Kathryn A. Cunningham, Ph.D.2011-12-202008-04-032011-12-202005-03-302005-03-09etd-03302005-192144http://hdl.handle.net/2152.3/75Serotonin (5-HT) released consequent to acute (+)-3,4-methylenedioxy-methamphetamine [(+)-MDMA; \"ecstasy\"] administration stimulates 5-HT<sub/>2C</sub> receptors (5-HT<sub/>2C</sub>R) to exert inhibitory influence on (+)-MDMA-induced behaviors. Thus, changes in 5-HT<sub/>2C</sub>R 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-HT<sub/>2C</sub>R agonist MK 212 results in enhanced (+)-MDMA-evoked locomotor activity (\"behavioral sensitization\") concurrent with decreased functional responsiveness of the 5-HT<sub/>2C</sub>R. 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-HT<sub/>2C</sub>R responsiveness, that coincides with enhanced (+)-MDMA-evoked hyperactivity at an early (24 h) withdrawal time-point. This suggests a role for 5-HT<sub/>2C</sub>R 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-HT<sub/>2C</sub>R responsiveness, MK 212-pretreated rats displayed persistent (> 2 wks) enhancement of (+)-MDMA-evoked hyperactivity despite recovery of 5-HT<sub/>2C</sub>R responsiveness. The loss of 5-HT<sub/>2C</sub>R responsiveness at 24h withdrawal was not linked to reduced 5-HT<sub/>2C</sub>R 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-HT<sub/>2C</sub>R 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-HT<sub/>2C</sub>R to limit the expression of (+)-MDMA-evoked hyperactivity is attributable to the inhibitory influence of 5-HT<sub/>2C</sub>R 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-HT<sub/>2C</sub>R 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-HT<sub/>2C</sub>R upon DA mesocorticoaccumbens pathway activation also exists. This may predominate under certain conditions, such as in response to repeated 5-HT<sub/>2C</sub>R stimulation, as a result of modifications in 5-HT<sub/>2C</sub>R responsiveness.electronicengCopyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.tyrosine hydroxylaseglutamic acid decarboxylaseFluoroGoldtext