Attention deficit induced by blockade of N-methyl d-aspartate receptors in the prefrontal cortex is associated with enhanced glutamate release and cAMP response element binding protein phosphorylation: role of metabotropic glutamate receptors 2/3

The hypothesis that attention deficits induced by the hypofunction of N-methyl d-aspartate (NMDA) receptors in the prefrontal cortex (PFC) might be associated with increased glutamate release and changes in the phosphorylation of the cyclic adenosine monophosphate response element-binding protein on serine 133 (p-S(133)CREB) was investigated in this study. Infusion of 50 ng/side 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid ((R)-CPP), a competitive glutamate NMDA receptor antagonist, into the medial prefrontal cortex (mPFC) of rats performing the five-choice serial reaction time (5-CSRT) task, reduced accuracy of visual discrimination (measured by % correct responses) and enhanced impulsivity (measured by the number of premature responses) and compulsivity (measured by the number of perseverative responses). The mGluR2/3 receptor agonist, LY379268, injected s.c. at 0.1 mg/kg, reduced (R)-CPP-induced impairment in attentional functioning (accuracy) and impulsivity but not compulsive perseveration. In parallel studies using microdialysis technique and Western blot analysis we found that (R)-CPP (100 μM) infused in the medial prefrontal cortex increased glutamate efflux whereas injected in the medial prefrontal cortex at a dose causing impairments in attentional performance (50 ng/side) increased p-S(133)CREB in the frontal cortex (FC), decreased it in the caudate-putamen (CPu) and was without effect in the nucleus accumbens (NAC). LY379268 at the dose effective in reducing (R)-CPP-induced behavioral deficit reduced both the (R)-CPP-induced rise in glutamate efflux in the prefrontal cortex and the increase in p-S(133)CREB in the frontal cortex but was without effect on the decrease in p-S(133)CREB in the caudate-putamen. The data provide evidence that enhanced glutamate release and phosphorylation of cAMP response element binding protein (CREB) on serine 133 may be associated to attention deficit and loss of impulse control. Furthermore they suggest that mGluR2/3 agonists have a therapeutic potential for cognitive deficits.