RT Journal Article SR Electronic T1 Nicotine Modifies Corticostriatal Plasticity and Amphetamine Rewarding Behaviors in Mice JF eneuro JO eneuro FD Society for Neuroscience SP ENEURO.0095-15.2015 DO 10.1523/ENEURO.0095-15.2015 VO 3 IS 1 A1 Granville P. Storey A1 Gabriel Gonzalez-Fernandez A1 Ian J. Bamford A1 Matthew Hur A1 Jonathan W. McKinley A1 Lauren Heimbigner A1 Ani Minasyan A1 Wendy M. Walwyn A1 Nigel S. Bamford YR 2016 UL http://www.eneuro.org/content/3/1/ENEURO.0095-15.2015.abstract AB Corticostriatal signaling participates in sensitized responses to drugs of abuse, where short-term increases in dopamine availability provoke persistent, yet reversible, changes in glutamate release. Prior studies in mice show that amphetamine withdrawal promotes a chronic presynaptic depression in glutamate release, whereas an amphetamine challenge reverses this depression by potentiating corticostriatal activity in direct pathway medium spiny neurons. This synaptic plasticity promotes corticostriatal activity and locomotor sensitization through upstream changes in the activity of tonically active cholinergic interneurons (ChIs). We used a model of operant drug-taking behaviors, in which mice self-administered amphetamine through an in-dwelling catheter. Mice acquired amphetamine self-administration under fixed and increasing schedules of reinforcement. Following a period of abstinence, we determined whether nicotinic acetylcholine receptors modified drug-seeking behavior and associated alterations in ChI firing and corticostriatal activity. Mice responding to conditioned reinforcement showed reduced ChI and corticostriatal activity ex vivo, which paradoxically increased following an amphetamine challenge. Nicotine, in a concentration that increases Ca2+ influx and desensitizes α4β2*-type nicotinic receptors, reduced amphetamine-seeking behaviors following abstinence and amphetamine-induced locomotor sensitization. Nicotine blocked the depression of ChI firing and corticostriatal activity and the potentiating response to an amphetamine challenge. Together, these results demonstrate that nicotine reduces reward-associated behaviors following repeated amphetamine and modifies the changes in ChIs firing and corticostriatal activity. By returning glutamatergic activity in amphetamine self-administering mice to a more stable and normalized state, nicotine limits the depression of striatal activity in withdrawal and the increase in activity following abstinence and a subsequent drug challenge.