GABA transmission, but not benzodiazepine receptor stimulation, modulates ethanol intake by rats

Daoust, M.; Saligaut, Christian; Lhuintre, J. P.; Moore, N; Flipo, J.L.; Boismare, F

doi:10.1016/0741-8329(87)90087-5

Cited by 92 publications

(49 citation statements)

References 14 publications

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“…Possible motor impairing and sedative effects of baclofen on alcohol and heroin self-administration were addressed. As shown in the experiments with cocaine, baclofen did not impair food intake, and it reduced alcohol intake if an ethanol versus water choice was given to the animals (77,86,314).…”

Section: A Addictionmentioning

confidence: 90%

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Molecular Structure and Physiological Functions of GABA_BReceptors

Bettler

Kaupmann

Mosbacher

et al. 2004

Physiological Reviews

783

720

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GABAB receptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. The cloning of the first GABAB receptor cDNAs in 1997 revived interest in these receptors and their potential as therapeutic targets. With the availability of molecular tools, rapid progress was made in our understanding of the GABAB system. This led to the surprising discovery that GABAB receptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G protein-coupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GABAB receptors allowed some important questions in the field to be answered. It is now clear that molecular studies do not support the existence of pharmacologically distinct GABAB receptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GABAB receptors and the receptors for γ-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GABAB receptor polymorphisms to epilepsy. Significantly, the cloning of GABAB receptors enabled identification of the first allosteric GABAB receptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GABAB receptors and discuss ongoing drug-discovery efforts.

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Section: A Addictionmentioning

confidence: 90%

“…This suggests that high and low doses of baclofen activate distinct cellular mechanisms. Low doses of baclofen (3 mg/kg) reduce alcohol intake in alcohol-preferring Long-Evans rats (86). A reduction of alcohol intake after baclofen treatment was also seen in Wistar rats (77).…”

Section: A Addictionmentioning

confidence: 95%

Molecular Structure and Physiological Functions of GABA_BReceptors

Bettler

Kaupmann

Mosbacher

et al. 2004

Physiological Reviews

783

720

View full text Add to dashboard Cite

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“…Indeed, other works reported that baclofen reduced, produced no change on, or even stimulated alcohol intake in rats given a choice between an alcohol solution and water. Specifically, four separate studies investigated the effect of baclofen on alcohol intake in alcohol-experienced rats ("maintenance" model) (Daoust et al, 1987;Tomkins and Fletcher, 1996;Smith et al, 1999;Perfumi et al, 2002). An initial work by Daoust and coworkers (1987) found that baclofen, administered daily at the single dose of 3 mg/kg for 14 consecutive days, reduced alcohol intake in Long Evans rats, with no compensatory increase in water intake.…”

Section: Preclinical Studies Reducing Effect Of Gaba B Receptor Agonimentioning

confidence: 99%

Role of GABAB receptor in alcohol dependence: Reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics

et al. 2004

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The present paper describes the results of recent preclinical and clinical studies conducted in this laboratory in order to characterize the anti-alcohol properties of the GABA(B) receptor agonist, baclofen. At a preclinical level, the repeated administration of non-sedative doses of baclofen dose-dependently suppressed the acquisition and maintenance of alcohol drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats tested under the homecage, 2-bottle "alcohol vs water" choice regimen. Acute injection of baclofen completely blocked the temporary increase in voluntary alcohol intake occurring after a period of alcohol abstinence (the so-called alcohol deprivation effect, which models alcohol relapses in human alcoholics). Acute treatment with baclofen also dose-dependently suppressed extinction responding for alcohol (an index of motivation to consume alcohol) in sP rats trained to lever-press for oral alcohol self-administration. Taken together, these results suggest the involvement of the GABA(B) receptor in the neural substrate mediating alcohol intake and alcohol motivational properties in an animal model of excessive alcohol consumption. Further, acutely administered baclofen dose-dependently reduced the severity of alcohol withdrawal signs in Wistar rats made physically dependent upon alcohol. Preliminary clinical surveys suggest that the anti-alcohol properties of baclofen observed in rats may generalize to human alcoholics. Indeed, a double-blind survey demonstrated that repeated daily treatment with baclofen was associated, when compared to placebo, with a higher percentage of subjects totally abstinent from alcohol and a higher number of days of total abstinence. Treatment with baclofen also suppressed the number of daily drinks and decreased the obsessive and compulsive components of alcohol craving. Finally, a single non-sedative dose of baclofen resulted in the rapid disappearance of alcohol withdrawal symptomatology, including delirium tremens, in alcohol-dependent patients. In both clinical studies, baclofen was well tolerated with minimal side effects. These results suggest that baclofen may represent a potentially effective medication in the treatment of alcohol-dependent patients.

