Attenuation of specific PCP-evoked behaviors by the potent mGlu2/3 receptor agonist, LY379268 and comparison with the atypical antipsychotic, clozapine.

A selective activator of metabotropic glutamate receptors (mGlu2/3), LY379268, reduces specific abnormal behaviors induced by the drug phencyclidine (PCP) in rats, similar to the antipsychotic clozapine. LY379268 and clozapine dose-dependently decreased PCP-evoked falling, turning, and back pedaling. At 30 minutes after PCP, 1 mg/kg LY379268 reduced falls by 89% and turns by 53%, while 1 mg/kg clozapine reduced turning by 70%. Low clozapine doses increased PCP-induced falls. Back pedaling was completely blocked by 1 mg/kg of either drug. However, clozapine's effects occurred only at doses that worsened PCP-evoked ataxia, whereas LY379268 did not. The findings suggest mGlu2/3 receptors selectively modulate certain PCP behaviors, supporting their potential as drug targets for schizophrenia.

Study at a glance

Abstract

Recent studies using phencyclidine (PCP) as a model for psychosis have implicated metabotropic glutamate (mGlu) receptors in schizophrenia. We have shown, using an automated motor activity monitoring system, that selective group II mGlu receptor agonists attenuate PCP (5 mg/kg)-evoked increases in ambulations and fine motor movements with similar profiles to the atypical antipsychotic, clozapine. Because the automated system does not discriminate between specific PCP-evoked behaviors, in this paper we examined the effects of the potent mGlu2/3 receptor agonist LY379268 on PCP-evoked behaviors as assessed by observational methods. Furthermore, we have compared the actions of LY379268 to the atypical antipsychotic clozapine. LY379268 and clozapine reduced the expression of PCP-induced falling, turning and back pedaling in a dose-dependent manner. Thirty minutes post-PCP administration, 1 mg/kg LY379269 reduced falls and turns by 89% and 53%, respectively, and 1 mg/kg clozapine attenuated turning by 70%. Interestingly, low doses of clozapine increased PCP-elicited falls. Back-pedaling was particularly sensitive to LY379268 and clozapine, with 1 mg/kg of either agent completely abolishing back-pedaling 30 min after PCP administration. However, in contrast to LY379268, attenuation of these behaviors by clozapine only occurred at doses that augmented PCP-evoked ataxia. Furthermore, LY379268 did not affect PCP-evoked forepaw treading. These results indicate that mGlu2/3 receptors do not mediate a generalized reduction in motor activity, but instead selectively modulate specific PCP behaviors, further implicating group II mGlu receptors as viable drug targets in the treatment of schizophrenia.