Interaction of [mGlu.sub.2/3] agonism with clozapine and lurasidone to restore novel object recognition in subchronic phencyclidine-treated rats

Rationale Subchronic administration to rodents of the N-methyl-D-aspartate non-competitive antagonist, phencyclidine (PCP), impairs novel object recognition (NOR). Atypical antipsychotic drugs (APDs) reverse the effects of subchronic PCP on NOR. The effect of metabotropic [glutamate.sub.2/3] receptor ([mGlu.sub.2/3]) agonists upon NOR is unknown. Objectives and methods We tested the hypotheses that the [mGlu.sub.2/3] agonist, LY379268, by itself, or in combination with APDs or pimavanserin, a 5-[HT.sub.2A] inverse agonist, would reverse the deficit in NOR induced by subchronic treatment with PCP (2 mg/kg, b.i.d., for 7 days). Results The [mGlu.sub.2/3] agonist LY379268 (1 or 3 mg/kg) did not attenuate the PCP-induced NOR deficit. However, together with sub-effective dose of the atypical APDs, clozapine (0.1 mg/kg) or lurasidone (0.03 mg/kg), but not --the typical APD, haloperidol (0.1 mg kg), or pimavanserin (3 mg/kg), LY379268, 1 mg/kg, significantly reversed the PCP-induced NOR deficit. Moreover, the effect of clozapine was blocked by the [mGlu.sub.2/3] antagonist, LY341495 (1 mg/kg). Conclusions These results indicate that [mGlu.sub.2/3] agonism can potentiate the ability of atypical, but not typical APDs, to ameliorate the effect of subchronic PCP on NOR, that [mGlu.sub.2/3] agonism may contribute to the ability of atypical APDs to acutely reverse the effect of subchronic PCP on NOR, but that by itself, [mGlu.sub.2/3] agonism, is ineffective in this model of cognitive impairment in schizophrenia. These results suggest that [mGlu.sub.2/3] receptor agonism should be investigated as an adjunctive treatment of cognitive impairment in schizophrenia rather than as monotherapy, which may be effective for control of psychosis, but not for cognitive impairment. Keywords Object recognition * [mGlu.sub.2/3] * Phencyclidine * Clozapine * Lurasidone * Glutamate * Dopamine * Antipsychotic * LY379268 * Metabotropic glutamate receptor * Microdialysis * Schizophrenia * Pimavanserin * Memory