Abstract

Tobacco smoking is partly attributed to the addictive properties of nicotine and constitutes a worldwide drug abuse problem with serious health effects. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the modulation of brain reward and cognitive processes. Acute or chronic administration of γ-aminobutyric acid B (GABAB) receptor agonists and/or positive allosteric modulators (PAMs) decreases self-administration of various drugs of abuse and inhibits cue-induced reinstatement of drug-seeking behavior. Impulsivity, a tendency to pursue rewarding stimuli without consideration for potential harmful/negative consequences, is strongly associated with habitual tobacco smoking. High impulsivity levels may be a risk factor for nicotine dependence, leading to its initiation and maintenance. Further, numerous studies have shown that γ-aminobutyric acid B (GABAB) receptor antagonists show cognitive enhancing effects. Little is known about the effects of GABAB receptor agonists or positive allosteric modulators (PAMs) in cognitive processes (e.g., attentional performance) and impulsivity/compulsivity. GABAB receptor PAMs may be potentially improved therapeutic compounds for the treatment of disorders, such as drug dependence, or cognitive impairment, than GABAB receptor agonists due to fewer adverse side-effects. In different experiments, BHF177 , a GABAB receptor PAM , decreased both the reinforcing and motivational effects of nicotine without affecting motivation for natural reinforcers, such as food, using the nicotine self-administration fixed-ratio 5 and progressive ratio procedures, respectively, both in rats from the general population as well as in high and low impulsive rats in a similar manner. Interestingly, BHF177 had a larger magnitude of effect in low impulsive rats at the highest dose tested. High/low impulsivity animals were selected based on the poor inhibitory control aspect of impulsivity, as assessed in the 5-choice serial reaction time task (5-CSRTT). Further, BHF177 dose-dependently and selectively blocked cue-induced reinstatement of nicotine seeking, a putative animal model of relapse in humans, and not food seeking, while chronic treatment with BHF177 decreased nicotine self-administration with only small tolerance developed in the general population. Further, BHF177 showed significantly fewer adverse effects than the GABAB receptor agonist CGP44532 in the 5-CSRTT. Thus, BHF177 , or other similar GABAB receptor PAMs, could be useful therapeutics for the treatment of different aspects of nicotine dependence, by assisting both in smoking cessation by decreasing the reinforcing effects of nicotine, as well as in preventing relapse to smoking in the general population and/or in both high and low impulsive individuals.