Investigations into the neurochemical mechanisms underlying 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity: Assessment of the role of GABA and the dopamine transporter
Abstract
The current study was undertaken to investigate the mechanism(s) underlying MDMA-induced selective loss of 5-HT neuron terminals in rat brain. We first examined whether enhancement of GABAergic transmission through an irreversible GABA transaminase inhibitor, gamma vinyl GABA (GVG), could counteract MDMA-induced hyperthermia and long-term reductions in 5-HT markers. Pretreatment with GVG (500 mg/kg i.p.) prior to MDMA (40 mg/kg, s.c.) produced significant protection (65–75%) against MDMA-induced loss of 5-HT markers in the cortex, hippocampus, and striatum, and abolished MDMA induced hyperthermia. In an effort to understand better the neurochemical mechanism underlying these neuroprotective effects of GVG, we studied the role of the GABA-B receptor using the GABA-B agonist, baclofen. Baclofen (18 mg/kg, i.p.) pretreatment blocked both MDMA-induced serotonergic deficits and hyperthermia. These results are consistent with the hypothesis that impaired GABAergic transmission might mediate, at least in part, the neurodegenerative effects of MDMA. Nevertheless, the importance of hypothermia in attenuating the neurotoxic effects of MDMA cannot be excluded. In the next series of experiments we examined the effect of antisense oligodeoxynucleotide (AS) mediated knockdown of the dopamine transporter (DAT), in order to delineate the role of the DAT in the MDMA neurodegenerative process. DAT-AS unilaterally microinfused into the substantia nigra gave a 70% reduction of the DAT and blocked MDMA-induced neurotoxicity only in the ipsilateral striatum. Interestingly, however, the hyperthermic response elicited by MDMA remained unaltered in the presence of DAT knockdown, suggesting that MDMA-induced hyperthermia may not be obligatory for 5-HT terminal damage. This result suggests that the DAT may play an essential role in MDMA-induced neurotoxicity. Finally, we briefly examined the role of COX-2 activation in MDMA-induced neurotoxicity. The results indicate a role for COX-2 mediated reactive products in the mechanism(s) of neurodegeneration associated with MDMA, at least in the cortex. Together, this work demonstrates that multiple neurochemical mechanisms, including the GABAergic system, the DAT, and oxidative stress, may all be involved in MDMA-induced neurotoxicity.
Degree
Ph.D.
Advisors
Nichols, Purdue University.
Subject Area
Pharmacology
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