5-HT2A and 5-HT2C receptor stimulation are differentially involved in the cortical dopamine efflux—Studied in 5-HT2A and 5-HT2C genetic mutant mice

Both 5-HT2A and 5-HT2C receptors modulate cortical dopamine efflux, but in opposite directions. We have now compared the ability of the three 5-HT2A/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-HT2A and 5-HT2C genetic mutant mice. In the 5-HT2A mice, the preferential 5-HT2A receptor agonist DOI (2.5 mg/kg, s.c.) induced a slight but significant increase in cortical dopamine efflux only in the wild type (WT) mice; MK-212 (2.5 mg/kg) reduced dopamine efflux in both WT and receptor knockout (KO) mice; moreover, MCPP, 2.5 mg/kg, had no effect in either types. In 5-HT2C 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-HT2A receptor stimulation enhances and 5-HT2C 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-HT2A and 5-HT2C receptors stimulation. Of these three agents, only DOI, the more selective 5-HT2A receptor agonist, is hallucinogenic. The absence of hallucinations with mCPP may be due to its relatively more potent 5-HT2C 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-HT2A rather than 5-HT2C receptor stimulation. These findings suggest that 5-HT2C receptor agonists may be useful as antipsychotics, consistent with previous suggestions.