Habituation deficits induced by metabotropic glutamate receptors 2/3 receptor blockade in mice:: Reversal by antipsychotic drugs

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-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.