thea Mulder-Krieger, Ilse Biesmans, Andrés A Trabanco, Jose María Cid, Hilde Lavreysen, Adriaan P IJzerman, Laura H Heitman,
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