Varenicline decreases ethanol intake and increases dopamine release via neuronal nicotinic acetylcholine receptors in the nucleus accumbens

Abstract

Background and PurposeVarenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*-containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline's effects on ethanol consumption.Experimental ApproachRats were trained to consume ethanol using the intermittent-access two-bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core-shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast-scan cyclic voltammetry (FSCV).Key ResultsMicroinfusion of varenicline into the NAc core and core-shell border, but not into the NAc shell or VTA, reduced ethanol intake following long-term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc.Conclusion and ImplicationsFollowing long-term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline's effects on ethanol consumption.

Varenicline Reduces Context-Induced Relapse to Alcohol-Seeking through Actions in the Nucleus Accumbens

“…Because varenicline is also a potent partial agonist of α4β2 nAChRs, our results corroborate the suggestion that α4β2 nAChRs in the VTA are not involved in cue-driven alcohol-seeking (Löf et al, 2007). Doses used in the present study (2 and 4 μg/0.3 μl/hemisphere) were higher than those employed in an earlier report in which intra-VTA varenicline (1 and 2 μg/0.5 μl/hemisphere) had no impact on oral alcohol intake (Feduccia et al, 2014). Future studies should test lower varenicline doses before ruling out the VTA as a neural target for the action of varenicline, as low varenicline doses sometimes produce effects that are not observed at high doses (Guillem and Peoples, 2010;Wouda et al, 2011).…”

“…However, varenicline in the NAc but not VTA reduced voluntary alcohol consumption in rats, highlighting a role for nAChRs in the NAc in alcohol reinforcement (Feduccia et al, 2014). As the present studies found that systemic varenicline reduced context-induced relapse to alcohol-seeking, we examined the effect of intra-NAc or intra-VTA varenicline on this behavior to determine the neural loci of varenicline's effects.…”

“…At 20-30 min before the relapse test in Context A, varenicline (0, 2 or 4 μg; 0.3 μl/hemisphere) was bilaterally microinfused into the VTA using a counterbalanced, within-subjects design (n = 18; doses based on Feduccia et al, 2014). Test 1 occurred after 18 PDT sessions in Context A and 8 extinction sessions in Context B.…”

“…At 20-30 min before the relapse test in Context A, varenicline (0 or 3.5 μg; 0.3 μl/hemisphere) was bilaterally microinfused into the NAc using a counterbalanced, withinsubjects design (n = 12; doses based on Feduccia et al, 2014). Published data show that varenicline (0.5, 1 or 2 μg; 0.5 μl/ hemisphere) in the NAc core-shell border, but not the NAc core or shell separately, reduced alcohol intake in the home cage (Feduccia et al, 2014).…”

“…Published data show that varenicline (0.5, 1 or 2 μg; 0.5 μl/ hemisphere) in the NAc core-shell border, but not the NAc core or shell separately, reduced alcohol intake in the home cage (Feduccia et al, 2014). We tested a higher varenicline dose because pilot data showed that 1 and 3 μg (0.3 μl/ hemisphere) doses in the NAc had only modest effects on port entry behavior.…”