Activation of group III metabotropic glutamate receptors inhibits basal and amphetamine-stimulated dopamine release in rat dorsal striatum: an in vivo microdialysis study

Abstract

Group III metabotropic glutamate (mGlu) receptors are negatively coupled to adenylate cyclase and are distributed pre-synaptically in the striatum. A behavioral study previously conducted in this laboratory shows that activation of this group of mGlu receptors attenuates acute amphetamine-stimulated motor activity. By administering a group III selective agonist or antagonist via the dialysis probe, the present study employed in vivo microdialysis to evaluate the capacity of the group III selective agents to alter extracellular levels of dopamine in the dorsal striatum of normal and amphetamine-treated rats. It was found that the group III agonist l-2-amino-4-phosphonobutyrate ( l-AP4) dose-dependently (1, 10 and 100 μM) reduced basal levels of extracellular dopamine. In contrast, the group III antagonist α-methyl-4-phosphonophenylglycine (MPPG) dose-dependently (10, 50 and 250 μM) elevated the basal release of extracellular dopamine. This elevation was antagonized by co-perfusion of l-AP4. Perfusion of 5-μM amphetamine through the dialysis probe increased extracellular dopamine in the dorsal striatum. Co-perfusion of l-AP4 (100 μM) significantly reduced amphetamine-stimulated dopamine levels, whereas co-perfusion of l-AP4 (100 μM) and MPPG (100 μM) did not alter the capacity of amphetamine to elicit dopamine release. The data obtained from this study demonstrate the presence of a tonically active glutamatergic tone on group III mGlu receptors in the dorsal striatum to pre-synaptically regulate basal dopamine release in an inhibitory fashion. Moreover, activation of l-AP4-sensitive group III mGlu receptors can suppress the phasic release of dopamine induced by a dopamine stimulant amphetamine.