title: Habituation deficits induced by metabotropic glutamate receptors 2/3 receptor blockade in mice: reversal by antipsychotic drugs.
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-quinolinecarboxamide (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-HT(3), and 5-HT(6) antagonists; 5-HT(1A) 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.
authors.affiliation: Neuroscience Discovery Research, Abbott GmbH and Co. KG, D-67008 Ludwigshafen, Germany. anton.bespalov@abbott.com
authors.forename: Anton
authors.initials: A
authors.lastname: Bespalov
authors.forename: Ana-Lucia
authors.initials: AL
authors.lastname: Jongen-Rêlo
authors.forename: Marcel
authors.initials: M
authors.lastname: van Gaalen
authors.forename: Silke
authors.initials: S
authors.lastname: Harich
authors.forename: Hans
authors.initials: H
authors.lastname: Schoemaker
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gross
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003072:Cognition Disorders / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006185:Habituation, Psychophysiologic / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014966:Xanthenes / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D009570:Nitriles; D018094:Receptors, Metabotropic Glutamate; C409982:SB 277011; D044005:Tetrahydroisoquinolines; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D008694:Methamphetamine; D006220:Haloperidol