Altered nicotine reward-associated behavior following [alpha]4 nAChR subunit deletion in ventral midbrain

• Published in: PloS one Vol. 12; no. 7; p. e0182142
• Main Authors: Peng, Can, Engle, Staci E, Yan, Yijin, Weera, Marcus M, Berry, Jennifer N, Arvin, Matthew C, Zhao, Guiqing, McIntosh, J. Michael, Chester, Julia A, Drenan, Ryan M
• Format: Journal Article
• Language: English
• Published: Public Library of Science 31-07-2017
• Subjects: Genetic aspects; Mesencephalon; Neurons; Nicotinic receptors; Physiological aspects; Psychological aspects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0182142

Nicotinic acetylcholine receptors containing [alpha]4 subunits ([alpha]4[beta]2* nAChRs) are critical for nicotinic cholinergic transmission and the addictive action of nicotine. To identify specific activities of these receptors in the adult mouse brain, we coupled targeted deletion of [alpha]4 nAChR subunits with behavioral and and electrophysiological measures of nicotine sensitivity. A viral-mediated Cre/lox approach allowed us to delete [alpha]4 from ventral midbrain (vMB) neurons. We used two behavioral assays commonly used to assess the motivational effects of drugs of abuse: home-cage oral self-administration, and place conditioning. Mice lacking [alpha]4 subunits in vMB consumed significantly more nicotine at the highest offered nicotine concentration (200 [mu]g/mL) compared to control mice. Deletion of [alpha]4 subunits in vMB blocked nicotine-induced conditioned place preference (CPP) without affecting locomotor activity. Acetylcholine-evoked currents as well as nicotine-mediated increases in synaptic potentiation were reduced in mice lacking [alpha]4 in vMB. Immunostaining verified that [alpha]4 subunits were deleted from both dopamine and non-dopamine neurons in the ventral tegmental area (VTA). These results reveal that attenuation of [alpha]4* nAChR function in reward-related brain circuitry of adult animals may increase nicotine intake by enhancing the rewarding effects and/or reducing the aversive effects of nicotine.