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 litt ermates to characterize the 5-HT2 receptor using the 5-HT2 agonists (+/-)-2 -dimethoxy-4-iodoamphetamine hydrochloride (DOI) and 1-(3-chlorophenyl)pipe razine (mCPP) applied locally in the orbitofrontal cortex (OFC) and head of the caudate nucleus. Microiontophoretically-applied 5-HT, DOI and mCPP ind uced 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 c urrent used. In contrast, there was a reduced ability of mCPP to inhibit fi ring activity in the OFC when ejected at 10 nA. Unexpectedly, there was a s mall but significant increase in mCPP-induced inhibition in the caudate nuc leus of mutant mice. In the OFC, the 5-HT2A antagonist MDL 100907 (2 mg/kg, i.p.) significantly antag onized the effect of both DOI and mCPP. In contr ast, the non-selective 5-HT antagonist clozapine (10 mg/kg, i.p.) significa ntly antagonized only mCPP in the wild-type mice. However, neither MDL 1009 07 nor clozapine antagonized DOI or mCPP in the caudate nucleus. Finally, i t required significantly less quisqualate to activate neurons in the 5-HT2C receptor mutants than in the wild-type mice, suggesting that 5-HT2C recept ors serve a tonic inhibitory role in membrane excitability. The present res ults indicate that the inhibitory action of DOI is predominantly mediated b y 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 ill the caudate nucleus through an atypical 5-HT2 receptor yet to be characterized.