Effects of a Positive Allosteric Modulator of Group II Metabotropic Glutamate Receptors, LY487379, on Cognitive Flexibility and Impulsive-Like Responding in Rats

Orthosteric group II metabotropic glutamate receptor (mGluR) agonists are regarded as novel, effective medications for all major symptom domains of schizophrenia, including cognitive disturbances. mGluR2s also can be affected in a more subtle way by positive allosteric modulators (PAMs) characterized by a unique degree of subtype selectivity and neuronal frequency-dependent activity. Because currently available treatments for schizophrenia do not improve cognitive dysfunction, the main aim of the present study was to examine the effects of a mGluR2 PAM, N-(4-(2-methoxyphenoxy)-phenyl-N-(2,2,2-trifluoroethyl-sulfonyl)-pyrid-3-ylmethylamine (LY487379), on rat cognitive flexibility and impulsive-like responding, assessed in an attentional set-shifting task (ASST) and a differential reinforcement of low-rate 72 s (DRL72) schedule of food reinforcement. In addition, in vivo microdialysis was used to assess the drug's impact on cortical levels of dopamine, norepinephrine, serotonin, and glutamate. Rats treated with LY487379 (30 mg/kg) required significantly fewer trials to criteria during the extradimensional shift phase of the ASST. Under a DRL72 schedule, LY487379 (30 mg/kg) decreased the response rate and increased the number of reinforcers obtained. These effects were accompanied by the shift of the frequency distribution of responses toward longer inter-response time durations. LY487379 significantly enhanced extracellular norepinephrine and serotonin levels in the medial prefrontal cortex. In summary, the present study demonstrates that a mGluR2 PAM, LY487379, promotes cognitive flexibility and facilitates behavioral inhibition. These procognitive effects may contribute to the therapeutic efficacy of agents stimulating mGluR2 in schizophrenia.