Differential regulation of alcohol taking and seeking by antagonism at α4β2 and α3β4 nAChRs

Alcoholism is a serious public health problem throughout the world. Current pharmacotherapies for the treatment of this disorder are poorly effective. Preclinical and clinical findings point to nicotinic acetylcholine receptors (nAChRs) as a promising target for the development of novel and effective medications. Assuage Pharmaceuticals, in collaboration with Torrey Pines Institute for Molecular Studies, has discovered a new class of potent and selective alpha 4 beta 2 nAChR antagonists. Here, it was hypothesized that alpha 4 beta 2 nAChR antagonism is a viable approach for treatment of alcohol use disorders. When tested in rats, one lead compound, AP-202, attenuated both operant alcohol and nicotine self-administration in a paradigm in which the two reinforcers were concurrently available. The conotoxin TP2212-59, a selective alpha 3 beta 4 nAChR antagonist, was only effective in reducing nicotine self-administration. AP-202 also reduced alcohol but not food responding when alcohol was presented as the only reinforcer, whereas the commercially available alpha 4 beta 2 nAChR antagonist dihydro-beta-erythroidine failed to alter alcohol self-administration. AP-202 did not block relapse-like behavior induced by previously alcohol-associated stimuli or yohimbine stress. In a reinstatement paradigm, in which alcohol seeking was triggered by a nicotine challenge, a behavior successfully inhibited by the nonselective nAChR antagonist mecamylamine, AP-202 was not effective, while pretreatment with TP2212-59 abolished nicotine-induced reinstatement of alcohol seeking. These findings suggest differential roles for alpha 4 beta 2 and alpha 3 beta 4 nAChR on alcohol taking and seeking with selective blockade of alpha 4 beta 2 nAChR being more implicated in modulating alcohol taking while selective blockade of alpha 3 beta 4 nAChR is involved in nicotine-induced alcohol seeking.