GABA_B Receptor-Positive Modulation-Induced Blockade of the Rewarding Properties of Nicotine Is Associated with a Reduction in Nucleus Accumbens ΔFosB Accumulation

Abstract

There is an increasing demand for a novel non-nicotinic, nondopaminergic therapeutic approach to nicotine addiction. GABAergic mechanisms have been implicated in drug dependence. Recently, a novel GABA B receptor allosteric-positive modulator, GS39783, was characterized. There are no investigations to date on the effects of GABA B receptor-positive modulators in animal models of nicotine reinforcement. Conditioned place preference (CPP) paradigms are based on the principle that animals, like humans, would learn to seek environmental stimuli that have been previously associated with rewarding events. Here we show that nicotine (0.06 mg/kg s.c.) induced a robust CPP response. Furthermore, GS39783 (30 -100 mg/kg p.o.) during the conditioning phase blocked the rewarding effects of nicotine in the CPP paradigm in rats. However, GS39783 did not significantly alter the CPP effects of nicotine when given only immediately before the CPP test. A growing body of evidence suggests that repeated administration of drugs of abuse induced long-term molecular changes in brain plasticity, most notably an accumulation of ⌬FosB, in the striatal complex that contribute to the manifestation of dependence. There was a significant accumulation of ⌬FosB in the nucleus accumbens, but not in the dorsal striatum, of rats treated daily for 5 days with nicotine (0.06 mg/kg i.p.). GS39783 completely (30 -100 mg/kg p.o.) counteracted these nicotineinduced molecular adaptations when given before the CPP acquisition phase but not when administered immediately before the test phase. Taken together, the behavioral and molecular changes induced by nicotine occur in concert and are concomitantly amenable to reversal by GABA B receptor-positive modulators.

The "Stop" and "Go" of Nicotine Dependence: Role of GABA and Glutamate

“…(Panel B is from Vlachou et al 2011b;reprinted, with permission, from Springer # 2011. ) of nicotine-induced CPP (Mombereau et al 2007). These data support a role for GABA B receptors in nicotine-induced reward and conditioned behavioral responses.…”

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.…”

GABAB Receptor-Positive Modulators: Enhancement of GABAB Receptor Agonist Effects In Vivo

“…In addition, positive modulators of GABA B receptors 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 all of these effects generally are thought to be mediated by positive modulation of GABA B receptors, to date such modulation has been examined almost exclusively in vitro.…”