Attenuation of nicotine taking and seeking in rats by the stoichiometry-selective alpha4beta2 nicotinic acetylcholine receptor positive allosteric modulator NS9283

The rewarding and reinforcing effects of nicotine are produced, in large part, by activation of neuronal alpha 4 beta 2* nicotinic acetylcholine receptors (nAChRs), pentameric protein complexes comprised of different stoichiometries of alpha 4 and beta 2 subunits. However, little is known about the functional role of distinct subtypes of alpha 4 beta 2* nAChRs in nicotine addiction. NS9283 represents a new class of stoichiometry-selective positive allosteric modulators (PAMs) that selectively bind to alpha 4 beta 2 nAChRs containing three alpha 4 and two beta 2 subunits (3(alpha 4)2(beta 2) nAChRs). The present experiments were designed to determine the effects of NS9283 on nicotine self-administration and the reinstatement of nicotine-seeking behavior, an animal model of smoking relapse. Parallel studies of sucrose self-administration and reinstatement were conducted in separate cohorts of rats to determine if the effects of NS9283 generalized to other reinforced behaviors. Acute and repeated administration of NS9283 dose-dependently reduced nicotine self-administration and reinstatement in male Sprague Dawley rats. These effects were reinforcer specific as no effects of NS9283 on sucrose self-administration and reinstatement were noted. NS9283 also failed to substitute for nicotine in supporting self-administration behavior suggesting that, at the doses tested, NS9283 alone is not reinforcing. Taken together, these results provide compelling evidence that stoichiometry-selective PAMs of 3(alpha 4)2(beta 2) nAChRs attenuate nicotine taking and seeking in rats and suggest that targeting 3(alpha 4)2(beta 2) nAChRs may represent a promising therapeutic strategy for preventing smoking relapse.