Impact of serotonin 2C receptor null mutation on physiology and behavior associated with nigrostriatal dopamine pathway function.
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(2C)R) 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(2C)Rs produces marked alterations in the activity and functional output of this pathway. 5-HT(2C)R 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 D(1) receptor agonist SKF 81297. Differences in DSt D(1) or D(2) 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(2C)Rs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt.
Abdallah
Luna
L
Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA.
Bonasera
Stephen J
SJ
Hopf
F Woodward
FW
O'Dell
Laura
L
Giorgetti
Marco
M
Jongsma
Minke
M
Carra
Scott
S
Pierucci
Massimo
M
Di Giovanni
Giuseppe
G
Esposito
Ennio
E
Parsons
Loren H
LH
Bonci
Antonello
A
Tecott
Laurence H
LH
D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000008:administration & dosage / Q000494:pharmacology; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004594:Electrophysiology; D006120:Grooming / Q000502:physiology; D008124:Locomotion / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009434:Neural Pathways / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D044405:Receptor, Serotonin, 5-HT2C / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013239:Stereotyped Behavior / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D001552:Benzazepines; D015259:Dopamine Agents; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D044405:Receptor, Serotonin, 5-HT2C; C067113:SK&F 81297; C043425:vanoxerine; D000661:Amphetamine; D004298:Dopamine