Brain Circuitry And Mechanisms Of Glutamate Release

Although evidence indicates that MA does not directly increase the release of glutamate in the stria-tum (25), several studies suggest that activation of the corticostriatal pathway following MA administration may be responsible for increased striatal extracellular glutamate concentrations. The increases in striatal extracellular glutamate that are typically observed after MA are tetrodotoxin (TTX) sensitive (Fig. 1), suggesting that MA-induced changes in glutamate are impulse mediated. Moreover, unilateral ablation of motor and premotor cortexes decreases striatal glutamate acitivity by eliminating a majority of corticostriatal efferents (38) and protects against MA-induced damage to DA terminals (Fig. 2). In addition, MA treatment increases extracellular concentrations of glutamate and decreases glutamate immunolabeling of nerve terminals in both the motor cortex and striatum, suggesting that a release of neuronal glutamate occurs in both these regions (36,39,40).

The presence or absence of increases in glutamate release within specific cortical subregions may be predictive of dopaminergic damage in their respective terminal fields. For example, the medial pre-frontal cortex and nucleus accumbens are DA-rich areas resistant to the toxic effects of MA (41). Accordingly, MA does not alter extracellular glutamate concentrations within the medial prefrontal cortex or within its primary target, the nucleus accumbens (9,42). In contrast, we have found that a neurotoxic regimen of MA produces a gradual but marked and significant increase in extracellular glutamate concentrations in the somatosensory (parietal) cortex of the rat (Fig. 3). A delayed rise in extracellular glutamate concentrations also occurs in the lateral striatum (33,42), the major terminal field of

Fig. 1. Intrastriatal perfusion with TTX+ and Ca2+-free medium blocks the increase in extracellular glutamate levels following repeated administration of MA (arrows indicate injection of 7.5 mg/kg MA at times 0, 120, and 240 min). Bar indicates time of perfusion.
Fig. 2. Unilateral cortical ablation prevents the loss of striatal DA content 1 wk following MA administration (10 mg/kg x 4 doses over 8 h). Removal of cortical inputs to the striatum did not alter DA tissue content. *p<0.05 verses other groups.

these cortical regions (43). MA also produces silver staining and reactive gliosis in these striatal and cortical regions, suggestive of a correlation between glutamate release and lasting neuronal damage (6,44,45). In addition, MA alters binding to NMDA receptors specifically within the striatum and somatosensory cortex (46) and degenerates cell bodies in this cortical region (47,48). Together, these data indicate that MA increases glutamatergic activity, specifically within the corticostriatal pathway, that, in turn, may produce damage to dopaminergic striatal nerve terminals and nonmonoaminergic cortical cell bodies.

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