Chronic treatment with a serotonin₂ receptor (5-HT₂R) agonist modulates the behavioral and cellular response to (+)-3,4- methylenedioxymethamphetamine [(+)-MDMA]

3,4-Methylenedioxymethamphetamine [MDMA; ecstasy] evokes a multifaceted subjective experience in human users which includes stimulation, feelings of well-being, mood elevation, empathy towards others as well as distortions in time, sensation and perception. Aspects of this unique psychopharmacology of MDMA are thought to be related to its potent actions to release serotonin (5-HT) and indirectly stimulate the 5-HT_2A receptor (5-HT_2AR). In the present studies, we examined the interrelationship between down-regulation of 5-HT_2AR expression and the behaviorally stimulatory effects generated by acute administration of (+)-MDMA, the most potent enantiomer of (±)-MDMA. Male Sprague-Dawley rats were chronically treated with the preferential 5-HT_2AR agonist 2,5-dimethoxy-4- iodoamphetamine (DOI) which has been shown to down-regulate expression of the 5-HT_2AR, but not the closely related 5-HT_2CR. While chronic DOI treatment did not alter the functional sensitivity of either the 5-HT_2AR or 5-HT_2CR, this regimen enhanced (+)-MDMA-evoked hyperactivity. Subsequent analysis of c-Fos and 5-HT_2AR immunoreactivity in brain sections demonstrated that DOI treatment decreased the number of (+)-MDMA-induced c-Fos immunopositive nuclei and 5-HT_2AR immunostaining in select cortical and striatal areas. These results indicate that chronic DOI exposure results in an enhanced behavioral response to (+)-MDMA and in a pattern of neuronal activation which resembles that seen in psychostimulant sensitization. These data also suggest that expression of the 5-HT_2AR in the NAc and PFC may play a role in the sensitivity to the locomotor-stimulating effects of (+)-MDMA and in the processes of neural regulation upon repeated psychostimulant administration.