Muscarinic receptors regulate extracellular glutamate levels in the rat striatum: an in vivo microdialysis study.

Regulation of extracellular glutamate levels by muscarinic receptors in the striatum of unanesthetized rats was investigated by microdialysis. Extracellular glutamate levels were elevated by intrastriatal perfusion of L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC), a competitive substrate of plasma membrane excitatory amino acid transporters. The nonselective muscarinic agonist, oxotremorine (0.5-54 microM) significantly decreased L-trans-PDC-evoked glutamate levels in a concentration-dependent manner. Scopolamine (0.1-10 microM), a nonselective muscarinic receptor antagonist, reversed the effect of oxotremorine, which confirms that muscarinic receptor activation mediated the reduction of L-trans-PDC-evoked glutamate levels. In addition, scopolamine (10 microM) significantly elevated basal extracellular glutamate levels, an effect prevented by oxotremorine, which suggests that acetylcholine tonically regulates glutamatergic transmission in the striatum. Previous data from this laboratory have shown that L-trans-PDC-evoked glutamate levels are partially calcium-dependent. The present study demonstrated that attenuation of L-trans-PDC-evoked glutamate levels by reduced calcium was not altered by oxotremorine. Therefore, it is likely that muscarinic receptors regulate calcium-dependent glutamate release evoked by L-trans-PDC.