Serotonin 5-HT<sub/>2C</sub> receptors: Role in (+)-MDMA sensitization and distribution in the ventral tegmental area

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Serotonin (5-HT) released consequent to acute (+)-3,4-methylenedioxy-methamphetamine [(+)-MDMA; "ecstasy"] administration stimulates 5-HT2C receptors (5-HT2CR) to exert inhibitory influence on (+)-MDMA-induced behaviors. Thus, changes in 5-HT2CR responsiveness upon repeated intermittent exposure to (+)-MDMA may contribute to the development and/or expression of behavioral sensitization. We tested the hypothesis that intermittent exposure to (+)-MDMA or the 5-HT2CR agonist MK 212 results in enhanced (+)-MDMA-evoked locomotor activity ("behavioral sensitization") concurrent with decreased functional responsiveness of the 5-HT2CR. Male Sprague-Dawley rats pretreated with saline, (+)-MDMA, or MK 212 for 7 days revealed that (+)-MDMA or MK 212 pretreatment results in transient tolerance to MK 212-induced hypomotility, indicating loss of 5-HT2CR responsiveness, that coincides with enhanced (+)-MDMA-evoked hyperactivity at an early (24 h) withdrawal time-point. This suggests a role for 5-HT2CR in the induction and early expression of (+)-MDMA sensitization. While behavioral sensitization in (+)-MDMA-pretreated rats was transient and paralleled the time-course of diminished 5-HT2CR responsiveness, MK 212-pretreated rats displayed persistent (> 2 wks) enhancement of (+)-MDMA-evoked hyperactivity despite recovery of 5-HT2CR responsiveness. The loss of 5-HT2CR responsiveness at 24h withdrawal was not linked to reduced 5-HT2CR protein expression in the ventral tegmental area (VTA), nucleus accumbens (NAc), or prefrontal cortex in either (+)-MDMA- or MK 212-pretreated rats. However, an up-regulation of 5-HT2CR protein expression was observed in the VTA at 2 wks withdrawal in MK 212-pretreated rats, which may contribute to the persistence of (+)-MDMA-evoked hyperactivity. The ability of 5-HT2CR to limit the expression of (+)-MDMA-evoked hyperactivity is attributable to the inhibitory influence of 5-HT2CR upon VTA dopamine (DA) neuron firing and DA release in the NAc. This effect may be mediated indirectly via depolarization of GABA neurons. However, we revealed (via double-label immunofluorescence and retrograde tracing) that 5-HT2CR are located on both GABA and DA neurons in the VTA, a subset of which project to the NAc. Thus, the potential for a direct stimulatory effect of 5-HT2CR upon DA mesocorticoaccumbens pathway activation also exists. This may predominate under certain conditions, such as in response to repeated 5-HT2CR stimulation, as a result of modifications in 5-HT2CR responsiveness.

tyrosine hydroxylase, glutamic acid decarboxylase, FluoroGold