5-HT(2A) and 5-HT(2C) receptor stimulation are differentially involved in the cortical dopamine efflux-Studied in 5-HT(2A) and 5-HT(2C) genetic mutant mice.

Both 5-HT(2A) and 5-HT(2C) receptors modulate cortical dopamine efflux, but in opposite directions. We have now compared the ability of the three 5-HT(2A/2C) receptor agonists, DOI (R(-)-2,5-dimethoxy-4-iodoamphetamine), mCPP (meta-chlorophenylpiperazine) and MK-212 (6-Chloro-2-(piperazinyl) pyrazine), to modulate cortical dopamine efflux in 5-HT(2A) and 5-HT(2C) genetic mutant mice. In the 5-HT(2A) mice, the preferential 5-HT(2A) receptor agonist DOI (2.5mg/kg, s.c.) induced a slight but significant increase in cortical dopamine efflux only in the wild type (WT) mice; MK-212 (2.5mg/kg) reduced dopamine efflux in both WT and receptor knockout (KO) mice; moreover, MCPP, 2.5mg/kg, had no effect in either types. In 5-HT(2C) mice, DOI increased dopamine efflux in both types; while MK-212 decreased dopamine efflux in the WT, but not the receptor KO mice. These results provide new evidence that 5-HT(2A) receptor stimulation enhances and 5-HT(2C) receptor stimulation inhibits cortical dopamine efflux, and suggest the effects of DOI, MK-212 and mCPP on the cortical dopamine efflux are due to their different abilities on 5-HT(2A) and 5-HT(2C) receptors stimulation. Of these three agents, only DOI, the more selective 5-HT(2A) receptor agonist, is hallucinogenic. The absence of hallucinations with mCPP may be due to its relatively more potent 5-HT(2C) receptor agonist effect, inhibiting the ability of mCPP to enhance dopamine efflux in cortical and perhaps limbic regions as well. The present data provide additional evidence that hallucinations are due, in part, to 5-HT(2A) rather than 5-HT(2C) receptor stimulation. These findings suggest that 5-HT(2C) receptor agonists may be useful as antipsychotics, consistent with previous suggestions.