Abstract
Accumulating evidence indicates that the serotonin system modulates the behavioral and neurochemical effects of cocaine, but the receptor subtypes mediating these effects remain unknown. Recent studies have demonstrated that pharmacological activation of the serotonin 2C receptor (5-HT2CR) attenuates the behavioral and neurochemical effects of cocaine in rodents, but such compounds have not been systematically evaluated in nonhuman primates. The present experiments sought to determine the impact of pretreatment with the preferential 5-HT2CR agonist m-chlorophenylpiperazine (mCPP) and the selective 5-HT2CR agonist Ro 60-0175 [(α-S)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine fumarate] on the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press according to a 300-s fixed-interval schedule of stimulus termination, pretreatment with either 5-HT2CR agonist dose-dependently and insurmountably attenuated the behavioral stimulant effects of cocaine. In subjects trained to self-administer cocaine, both compounds dose-dependently and insurmountably attenuated cocaine-induced reinstatement of previously extinguished responding in an antagonist-reversible manner, and the selective agonist Ro 60-0175 also attenuated the reinforcing effects of cocaine during ongoing cocaine self-administration. It is noteworthy that the selective agonist Ro 60-0175 exhibited behavioral specificity because it did not significantly alter nondrug-maintained responding. Finally, in vivo microdialysis studies revealed that pretreatment with Ro 60-0175 caused a reduction of cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus. These results suggest that 5-HT2CR agonists functionally antagonize the behavioral effects of cocaine in nonhuman primates, possibly via a selective modulation of cocaine-induced dopamine increases within the mesolimbic dopamine system and may therefore represent a novel class of pharmacotherapeutics for the treatment of cocaine abuse.
Footnotes
These studies were funded by the National Institutes of Health National Institute on Drug Abuse [Grants DA12514, DA00517, F31-DA026262]; the National Institutes of Health National Center for Research Resources [Grant RR00165]; 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.
Preliminary findings from these experiments were presented previously: Manvich DF and Howell LL (2011) Cocaine-induced reinstatement is differentially modulated by agonism and antagonism of the serotonin 5-HT2C receptor in nonhuman primates, at the American Society for Pharmacology and Experimental Therapeutics meeting; 2011 April 9–13; Washington, DC. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD. Manvich DF and Howell LL (2010) m-Chlorophenylpiperazine (mCPP) attenuates the behavioral-stimulant effects of cocaine via activation of the 5-HT2C receptor in nonhuman primates, at the American Society for Pharmacology and Experimental Therapeutics meeting; 2010 April 24–28; Anaheim, CA. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- DA
- dopamine
- 5-HT
- 5-hydroxytryptamine
- 5-HT2CR
- 5-HT2C receptor
- ANOVA
- analysis of variance
- mCPP
- m-chlorophenylpiperazine
- NAc
- nucleus accumbens
- VTA
- ventral tegmental area
- veh
- vehicle
- FR20
- fixed-ratio 20
- aCSF
- artificial cerebrospinal fluid
- Ro 60-0175
- (α-S)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine fumarate
- SB 242084
- 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride.
- Received August 15, 2011.
- Accepted February 9, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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