Glutamate Mediation Of Dopamine And 5ht Toxicity

Although MA has been found to damage DA terminals in the striatum and 5-HT terminals in multiple brain regions, factors that mediate damage to these monoamine systems may differ on a fundamental level. A growing body of evidence suggests that DA-containing nerve terminals are inherently more vulnerable to damage following metabolic inhibition compared with 5-HT containing terminals. Additionally, increased extracellular glutamate may have a more direct effect in mediating toxicity to DA systems following MA administration.

Glutamate overflow and subsequent activation of the NOS pathway may differentially mediate DA and 5-HT toxicity. Glutamate overflow is not correlated with the depletion of 5-HT content in different brain regions after MA. In fact, 3,4-methylenedioxy-methamphetamine (MDMA), a more selective 5-HT toxin structurally similar to MA, damages striatal 5-HT terminals but does not result in glutamate overflow in this region (33) Abekawa et al. (149) report that administration of the NOS inhibitor l-NAME protects against MA-induced DA loss in the striatum, but it does not attenuate 5-HT toxicity in the striatum, nucleus accumbens, and medial frontal cortex of the same animals (150). However, pretreatment with a different NOS inhibitor, N®-nitro-l-arginine (l-NOARG), partially protects against long-term 5-HT depletion induced by MDMA in frontal cortex and parietal cortex, but not in other brain regions (152). The interaction between glutamate and lasting depletion of 5-HT may, therefore, be brain region dependent.

The differential role of glutamate in mediating DA versus 5-HT toxicity also is evidenced by the inherent vulnerabilities of these systems to metabolic stress. In cultured mesencephalic neurons and synaptosomal preparations, inhibitors of oxidative phosphorylation decrease DA uptake to a greater degree compared to uptake of GABA, 5-HT, and norepinephrine (156). Inherent differences in the effects of mitochondrial inhinition on neurotransmitter release in vivo may predict lasting toxicity to these systems. MA decreases cytochrome-c oxidase activity in DA-rich areas, but not in regions where MA toxicity manifests as a loss of 5-HT (130), implicating DA release in mediating metabolic stress following MA. Furthermore, the local perfusion of the succinate dehydrogenase inhibitor malonate increases DA overflow more than 100-fold, whereas 5-HT release increases merely 5-fold (157). In addition to differentially affecting the release of monoamines, intrastriatal infusions of malonate preferentially damage DA systems compared to GABA- or 5-HT-containing nerve terminals (25,157,158). Coperfusion of MA and malonate synergize to produce even greater depletions of DA without affecting 5-HT tissue levels (25,157), suggestive of the correlation between the degree of transmitter release and the differential toxic profiles of mitochondrial inhibitors on monoamine systems.

The possible mediation of serotonergic damage by extracellular glutamate is less studied and remains unclear. However, there is some evidence that indicates an NMDA receptor mediation of 5-HT loss. Pretreatment with the NMDA receptor antagonist MK-801 blocks both 5-HT and DA loss after MA, and 5-HT depletion following MDMA (159). However, the protective effects of MK-801 may be related to the attenuation of stimulant-induced hyperthermia and, thus, may not be selectively mediated by the glutamate pathway (160-162). Further studies are necessary to clarify the mechanism by which glutamate receptor antagonists convey neuroprotection.

The majority of available data are consistent with the conclusion that dopaminergic neurons are inherently more sensitive than 5-HT neurons to damage mediated by metabolic stress. In addition, vulnerability to mitochondrial inhibition may underlie DA-specific neurodegenerative disorders such as Parkinson's disease (163). Although the etiology of the vulnerability of DA versus 5-HT neurons to excitotoxic, metabolic, and oxidative insults is not known, the ability of DA to autoxidize, combined with the enzymatic oxidation of DA to form H2O2, may lead to elevated concentrations of intracellular reactive oxygen species that render DA neurons more vulnerable to metabolic inhibition or excitotoxic events.

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