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

• Published in: The Journal of neuroscience Vol. 22; no. 22; pp. 10039 - 10045
• Main Authors: Rocha, Beatriz A, Goulding, Evan H, O'Dell, Laura E, Mead, Andy N, Coufal, Nicole G, Parsons, Loren H, Tecott, Laurence H
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 15.11.2002; Society for Neuroscience
• Subjects: Animals; Behavior, Animal - drug effects; Brain Chemistry - drug effects; Cocaine - administration & dosage; Cocaine - pharmacology; Cocaine-Related Disorders - genetics; Cocaine-Related Disorders - metabolism; Conditioning, Operant - drug effects; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Disease Models, Animal; Dopamine - analysis; Dopamine - metabolism; Drug Resistance - genetics; Exploratory Behavior - drug effects; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microdialysis; Motor Activity - drug effects; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin - deficiency; Receptors, Serotonin - genetics; Reinforcement (Psychology); Self Administration
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.22-22-10039.2002

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.