The development of medication for alcohol-use disorders targeting the GABAB receptor system

The present paper summarizes experimental and clinical data suggesting the therapeutic potential of the prototypic GABAB receptor agonist, baclofen, for the treatment of alcohol-use disorders (AUDs). Numerous studies have reported baclofen-induced suppression of alcohol drinking, relapse-like drinking, and alcohol reinforcing, rewarding, stimulating, and motivational properties in rats and mice. The majority of clinical surveys conducted to date have demonstrated the capacity of baclofen to suppress alcohol consumption, craving for alcohol, and alcohol withdrawal symptomatology in alcohol-dependent patients. More recently, the discovery of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, provided a new tool for pharmacological manipulations of the GABAB receptor. Accumulating lines of preclinical evidence suggest that positive allosteric modulators of the GABAB receptor (GABAB PAMs), such as GS39783, display a high therapeutic index and retain baclofen’s capacity to suppress alcohol consumption and alcohol reinforcing and motivational properties. The present paper also summarizes the most relevant patents on GABAB receptor agonists and GABAB PAMs as possible pharmacotherapies for AUDs

Endogenous gamma-aminobutyric acid (GABA)(A) receptor active neurosteroids and the sedative/hypnotic action of gamma-hydroxybutyric acid (GHB): A study in GHB-S (sensitive) and GHB-R (resistant) rat lines

In the rat brain, gamma-hydroxybutyric-acid (GHB) increases the concentrations of 3 alpha-hydroxy,5 alpha-pregnan-20-one (allopregnanolone, 3 alpha,5 alpha-THP) and 3 alpha,21-dihydroxy,5 alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone/3 alpha,5 alpha THDOC), two neurosteroids acting as positive allosteric modulators of gamma-aminobutyric acid (GABA)A receptors. This study was aimed at assessing whether neurosteroids play a role in GHB-induced loss of righting reflex (LORR). Basal and GHB-stimulated brain concentrations of endogenous 3 alpha,5 alpha-THP and 3 alpha,5 alpha-THDOC were analyzed in two rat lines, GHB-sensitive (GHB-S) and GHB-resistant (GHB-R), selectively bred for opposite sensitivity to GHB-induced sedation/hypnosis. Basal neurosteroid concentrations were similar in brain cortex of the two rat lines. However, in male GHB-S rats, administration of GHB (1000 mg/kg, i.p., 30 min) increased brain cortical concentrations of 3 alpha,5 alpha-THP and 3 alpha,5 alpha-THDOC 7- and 2.5-fold, respectively, whilst male GHB-R animals displayed only a 4- and 2-fold increase, respectively. In GHB-S rats this increase lasted up to 90 min and declined 180 min following GHB administration, a time course that matches LORR onset and duration. In contrast, in GHB-R rats, which failed to show GHB-induced LORR, brain cortical 3 alpha,5 alpha-THP and 3 alpha,5 alpha-THDOC had returned to control values within 90 min. At onset of LORR, a similar increase in brain cortical levels of 3 alpha,5 alpha-THP and 3 alpha,5 alpha-THDOC (2-3-fold) was observed in GHB-S female rats and in the few female GHB-R rats that lost the righting reflex after GHB administration, but not in female GHB-R rats failing to show LORR. Sub-hypnotic doses (7.5 and 12.5 mg/kg, i.p.) of pregnanolone, administered 10 min before GHB, dose-dependently facilitated the expression of GHB-induced LORR in GHB-R male rats. These results suggest that the GHB-induced increases of brain 3 alpha,5 alpha-THP and 3 alpha,5 alpha-THDOC concentrations are implicated in the eliciting of the sedative/hypnotic action of GHB. (c) 2005 Elsevier Ltd. All rights reserved

GABA(B)-receptor mediation of the inhibitory effect of gamma-hydroxybutyric acid on intestinal motility in mice

The effect of acutely administered gamma-hydroxybutyric acid (GHB) and GHB receptor antagonist, NCS-382, on the propulsive activity in the mouse small intestine was assessed by measuring the transit of an orally administered, non absorbable marker. Both GHB (0, 25, 50, 100, 200 and 300 mg/kg; i.p.) and NCS-382 (0, 25, 50 and 75 mg/kg, i.p.) induced a dose-dependent inhibition (up to 50-60%) of the marker transit. Pretreatment with the GABA(B) receptor antagonist, SCH 50911 (100 mg/kg; i.p.), resulted in the blockade of the inhibiting effect of both GHB and NCS-382. These results suggest that the constipating effect of GHB and NCS-382 are secondary to stimulation of the GABAB receptor. (C) 2002 Elsevier Science Inc. All rights reserved

Direct agonists and positive allosteric modulators of the GABA(B) receptor suppress alcohol's motivational properties and alcohol-seeking behavior in alcohol-preferring rats

DIRECT AGONISTS AND POSITIVE ALLOSTERIC MODULATORS OF THE GABA(B) RECEPTOR SUPPRESS ALCOHOL’S MOTIVATIONAL PROPERTIES AND ALCOHOLSEEKING BEHAVIOR IN ALCOHOL-PREFERRING RATS G. Colombo, P. Maccioni, M.A.M. Carai, C. Lobina, G. Addolorato, R. Agabio, G.L. Gessa CNR Institute of Neuroscience, Cagliari, Italy; Department of Neuroscience, University of Cagliari, Italy; Institute of Internal Medicine, Catholic University, Rome, Italy Accumulating lines of experimental evidence suggest the capacity of GABA(B) receptor direct agonists (e.g., baclofen) and positive allosteric modulators (e.g., GS39783) to suppress different alcohol-motivated behaviors, including alcohol drinking and self-administration. The purpose of the present study was two-fold: first, comparison of the effect of baclofen and GS39783 in an experimental procedure that assesses alcohol’s motivational properties (Experiment 1); second, evaluation of the effect of baclofen on the reinstatement of alcoholseeking behavior (an experimental model of alcohol relapse) (Experiment 2). In both experiments, Sardinian alcohol-preferring rats were initially trained to lever-press for alcohol under a fixed ratio 4 schedule of reinforcement in daily 30-min sessions. Once the selfadministration behavior stabilized, independent groups of rats were assigned to the two experiments. In Experiment 1, rats were exposed to sessions with a progressive ratio schedule of reinforcement. Baclofen (0-3 mg/kg i.p.) or GS39783 (0-100 mg/kg i.g.) were administered 30-60 min before the test sessions. In Experiment 2, rats were exposed to 70- min extinction/reinstatement sessions, during which, after a 60-min extinction phase, an alcohol-associated stimulus complex was presented (reinstatement phase). Baclofen (0 and 3 mg/kg) was administered via a permanent i.p. catheter, 30 min before the reinstatement phase. In Experiment 1, both baclofen and GS39783 dose-dependently suppressed breakpoint for alcohol (defined as the lowest response requirement not achieved by each rat; index of the motivational strength of alcohol). The effect of GS39783, but not that of baclofen, was specific for alcohol, as it did not alter breakpoint for a sucrose solution in a separate rat group. These results indicate that baclofen and GS39783 have the capacity to suppress alcohol’s motivational properties in sP rats. In Experiment 2, baclofen administration reduced, by approximately 60%, the resumption of extinguished lever-pressing for alcohol induced by the alcohol-associated stimulus complex. These results indicate that baclofen is capable to reduce cue-induced reinstatement of alcohol-seeking behavior in sP rats