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“…Administration of GABA antagonists (IP) have consistently been shown to reduce intake of (Boyle et al 1993) and operant responding for (Samson et al 1987;Rassnick et al 1993) EtOH in rats. Studies of the effect of GABA agonists (IP) on EtOH intake, however, have provided mixed results (Fadda et al 1983;Boismare et al 1984;Daoust et al 1987;Boyle et al 1992Boyle et al , 1993Smith et al 1992;Wegelius et al 1993). The CNS sites and neuronal circuitries in- Wise and Rompre 1989;Le Moal and Simon 1991).…”

Section: Introductionmentioning

confidence: 97%

Blocking GABA A receptors in the anterior ventral tegmental area attenuates ethanol intake of the alcohol-preferring P rat

et al. 1998

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The effect of blocking the A subtype of gamma-aminobutyric acid (GABA(A)) receptors in the anterior ventral tegmental area (VTA) on ethanol (EtOH; 10% v/v) and saccharin (SACC; 0.0125%) consumption was investigated in alcohol-preferring P rats. Picrotoxin (0.005, 0.01, 0.05 and 0.10 microg/0.5 microl) was injected into the VTA, and consumption of EtOH and SACC was assessed in two 2-h limited-access drinking paradigms (concurrent EtOH/SACC access, and alternate-day-access to EtOH and SACC). Under concurrent-access conditions, the picrotoxin microinjections resulted in a 55 and 84% decrease in EtOH consumption at the 0.05 and 0.10 microg doses, respectively, compared with consumption following microinjections of vehicle solution (P<0.05). Saccharin intake was not significantly altered by picrotoxin. Under alternate-day-access drinking conditions, the picrotoxin microinjections resulted in dose-dependent decreases in EtOH consumption of 37-68%, with significant decreases following the 0.005, 0.05 and 0.10 microg doses (P<0.04). Saccharin intake was significantly reduced only at the 0.05 microg dose. The decrease in EtOH consumption after 0.10 microg picrotoxin was attenuated by co-administration of 0.01 microg muscimol. This dose of muscimol had no effect on EtOH consumption when injected alone. Intra-VTA injections of bicuculline (0.04 microg), another GABA(A) antagonist, reduced EtOH intake, comparable to the reduction following 0.10 microg picrotoxin. Microinjections of 0.10 microg picrotoxin in regions outside the VTA failed to decrease EtOH intake. These results suggest that anterior VTA mechanisms regulating alcohol drinking behavior are under tonic GABA inhibition, mediated by GABA(A) receptors. The results also suggest that different neural mechanisms are regulating voluntary EtOH and SACC drinking behaviors.

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GABA transmission, but not benzodiazepine receptor stimulation, modulates ethanol intake by rats

Cited by 92 publications

References 14 publications

Molecular Structure and Physiological Functions of GABA_BReceptors

Molecular Structure and Physiological Functions of GABA_BReceptors

Role of GABAB receptor in alcohol dependence: Reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics

Blocking GABA A receptors in the anterior ventral tegmental area attenuates ethanol intake of the alcohol-preferring P rat

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GABA transmission, but not benzodiazepine receptor stimulation, modulates ethanol intake by rats

Cited by 92 publications

References 14 publications

Molecular Structure and Physiological Functions of GABABReceptors

Molecular Structure and Physiological Functions of GABABReceptors

Role of GABAB receptor in alcohol dependence: Reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics

Blocking GABA A receptors in the anterior ventral tegmental area attenuates ethanol intake of the alcohol-preferring P rat

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Molecular Structure and Physiological Functions of GABA_BReceptors

Molecular Structure and Physiological Functions of GABA_BReceptors