title: GABAB receptor-positive modulation-induced blockade of the rewarding properties of nicotine is associated with a reduction in nucleus accumbens DeltaFosB 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 GABAB receptor allosteric-positive modulator, GS39783, was characterized. There are no investigations to date on the effects of GABAB 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 DeltaFosB, in the striatal complex that contribute to the manifestation of dependence. There was a significant accumulation of DeltaFosB 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 nicotine-induced 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 GABAB receptor-positive modulators.
authors.affiliation: Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Cedric
authors.initials: C
authors.lastname: Mombereau
authors.forename: Loic
authors.initials: L
authors.lastname: Lhuillier
authors.forename: Klemens
authors.initials: K
authors.lastname: Kaupmann
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003216:Conditioning, Operant / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D009538:Nicotine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000502:physiology*; D012054:Reinforcement, Psychology; D012201:Reward
chemical_list: D003517:Cyclopentanes; D018757:GABA Modulators; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; D018722:Nicotinic Agonists; D016760:Proto-Oncogene Proteins c-fos; D011743:Pyrimidines; D018080:Receptors, GABA-B; D009538:Nicotine