Dose-dependent and sustained effects of varenicline on dopamine D2/3 receptor availability in rats

Imaging studies in drug-dependent subjects show reduced striatal dopamine D2/3 receptor (DRD2/3) availability, and it is hypothesized that increasing DRD2/3 availability is a promising strategy to treat drug dependence. We recently showed that rats treated for two weeks with 2 mg/kg/day varenicline (a partial agonist at α4β2 nicotinic acetylcholine receptors) showed higher striatal DRD2/3 availability compared to control rats. The present study examined the effects of lower varenicline doses as well as the duration of the effect after treatment discontinuation. DRD2/3 availability in striatal areas was studied in 80 rats following two-week treatment with 0.5, 1 or 2 mg/kg/day varenicline or vehicle and survival of the effects of varenicline on DRD2/3 availability up to 2 weeks after treatment discontinuation using 123I-IBZM storage phosphor imaging. For all varenicline doses, varenicline treated rats showed a comparable significantly higher DRD2/3 availability in the ventral striatum of approximately 11% compared to control rats, while only the rats treated with 1 and 2 mg/kg/day dose showed significantly higher DRD2/3 availability in the dorsal striatum by 12.5% and 13.2% compared to control rats, respectively. Two weeks after discontinuation of the active treatment with 2 mg/kg/day varenicline, DRD2/3 binding in ventral, but not dorsal, striatum was still significantly higher (11.7%) compared to vehicle. Varenicline induces dose-dependent and sustained increases in striatal DRD2/3 in rats, particularly in the ventral striatum. These observations suggest that increased DRD2/3 availability may contribute to varenicline's efficacy for smoking cessation and show promise for varenicline as a treatment of other types of drug dependence.