The behavioral and neurochemical effects of chronic unpredictable stress in rats pre-exposed to (+)3,4-methlyenedioxymethamphetamine (MDMA)

MDMA is a popular psychostimulant drug of abuse that produces long-term toxicity to serotonin (5-HT) neurons in the brain. A decrease in 5-HT has adverse effects on cognitive behavior and the stress response. Therefore, the overall objective of this research was to determine if prior exposure to MDMA alters the behavioral and neurochemical consequences of chronic unpredictable stress in rats. The combination of MDMA and chronic stress did not alter anxiety-like behavior in the elevated plus maze; however, prior exposure to MDMA produced chronic stress-induced learning impairment in the Morris water maze. Chronic stress did not potentiate MDMA-induced 5-HT depletion in the hippocampus, indicating that MDMA and stress-induced learning impairments were produced by damage to neurons other than 5-HT terminals in the hippocampus. To determine if MDMA pretreatment produced a disinhibited stress response and increased hippocampal susceptibility to glutamate-mediated damage, corticosterone responses to novel stressors and markers of excitotoxic damage were measured after chronic stress in MDMA pretreated rats. Despite stress-induced increases in basal concentration of corticosterone and MDMA-induced increases in extracellular concentrations of glutamate, the combination of MDMA and stress did not alter the stress response to novel stressors or increase markers of excitotoxic damage in the hippocampus. To further examine the potential for MDMA and chronic stress to produce damage to hippocampal neurons other than 5-HT terminals, glutamic acid decarboxylase 67 (GAD67) was measured. The combination of MDMA and chronic stress produced a significant decrease in GAD67 expression, which indicated damage to GABA interneurons in the hippocampus. Stereological assessment of the dorsal hippocampus revealed that MDMA and chronic stress produced regional decreases in parvalbumin-immunoreactive GABA interneurons. The decreases in parvalbumin-immunoreactive GABA interneurons, but not 5-HT terminal damage produced by MDMA, were blocked by the anti-inflammatory drug, ketoprofen, indicating that MDMA and chronic stress-induced neuroinflammation affect GABA neurons in the hippocampus. Overall, these studies demonstrate that the combination of MDMA and chronic stress-induced toxicity to GABA interneurons within the hippocampus in concert with 5-HT terminal damage produced by MDMA contribute to deficits in hippocampal-dependent learning behavior.