Neuropharmacology and Neurotoxicity of 3,4-Methylenedioxymethamphetamine - Drugs of Abuse: Neurological Reviews and Protocols - page 58

65 , 66) . The MDMA-induced generation of hydroxyl radicals appears to be
dependent on the activation of both the dopamine and 5-HT transporter (43 , 51) .
There are several potential sources for free radicals generated by MDMA.
Dopamine may undergo enzymatic or nonenzymatic oxidation to form super-
oxide radical and hydrogen peroxide. The importance of superoxide radicals in
MDMA neurotoxicity is evident in transgenic mice that overexpress superoxide
dismutase, which is responsible for the degradation of superoxide radicals.
These transgenic mice are resistant to MDMA-induced neurotoxicity (67) .
Alternatively, metabolites of MDMA may serve as sources of free radicals.
Quinone thioethers described in the preceding section have the capability of
redox cycling to produce reactive oxygen species.
Reactive species that contribute to MDMA toxicity may not be limited
to oxygen-based radicals but also may include reactive nitrogen species, for
example, nitric oxide and peroxynitrite. Inhibitors of nitric oxide synthase
(NOS) provide protection against MDMA-induced dopamine depletion in the
mouse (68) , as well as 5-HT depletion in the rat (69 , 70) . However, it has not
been possible to ascribe the neuroprotective effects of these drugs specifi cally to
the inhibition of NOS, inasmuch as NOS inhibitors, for the most part, markedly
attenuate MDMA-induced hyperthermia (69) . However, the NOS inhibitor
S -methyl- L -thiocitrulline attenuates MDMA-induced dopamine toxicity in the
mouse without modifying MDMA-induced hyperthermia (68) . S -Methyl- L -
citrulline also attenuates the long-term depletion of 5-HT, as well as dopamine,
in the striatum of the rat following the intrastriatal administration of MDMA
and malonate (Gudelsky, unpublished observations ).
The exact mechanism whereby MDMA increases the formation of reactive
nitrogen species is unknown, but it is unlikely to involve an increase in the
release of glutamate (71) or glutamate receptor stimulation (68) . Conceivably,
treatment with MDMA may produce an increase in intracellular calcium
through impairment of cellular energetics (61) , disruption of mitochondrial
function (72) , or activation of protein kinase C (52) that ultimately results in the
activation of NOS. Regardless of the nature of the reactive oxygen or nitrogen
species, the importance of the 5-HT transporter itself in the generation of
reactive oxygen or nitrogen species is underscored by the fi nding that MDMA-
induced free radical formation is absent in rats treated with fl uoxetine (51) or in
rats in which 5-HT terminals have been disrupted by fenfl uramine (65) .
The administration of MDMA also results in cellular damage or changes
consistent with the induction of oxidative stress. MDMA increases the forma-
tion of malondialdehyde-related substances that are indicative of free radical-
induced lipid peroxidation (73 , 74) . MDMA also increases the formation
of nitro-tyrosine residues (Yamamoto, unpublished observations ) that is
consistent with nitric oxide- or peroxynitrite-induced protein nitration. Finally, a