Previous preclinical and clinical studies have demonstrated the efficacy of group
II metabotropic glutamate receptor (mGluR) agonists as potential antipsychotics. Recent
studies utilizing mGluR2-, mGluR3-, and double knockout mice support that the antipsychotic
effects of those compounds are mediated by mGluR2. Indeed, biphenyl indanone-A (BINA),
an allosteric potentiator of mGluR2, is effective in experimental models of psychosis,
blocking phencyclidine (PCP)-induced hyperlocomotion and prepulse inhibition deficits
in mice. In this study, we administered the NMDA receptor antagonist PCP (5.6 mg/kg
i.p.) to rats, an established animal model predictive of schizophrenia. Here, we show
that BINA (32 mg/kg i.p.) attenuated PCP-induced locomotor activity in rats. Using
behaviorally relevant doses of BINA and PCP, we performed pharmacological magnetic
resonance imaging (phMRI) to assess the specific brain regions that underlie the psychotomimetic
effects of PCP, and examined how BINA modulated the PCP-induced functional changes
in vivo. In anesthetized rats, acute administration of PCP produced robust, sustained
blood oxygenation level-dependent (BOLD) activation in specific cortical, limbic,
thalamic, and striatal regions. Pretreatment with BINA suppressed the amplitude of
the BOLD response to PCP in the prefrontal cortex, caudaute-putamen, nucleus accumbens,
and mediodorsal thalamus. Our results show key brain structures underlying PCP-induced
behaviors in a preclinical model of schizophrenia, and, importantly, its reversal
by potentiation of mGluR2 by BINA, revealing specific brain regions functionally involved
in its pharmacological action. Finally, our findings bolster the growing body of evidence
that mGluR2 is a viable target for the treatment of schizophrenia.
2010 IBRO. Published by Elsevier Ltd. All rights reserved.