title: Metabotropic glutamate receptor activation produces extrapyramidal motor system activation that is mediated by striatal dopamine.
abstract: Little is known about the in vivo function of the GTP-binding protein-coupled "metabotropic" excitatory amino acid (EAA) receptor. In vitro studies on agonist-induced brain phosphoinositide hydrolysis have shown that (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid is a highly selective and efficacious metabotropic EAA agonist. We have recently reported that in vivo unilateral intrastriatal injection of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid induces transient extrapyramidal motor activation that manifests itself as contralateral turning. In this study, we fully characterized the onset of turning behavior following intrastriatal (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid injection and the possible involvement of striatal dopamine neurons in the mediation of this effect. Rats were anesthetized with the short-acting agent halothane to allow for rapid surgical recovery and thus early behavioral measurements. Intrastriatal (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1 mumol/2 microliters) produced an incremental increase in contralateral turning starting at 1 h and plateauing 3-6 h after injection (peak effect, 39.1 +/- 6.7 rotations per 5 min). Dopamine depletion with alpha-methyl-DL-p-tyrosine (250 mg/kg i.p., 80% depletion) resulted in greater than 85% inhibition of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced contralateral turning. The dopamine antagonist haloperidol (0.3 mg/kg i.p.) produced 48% inhibition of the (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid response. In time course studies, turning behavior correlated with increases in levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid. These results suggest a functional interaction between the metabotropic EAA receptor and the dopaminergic system in the striatum.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: A I
authors.initials: AI
authors.lastname: Sacaan
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: D D
authors.initials: DD
authors.lastname: Schoepp
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D018492:Dopamine Antagonists; D005116:Extrapyramidal Tracts / Q000502:physiology*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter / Q000502:physiology*
chemical_list: D018492:Dopamine Antagonists; D009498:Neurotoxins; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D006220:Haloperidol; D011188:Potassium; D004298:Dopamine