Nicotine Modifies Corticostriatal Plasticity and Amphetamine Rewarding Behaviors in Mice

Abstract

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.

Acute and chronic modulation of striatal endocannabinoid‐mediated plasticity by nicotine

“…This hypothesis is also supported by the data presented here showing that nicotine exposure was insufficient to facilitate eCB-LTD in slices pre-treated with dopamine D2 agonist or mAChR antagonist. Importantly, the firing frequency of striatal cholinergic interneurons has been shown to be reduced following nicotine administration ex vivo (Storey et al 2016). Nicotine-induced suppression of cholinergic activity could thus reduce mAChR activation, thereby relieving the break on L-type calcium channels to allow postsynaptic calcium to reach the threshold required for eCB production (Howe & Surmeier 1995;Wang et al 2006;Adermark & Lovinger 2007a).…”

Corticostriatal plasticity in the nucleus accumbens core

“…Mice were then sacrificed on WD 10 or WD 21 and acute sagittal slices encompassing the PFC and NAc core were prepared for electrophysiology (Figure a,b). Experiments in 4–8 week‐old C57B/6 mice allowed comparisons with prior work in the NAc core (Wang et al, ) while the experimental time points of WD 10 and WD 21 allowed comparisons with earlier work in SPNs from the dorsal striatum following withdrawal from contingent and non‐contingent use of psychostimulants (Bamford et al, ; Beutler et al, ; Storey et al, ; Wang et al, ). The passive cell membrane properties of SPNs from saline‐treated mice ( n = 13) were compared with those from amphetamine‐treated mice ( n = 26).…”

“…Since reinstatement of drug‐seeking behaviors can be generated by changes in glutamatergic activity within the NAc core (Baker et al, ; Bell, Duffy, & Kalivas, ; McFarland et al, ; Pierce, Bell, Duffy, & Kalivas, ) as well as within the dorsal striatum (Bamford et al, ; Storey et al, ; Wang et al, ), we tested whether an amphetamine challenge in withdrawal would reverse or block the synaptic depression observed in the NAc core. Mice were treated with saline or amphetamine for 5 days (Figure a).…”

“…Evidence suggests that amphetamine‐induced adaptations in glutamatergic signaling may underlie locomotor sensitization (Cornish, Duffy, & Kalivas, ; Ghasemzadeh, Permenter, Lake, Worley, & Kalivas, ; Knackstedt & Kalivas, ; Li et al, ; Storey et al, ; Wang et al, ). To investigate further, we treated mice with saline ( n = 8) or amphetamine ( n = 5) for five consecutive days and monitored their locomotor activity.…”

“…These experiments were performed in young adolescent mice and at time points that corresponded to our earlier work in the dorsal and ventral striatum (Bamford et al, ; Beutler et al, ; Storey et al, ; Wang et al, ). Limitations of the study include the use of young mice rather than older rats that have been used extensively to analyse the effects of contingent psychostimulant use but see (Storey et al, ). The electrophysiology and optical data were collected in the slice preparation and may differ from plasticity that occurs in vivo , therefore presenting an avenue for future research.…”