Blockade of Striatal 5‐Hydroxytryptmine₂ Receptors Reduces the Increase in Extracellullar Concentrations of Dopamine Produced by the Amphhetamine analogue 3,4‐Methylenedioxymethamphetamine

Abstract

5‐Hydroxytryptamine2 (5‐HT2) receptor antagonists have been shown to interfere with the stimulation of striatal dopamine synthesis and release produced by the amphetamine analogue 3,4‐methylenedioxymethamphetamine (MDMA). To localize the receptors responsible for the attenuation of MDMA‐induced release, 5‐HT2 receptor antagonists were infused via the microdialysis probe directly into the brains of awake, freely moving rats before the systemic administration of MDMA. Intrastriatal infusions of the selective 5‐HT2 antagonist MDL 100, 907 produced a concentration‐dependent inhibition of MDMA‐induced dopamine release. Similar results were observed with intrastriatal infusions of the 5‐HT2 antagonist amperozide. In contrast, infusion of MDL 100, 907 into the midbrain region near the dopaminergic cell bodies was with out effect on the MDMA‐induced elevation of extracellular dopamine in the ipsilateral striatum. Neither antagonist attenuated basal transmitter efflux nor the MDMA‐stimulated release of [3H]dopamine from striatal slices in vitro indicating that the in vivo effect of the antagonists was not due to inhibition of the dopamine uptake carrier. Intrastriatal infusion of tetrodotoxin reduced both basal and MDMA‐stimulated dopamine efflux and eliminated the effect of intrastriatal MDL 100, 907. The results indicate that 5‐HT2 receptors located in the striatum augment the release of dopamine produced by high doses of MDMA. Furthermore, these 5‐HT2 receptors appear to be located on nondopaminergic elements of the striatum.

Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome: Clues from an In Vivo Neurochemistry Study with PET

“…Similarly, because of the known literature demonstrating the relationship between 5-HT 2A R antagonists and DA (Porras et al, 2002;Schmidt et al, 1994), this upregulated 5-HT 2A R and decreased 5-HT could further enhance DA rel . Although, to date, we have studied three of our subjects at both DA and 5-HT systems (Figure 5), it does provide further preliminary support for this concept.…”

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

“…M100907 also blocked 3,4-methylenedioxymethamphetamine (MDMA)-evoked DA efflux in the striatum (Schmidt et al, 1994). The mixed 5-HT2A/C receptor agonist DOI potentiated amphetamine-stimulated DA outflow and attenuated apomorphine-induced decreases in DA (Ichikawa and Meltzer, 1995).…”

Presynaptic control of serotonin on striatal dopamine function

“…Similar findings have been observed with the non-selective DA antagonists haloperidol and raclopride (Andersson et al 1995;Lucas et al 2000b). On the one hand, the facilitatory effect of MDMA or haloperidol in vivo can be reduced by the intrastriatal administration of 5-HT 2A antagonists (Lucas and Spampinato 2000;Schmidt et al 1994;Yamamoto et al 1995). These data strongly suggested that striatal 5-HT 2A receptors stimulate striatal DA release.…”