Abstract
The serotonin2C (5-hydroxytryptamine2C; 5-HT2C) receptor (5-HT2CR) is found in abundance in dopamine (DA) mesocorticolimbic pathways and is one of the important target proteins that modulates the behavioral effects of cocaine. In the present study, the hypothesis was tested that the 5-HT2CR in the prefrontal cortex (PFC) may control either spontaneous or cocaine-evoked locomotor activity as well as the discriminative stimulus properties of cocaine. In male Sprague-Dawley rats implanted with bilateral cannulae aimed at the PFC, local microinjections of the preferential 5-HT2CR agonist 6-chloro-2-(1-piperazinyl)pyrazine hydrochloride (MK 212) (0.05–0.5 μg/side) did not alter spontaneous activity, but dose-dependently decreased horizontal hyperactivity evoked by cocaine (10 mg/kg i.p.). Given alone, the selective 5-HT2CR antagonist 8-[5-(2,4-dimethoxy-5-(4-trifluorophenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazo-spiro[4.5]decane-2,4-dione hydrochloride (RS 102221) (5 μg/side) increased basal locomotor activity of rats expressed in the vertical plane. Microinjections of RS 102221 (5 μg/side, but not 0.15–1.5 μg/side) significantly enhanced the horizontal activity induced by cocaine (10 mg/kg). In rats trained to discriminate cocaine (10 mg/kg i.p.) from saline (i.p.) in a two-lever, water-reinforced fixed ratio 20 task, intra-PFC microinjections of MK 212 (0.05 and 0.5 μg/side) did not substitute for cocaine, but attenuated the stimulus effects of cocaine. However, intra-PFC microinjections of RS 102221 (1.5 and 5 μg/side) evoked 13 and 40% cocaine-lever responding when tested alone and enhanced the recognition of cocaine. These data indicate that the PFC is a brain site at which the 5-HT2CR exerts an inhibitory control over the hyperactive and discriminative stimulus effects of cocaine known to be dependent upon activation of the DA mesoaccumbens circuit.
Footnotes
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This research was supported by the U.S.-Poland Joint Commission Maria Sklodowska-Curie Fund (M.F. and K.A.C.); a National Science Foundation-North Atlantic Treaty Organization Visiting Scientist Fellowship (M.F.); and by National Institute on Drug Abuse Grants DA 05708 and DA 06511 (K.A.C.).
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Portions of these data were presented at the 62nd annual meeting of the College on Problems of Drug Dependence (San Juan, Puerto Rico, 2000) and at the XXIInd Collegium Internationale Neuro-Psychopharmacologicum Congress (Brussels, Belgium, 2000).
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DOI: 10.1124/jpet.102.045716.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine (serotonin); 5-HT2CR, 5-HT2C receptor; DA, dopamine; PFC, prefrontal cortex; MK 212, 6-chloro-2-(1-piperazinyl)pyrazine hydrochloride; RS 102221, 8-[5-(2,4-dimethoxy-5-(4-trifluorophenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazo-spiro[4.5]decane-2,4-dione hydrochloride; VTA, ventral tegmental area; NAc, nucleus accumbens; FR, fixed ratio; mCPP, m-chlorophenylpiperazine; RO 60-0175, (S)-2-(6-chloro-5-fluroindol-1-yl)-1-methylethylamine fumarate; SB 242084, 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride; SDZ SER 082, (+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7BC)(2,6)naphthyridine.
- Received October 21, 2002.
- Accepted April 18, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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