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The Journal of Neuroscience, November 15, 2002, 22(22):10039-10045

Enhanced Locomotor, Reinforcing, and Neurochemical Effects of Cocaine in Serotonin 5-Hydroxytryptamine 2C Receptor Mutant Mice

Beatriz A. Rocha^{1, 2, *}, Evan H. Goulding^{3, *}, Laura E. O'Dell⁴, Andy N. Mead¹, Nicole G. Coufal³, Loren H. Parsons⁴, and Laurence H. Tecott³

¹ National Institute on Drug Abuse/Intramural Research Program, Baltimore, Maryland 21224, ² University of Maryland/Maryland Psychiatric Research Center, Baltimore, Maryland 21247, ³ Department of Psychiatry and Center for Neurobiology and Psychiatry, University of California, San Francisco, San Francisco, California 94143-0984, and ⁴ Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037

Brain serotonin [5-hydroxytryptamine (5-HT)] systems substantially influence the effects of cocaine; however, the contributions of individual 5-HT receptor subtypes to the regulation of cocaine responses are unclear. A line of mutant mice devoid of 5-HT2C receptors was used to examine the contribution of this receptor subtype to the serotonergic modulation of cocaine responses. Mutants display enhanced exploration of a novel environment and increased sensitivity to the locomotor stimulant effects of cocaine. In an operant intravenous self-administration model under a progressive ratio schedule of reinforcement, mutants display elevated levels of lever pressing for cocaine injections, indicating that the drug is more reinforcing in these mice. Moreover, mutants exhibit enhanced cocaine-induced elevations of dopamine (DA) levels in the nucleus accumbens, a brain region implicated in the stimulant and rewarding properties of cocaine. In contrast, phenotypic differences in dorsal striatal DA levels were not produced by cocaine treatment. These findings strongly implicate 5-HT2C receptors in the serotonergic suppression of DA-mediated behavioral responses to cocaine and as a potential therapeutic target for cocaine abuse.

Key words: cocaine; serotonin; serotonin 2c receptor; behavior; reinforcement; mice

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^* B.A.R. and E.H.G. contributed equally to this work.

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Copyright © 2002 Society for Neuroscience  0270-6474/02/222210039-07$05.00/0

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