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Description:
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Serotonin (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 . |