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

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 nAC...

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Bibliographic Details
Published in:PloS one 2017-07, Vol.12 (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: Article
Language:English
Subjects:
Genetic aspects
Mesencephalon
Neurons
Nicotinic receptors
Physiological aspects
Psychological aspects
Online Access:Get full text
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0182142