Altered nicotine reward-associated behavior following α4 nAChR subunit deletion in ventral midbrain

PLoS One. 2017 Jul 31;12(7):e0182142. doi: 10.1371/journal.pone.0182142. eCollection 2017.


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.

MeSH terms

  • Animals
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / physiology
  • Drug-Seeking Behavior
  • Female
  • Gene Deletion
  • Long-Term Potentiation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nicotine / metabolism*
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism*
  • Reward*
  • Synaptic Potentials
  • Ventral Tegmental Area / metabolism*
  • Ventral Tegmental Area / physiology


  • Receptors, Nicotinic
  • nicotinic acetylcholine receptor alpha4 subunit
  • Nicotine