title: Interaction of mGlu2/3 agonism with clozapine and lurasidone to restore novel object recognition in subchronic phencyclidine-treated rats.
abstract: BACKGROUND
  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 glutamate₂/₃ receptor (mGlu₂/₃) agonists upon NOR is unknown.
  
  
  OBJECTIVE
  We tested the hypotheses that the mGlu₂/₃ agonist, LY379268, by itself, or in combination with APDs or pimavanserin, a 5-HT(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 mGlu₂/₃ 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 mGlu₂/₃ antagonist, LY341495 (1 mg/kg).
  
  
  CONCLUSIONS
  These results indicate that mGlu₂/₃ agonism can potentiate the ability of atypical, but not typical APDs, to ameliorate the effect of subchronic PCP on NOR, that mGlu₂/₃ agonism may contribute to the ability of atypical APDs to acutely reverse the effect of subchronic PCP on NOR, but that by itself, mGlu₂/₃ agonism, is ineffective in this model of cognitive impairment in schizophrenia. These results suggest that mGlu₂/₃ 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.
authors: Division of Psychopharmacology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
authors: Masakuni
authors: M
authors: Horiguchi
authors: Mei
authors: M
authors: Huang
authors: Herbert Y
authors: HY
authors: Meltzer
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D054313:Drug Agonism; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D054833:Isoindoles / Q000494:pharmacology; D000069056:Lurasidone Hydrochloride; D010622:Phencyclidine / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D021641:Recognition, Psychology / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018691:Excitatory Amino Acid Antagonists; D054833:Isoindoles; C118218:LY 379268; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D010622:Phencyclidine; D003024:Clozapine; D000069056:Lurasidone Hydrochloride