5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine

The highly selective 5-HT2 receptor antagonist MDL 100,907 blocked MDMA-stimulated dopamine synthesis in vivo without affecting basal synthesis. It also prevented long-term deficits in serotonin concentrations believed to result from MDMA-induced dopamine release. Microdialysis showed that MDL 100,907 attenuated MDMA-induced increases in extracellular striatal dopamine. However, MDL 100,907 did not alter dopamine synthesis stimulated by haloperidol or reserpine, nor dopamine release produced by haloperidol. The results suggest a permissive role for 5-HT2 receptors in activating the dopamine system during states of high serotonergic activity or elevated dopamine efflux with high D2 receptor occupancy.

Study at a glance

Abstract

The highly selective 5-HT2 receptor antagonist, MDL 100,907, was used to explore the role of serotonin in the stimulation of dopaminergic function produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA). MDL 100,907 blocked MDMA-stimulated dopamine synthesis in vivo without affecting basal synthesis. The long-term deficits in 5-HT concentrations believed to be a consequence of MDMA-induced dopamine release were also blocked by MDL 100,907 over the same dose range. In vivo microdialysis confirmed that 5-HT2 receptor blockade with MDL 100,907 attenuated MDMA-induced increases in extracellular concentrations of striatal dopamine. In contrast to its effect on MDMA-induced synthesis, MDL 100,907 did not alter dopamine synthesis stimulated by haloperidol or reserpine. In vivo dopamine release produced by haloperidol was also unaffected by MDL 100,907. The results suggest a permissive role for 5-HT2 receptors in the activation of the dopamine system which occurs during states of high serotonergic activity or during conditions of elevated dopamine efflux with high D2 receptor occupancy.