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 D(2/3) 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 2mg/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 2mg/kg/day varenicline or vehicle and survival of the effects of varenicline on DRD2/3 availability up to 2 weeks after treatment discontinuation using (123)I-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 2mg/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 2mg/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.
Amsterdam Institute for Addiction Research and Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. C.L.Crunelle@amc.uva.nl
Cleo L
CL
Crunelle
Sybille
S
Schulz
Kora
K
de Bruin
Michelle L
ML
Miller
Wim
W
van den Brink
Jan
J
Booij
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000502:physiology*; D013997:Time Factors; D014029:Tobacco Use Disorder / Q000188:drug therapy; D000068580:Varenicline
D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D000068580:Varenicline