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The Journal of Neuroscience, June 24, 2009, 29(25):8156-8165; doi:10.1523/JNEUROSCI.3905-08.2009

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Behavioral/Systems/Cognitive
Impact of Serotonin 2C Receptor Null Mutation on Physiology and Behavior Associated with Nigrostriatal Dopamine Pathway Function

Luna Abdallah,^1 * Stephen J. Bonasera,^2 * F. Woodward Hopf,⁸ Laura O'Dell,³ Marco Giorgetti,⁵ Minke Jongsma,⁴ Scott Carra,¹ Massimo Pierucci,⁶ Giuseppe Di Giovanni,⁶ Ennio Esposito,⁶ Loren H. Parsons,⁷ Antonello Bonci,⁸ and Laurence H. Tecott¹

¹Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, ²Division of Geriatrics, Department of Medicine, University of California, San Francisco, San Francisco, California 94143, ³Department of Psychology, University of Texas, El Paso, El Paso, Texas 79968, ⁴Brains On-Line, San Francisco, California 94158, ⁵Division of Pharmacology, Amgen, South San Francisco, California 94080, ⁶Istituto Di Ricerche Farmacologiche "Mario Negri," Consorzio "Mario Negri Sud," 66030 Santa Maria Imbaro, Chieti, Italy, ⁷Committee on the Neurobiology of Addictive Disorders, SP30–2120, The Scripps Research Institute, La Jolla, California 92037, and ⁸Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, California 94608

Correspondence should be addressed to Laurence H. Tecott at the above address. Email: larry.tecott{at}ucsf.edu

The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT_2CR) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT_2CRs produces marked alterations in the activity and functional output of this pathway. 5-HT_2CR mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of D-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D₁ receptor agonist SKF 81297. Differences in DSt D₁ or D₂ receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT_2CRs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt.

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Received Aug. 15, 2008; revised Dec. 19, 2008; accepted Jan. 12, 2009.

Correspondence should be addressed to Laurence H. Tecott at the above address. Email: larry.tecott{at}ucsf.edu

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