In vivo electrophysiological examination of 5-HT2 responses in 5-HT2C receptor mutant mice.
The present study used 5-HT2C receptor mutant mice and their wild-type littermates to characterize the 5-HT2 receptor using the 5-HT2 agonists (+/-)-2-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and 1-(3-chlorophenyl)piperazine (mCPP) applied locally in the orbitofrontal cortex (OFC) and head of the caudate nucleus. Microiontophoretically-applied 5-HT, DOI and mCPP induced current-dependent inhibition of neuronal firing activity in both brain regions. There was no difference between 5-HT2C receptor mutants and wild-type mice in the ability of 5-HT or DOI to inhibit neuronal firing at any current used. In contrast, there was a reduced ability of mCPP to inhibit firing activity in the OFC when ejected at 10 nA. Unexpectedly, there was a small but significant increase in mCPP-induced inhibition in the caudate nucleus of mutant mice. In the OFC, the 5-HT2A antagonist MDL 100907 (2 mg/kg, i.p.) significantly antagonized the effect of both DOI and mCPP. In contrast, the non-selective 5-HT antagonist clozapine (10 mg/kg, i.p.) significantly antagonized only mCPP in the wild-type mice. However, neither MDL 100907 nor clozapine antagonized DOI or mCPP in the caudate nucleus. Finally, it required significantly less quisqualate to activate neurons in the 5-HT2C receptor mutants than in the wild-type mice, suggesting that 5-HT2C receptors serve a tonic inhibitory role in membrane excitability. The present results indicate that the inhibitory action of DOI is predominantly mediated by the 5-HT2A receptor in the OFC. mCPP, when applied locally, inhibits OFC firing activity by acting on both 5-HT2A and 5-HT2C receptors. However, DOI and mCPP might be acting in the caudate nucleus through an atypical 5-HT2 receptor yet to be characterized.
Rueter
L E
LE
Neurobiological Psychiatry Unit, McGill University, Montréal, Canada.
Tecott
L H
LH
Blier
P
P
D000704:Analysis of Variance; D000818:Animals; D002421:Caudate Nucleus / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D004594:Electrophysiology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009474:Neurons / Q000502:physiology; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000235:genetics / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists