Neuropharmacology and Neurotoxicity of 3,4-Methylenedioxymethamphetamine - Drugs of Abuse: Neurological Reviews and Protocols - page 59

neurotoxic regimen of MDMA depletes brain concentrations of the endogenous
antioxidants vitamin E and ascorbic acid (75) .
The contribution of free radical-induced damage in the process of MDMA
neurotoxicity is inferred from the fi ndings that the administration of antioxi-
dants (50 , 59 , 75) or spin trap agents (76 , 77) prevents the MDMA-induced
depletion of brain 5-HT. Furthermore, as discussed previously, overexpression
of superoxide dismutase renders transgenic mice resistant to MDMA-induced
dopamine toxicity (67) .
In addition to a role of oxidative stress in MDMA-induced neurotoxicity,
alterations in energy metabolism also may contribute to the process of neuro-
toxicty induced by psychostimulant drugs. Methamphetamine reduces brain
concentrations of ATP (78) and increases the extracellular concentration of
lactate (79) . In addition, the administration of energy substrates attenuates
dopamine neurotoxicity elicited by methamphetamine (79 , 80) . These fi ndings
suggest that psychostimulants may acutely impair mitochondrial function.
Indeed, methamphetamine and MDMA acutely inhibit the activity of the
mitochondrial enzyme cytochrome oxidase (72) . Furthermore, the combined
administration of methamphetamine and malonate, a complex II inhibitor of
mitochondrial function, synergize to deplete striatal dopamine concentrations
(81 , 82) . The intrastriatal administration of malonate and MDMA, neither of
which alone depletes tissue 5-HT concentrations, together produces signifi cant
reductions in striatal 5-HT and dopamine concentrations (55) . These data
suggest a role for bioenergetic stress in the long-term effects of MDMA on
5-HT, and possibly dopamine, nerve terminals.
MDMA, as well as methamphetamine and parachloroamphetamine, appear
to disrupt cellular energetics by further promoting glycogenolysis (61 , 83) .
MDMA and methamphetamine produce a transient decrease in brain glycogen
concentrations that may involve the 5-HT 2 receptor-dependent activation of
glycogen phosphorylase (84) . MDMA also produces a sustained elevation
in the extracellular concentration of glucose in the brain (61) . The increased
extracellular concentration of glucose may be indicative of increaesd regional
cerebral blood fl ow and glucose utilization. This ability of MDMA to promote
glycogenolysis is associated with the hyperthermia produced by MDMA
(61) . Thus, the involvement of hyperthermia in the process by which MDMA
depletes energy stores may be the same mechanism through which hyperthermia
exacerbates MDMA-induced 5-HT neurotoxicity.
7. Functional Consequences of MDMA Neurotoxicity
Although the long-term effects of MDMA on 5-HT axon terminals have
been well documented, the potential functional consequences associated with
MDMA-induced 5-HT depletion have been investigated only recently. It is