Positive Modulation of GABA_B Receptors Decreased Nicotine Self-Administration and Counteracted Nicotine-Induced Enhancement of Brain Reward Function in Rats

Abstract

Acute administration of ␥-aminobutyric acid (GABA)-B receptor agonists decreases nicotine, cocaine, ethanol, and heroin selfadministration and also decreases food-maintained responding and suppresses locomotor activity at high doses. GABA B receptor-positive modulators may represent potentially improved therapeutic compounds because of their fewer side effects than receptor agonists. The present study investigated the effects of administration of the GABA B receptor-positive modulators 2,6-di- tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) and coadministration of the GABA B receptor-positive modulator N,NЈ-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) with the GABA B receptor agonist (3-amino-2[S]-hydroxypropyl)-methylphosphinic acid (CGP44532) on nicotineand food-maintained responding under fixed ratio (FR) 5 and progressive ratio schedules of reinforcement. Furthermore, the effects of BHF177 and CGP44532 on nicotine-induced enhancement of brain reward function were evaluated. The results indicated that administration of CGP7930 decreased nicotine selfadministration under an FR5 schedule. Administration of either GS39783 or CGP44532 selectively decreased nicotine selfadministration, whereas coadministration of these compounds had additive effects. BHF177 administration selectively decreased nicotine-but not food-maintained responding under FR5 and progressive ratio schedules. The nicotine-induced enhancement of brain reward function was blocked by BHF177 or CGP44532, although the highest doses of both compounds, particularly CGP44532, decreased brain reward function when administered alone, suggesting an additive, rather than interactive, effect. Overall, the present results indicate that GABA B receptor-positive modulators, similarly to GABA B receptor agonists, attenuated the reinforcing and reward-enhancing effects of nicotine, perhaps with higher selectivity than GABA B receptor agonists. Thus, GABA B receptor-positive modulators may be useful antismoking medications.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…GABA B Receptor Ligands and Other GABAergic Drugs. The clinically available and nonscheduled GABA B agonist baclofen only depresses ICSS, and similar effects have been obtained with other GABA B agonists, antagonists, and positive allosteric modulators (Fenton and Liebman, 1982;Macey et al, 2001;Slattery et al, 2005;Paterson et al, 2008;. Other drugs acting at GABA receptors have a more varied profile of effects.…”

Effects of the GABAB Receptor-Positive Modulators CGP7930 and rac-BHFF in Baclofen- and γ-Hydroxybutyrate-Discriminating Pigeons

“…In vivo results suggest positive GABA B receptor modulators to have anxiolyticand antidepressant-like properties in elevated-maze and forced-swimming tests, respectively (Cryan et al, 2004;Frankowska et al, 2007;Jacobson and Cryan, 2008). In addition, they reduce self-administration of alcohol (Orrù et al, 2005;Liang et al, 2006;Maccioni et al, 2008Maccioni et al, , 2009, cocaine , and nicotine (Mombereau et al, 2007;Paterson et al, 2008). Although these effects are thought to be mediated by positive modulation of GABA B receptors, such modulation has been examined almost exclusively in vitro.…”

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

“…At the same time, GS39783 completely counteracted nicotine-induced accumulation of ⌬FosB in the nucleus accumbens of these animals. Paterson et al (2008) reported that positive GABA B receptor modulators, similarly to agonists, attenuated the reinforcing and reward-enhancing effects of nicotine. It is noteworthy that in these studies, the effects of GS39783 were observed in a dose range that exactly matched active doses producing the biochemical effects in in vivo microdialysis experiments (Gjoni et al, 2006).…”