Altered nicotine reward-associated behavior following α4 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: United States Public Library of Science 01-07-2017; Public Library of Science (PLoS)
• Subjects: Acetylcholine receptors (nicotinic); Animals; Behavior; Biology and Life Sciences; Brain; Cholinergic transmission; Circuits; Cocaine; Conditioning; Dopamine; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - physiology; Drug abuse; Drug dosages; Drug self-administration; Drug-Seeking Behavior; Drugs; Female; Gene Deletion; Liquid oxygen; Locomotor activity; Long-Term Potentiation; Male; Medicine; Medicine and Health Sciences; Mesencephalon; Mice; Mice, Inbred C57BL; Neurons; Nicotine; Nicotine - metabolism; Pharmaceutical sciences; Pharmacology; Physical Sciences; Place preference conditioning; Potentiation; Receptors; Receptors, Nicotinic - genetics; Receptors, Nicotinic - metabolism; Reinforcement; Research and Analysis Methods; Reward; Rodents; Studies; Synaptic Potentials; Ventral Tegmental Area - metabolism; Ventral Tegmental Area - physiology; Ventral tegmentum; Chicago Illinois; Indiana; United States > US; Illinois
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0182142

Nicotinic acetylcholine receptors containing α4 subunits (α4β2* 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 α4 nAChR subunits with behavioral and and electrophysiological measures of nicotine sensitivity. A viral-mediated Cre/lox approach allowed us to delete α4 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 α4 subunits in vMB consumed significantly more nicotine at the highest offered nicotine concentration (200 μg/mL) compared to control mice. Deletion of α4 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 α4 in vMB. Immunostaining verified that α4 subunits were deleted from both dopamine and non-dopamine neurons in the ventral tegmental area (VTA). These results reveal that attenuation of α4* 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.