Intrastriatal injection of a selective metabotropic excitatory amino acid receptor agonist induces contralateral turning in the rat
Sacaan, A.I.; Monn, J.A.; Schoepp, D.D.
Journal of Pharmacology and Experimental Therapeutics 259(3): 1366-1370
1991
ISSN/ISBN: 0022-3565 PMID: 1662277 Document Number: 378670
The consequence of in vivo activation of the phosphoinositide-coupled (metabotropic) excitatory amino acid (EAA) receptor subtype was investigated. We report that unilateral intrastrial injection of 1S,3R-1 aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), a selective metabotropic EAA receptor agonist, produced turning behavior (rotations) contralateral to the site of injection. This effect peaked at 5 to 8 hr after injection and was dose-related (EC50 = 0.59 .mu.mol), producing a maximal effect at 1 .mu.mol (32 .+-. 4 rotations per 5 min). 1S,3R-ACPD-induced rotations were not mimicked by intrastriatal injection of vehicle (2 .mu.l of normal saline) or up to 2 .mu.mol of 1R,3S-ACPD, the inactive ACPD isomer at the metabotropic EAA receptor. The selective competive N-methyl-d-aspartate receptor antagonist LY27461 4 (up to 5 mg/kg i.p.) did not significantly affect 1S,3R-ACPD-induced rotations. However, coinjection of the metabotropic EAA receptor antagonist L-2-amino-3-phosphonopropionic acid (1 .mu.mol) significantly reduced 1S,3R-ACPD-induced contralateral rotations. 1S,3R-ACPD at a dose which produced maximal contralateral rotations did not produce any loss of striatal .gamma.-aminobutyric acid neurons as indexed by glutamic acid decarboxylase enzyme activity in the injected striatum. In contrast to 1S,3R-ACPD, a dose of N-methyl-D-aspartate (0.2 .mu.mol), which only very modestly induces contralateral rotations results in highly significant neuronal degeneration (50% loss of glutamic acid decarboxylase activity), and is associated with other excitatory behaviors such as clonic convulsions. These pharmacological data suggest that 1S,3R-ACPD-induced contralateral rotations are a behavioral manifestation of selectively activating the metabotropic EAA receptor in vivo. Furthermore, unlike ionotropic EAA receptor activation, direct in vivo activation of the striatal metabotropic EAA receptor is not associated with convulsions and/or excitotoxicity.