Received for publication July 14, 2006.
Revised November 20, 2006.
Accepted for publication November 22, 2006.

Habituation deficits induced by mGlu2/3 receptor blockade in mice: Reversal by antipsychotic drugs

Abstract

Cortical metabotropic glutamate receptors (mGluRs) appear 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, LY-341495, thirty min prior to being placed into novel arenas for automatic motor activity recording (two-hour 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 prior to 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, 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-HT2A, 5-HT3 and 5-HT6 antagonists, 5-HT1A agonist, D4 antagonist, CB1 antagonist, AMPAkines, 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.

Key words: Antipsychotics, Habituation, LY-341495, Locomotor activity, Metabotropic glutamate receptors, Mice

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