Abstract
Cortical metabotropic glutamate receptors (mGluRs) seem to be involved in habituation of simple stimulus-bound behaviors (e.g., habituation to acoustic startle or odor-elicited orienting response). Habituation deficits may contribute to the cognitive symptoms of schizophrenia. In the present study, male NMRI mice were injected with mGluR2/3 antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY-341495) 30 min before being placed into novel arenas for automatic motor activity recording (2-h sessions). Administration of LY-341495 (1–10 mg/kg s.c.) dose-dependently prevented the habituation of the locomotor activity. Effects of LY-341495 (10 mg/kg) were fully and dose-dependently reversed by i.p. administration of haloperidol (0.03–0.3 mg/kg), clozapine (1–10 mg/kg), risperidone (0.01–0.1 mg/kg), olanzapine (0.3–3 mg/kg), aripiprazole (1–10 mg/kg), and sulpiride (3–30 mg/kg), each of which was given 15 min before the test. Effects of antipsychotic drugs were observed at the dose levels that did not affect spontaneous motor activity. LY-341495-induced delayed hyperactivity was also partially attenuated by lithium (50–200 mg/kg), amisulpride (1–10 mg/kg), and the selective dopamine D3 antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolin-ecarboxamide (SB-277011A; 3–30 mg/kg). Application of diazepam, imipramine, or several agonists and/or antagonists acting at various receptors that are thought to be relevant for antipsychotic treatment [e.g., 5-hydroxytryptamine (5-HT)2A, 5-HT3, and 5-HT6 antagonists; 5-HT1A agonist; D4 antagonist; CB1 antagonist; ampakines; and glycine transporter inhibitor) had no appreciable effects. Thus, behavioral deficits induced by mGluR2/3 blockade (such as delayed motor hyperactivity) are selectively reversed by clinically used antipsychotic drugs.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.110684.
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ABBREVIATIONS: PCP, phencyclidine; NMDA, N-methyl-d-aspartate; mGluR, metabotropic glutamate receptor; 8-OH-DPAT, 8-hydroxy-2-[din-propylamino] tetralin; LY-341495, 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid; CX-516, 1-(quinoxaline-6-yl-carbonyl)piperidine hydrochloride; LY-392098, N-2-(4-(3-thienyl)phenyl)propyl 2-propanesulfonamide; L-741626, 3-(4-(4-chloro)phenyl-4-hydropiperidino)-methyl)indole; SB-277011A, trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide; MDL-100907, α-(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl)ethyl)]-4-piperidine –methanol; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline; SSR-504734, 2-chloro-N-[(S)-phenyl[(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide hydrochloride; SR-141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl; ANOVA, analysis of variance; GlyT1, GlyT1, glycine transporter 1; 5-HT, 5-hydroxytryptamine; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid; MDL-72222, tropanyl 3,5-dichlorobenzoate.
- Received July 14, 2006.
- Accepted November 22, 2006.
- The American Society for Pharmacology and Experimental Therapeutics