Abstract
Antagonists of the serotonin (5-hydroxytryptamine; 5-HT) type 2C receptor (5-HT2CR) are being considered as potential pharmacotherapeutics for various affective disorders, but evidence suggests that these compounds enhance the effects of cocaine and related psychostimulants in rodents. However, the effects of selective 5-HT2CR antagonists have not been evaluated in nonhuman primates. The present studies used operant-behavioral and in vivo microdialysis techniques to assess the impact of 5-HT2CR antagonism on the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press on a fixed-interval schedule of stimulus termination, pretreatment with the highly selective 5-HT2CR antagonist 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride (SB 242084) (vehicle, 0.01–0.1 mg/kg) produced behavioral-stimulant effects alone and interacted with cocaine in an apparently additive manner. In monkeys trained to self-administer intravenous cocaine according to a second-order schedule of drug delivery, SB 242084 (vehicle, 0.03–0.1 mg/kg) modulated cocaine-induced reinstatement of previously extinguished responding and maintained self-administration behavior when substituted for cocaine availability. These studies are the first to assess the direct reinforcing effects of a 5-HT2CR-selective antagonist in any species. Finally, in vivo microdialysis studies revealed that pretreatment with SB 242084 (0.1 mg/kg) modulated cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus, of awake subjects. Taken together, the results suggest that SB 242084 exhibits a behavioral profile that is qualitatively similar to other psychostimulants, although its efficacy is modest compared with cocaine. The observed interactions with cocaine and the substitution for cocaine self-administration may be indicative of some degree of abuse potential in humans.
Footnotes
These studies were funded by the National Institutes of Health National Institute on Drug Abuse [Grants DA12514, DA00517, F31DA026262]; the National Institutes of Health National Center for Research Resources [Grant P51RR165]; the National Institutes of Health Office of the Director Office of Research Infrastructure Program [Grant OD P51OD11132]; and the American Recovery and Reinvestment Act of 2009 [Grant F31DA026262].
These studies represent partial fulfillment of D.F.M.'s Ph.D. dissertation research at Emory University.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- 5-HT
- 5-hydroxytryptamine (serotonin)
- 5-HT2CR
- 5-HT2C receptor
- ANOVA
- analysis of variance
- DA
- dopamine
- FI
- fixed interval
- FR20
- fixed-ratio 20
- NAc
- nucleus accumbens
- SB 242084
- 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride
- veh
- vehicle
- VTA
- ventral tegmental area.
- Received April 2, 2012.
- Accepted June 7, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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