Activation of medial prefrontal cortex neurons by phencyclidine is mediated via AMPA/kainate glutamate receptors in anesthetized rats

Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia

“…NAAG peptidase inhibitors have been shown to reduce positive, negative, and cognitive behaviors elicited by PCP and D-amphetamine in these models (25,26,47,57). 5 The data presented here represent the first demonstration of the neurochemical effects of NAAG peptidase inhibition in brain regions associated with schizophrenia. Their efficacy in dramatically elevating extracellular levels of NAAG and in blocking PCP-induced motor activation and increases in glutamate, but not dopamine release, in the mPFC and NAc provides a framework for defining the molecular pathway that mediates their behavioral effects.…”

“…4 We found that potent glutamate carboxypeptidase II inhibitors also reduced the behavioral effects of PCP, dizocilpine and D-amphetamine in validated animal models of positive, negative, and cognitive schizophrenia-like behaviors (24 -26). 5 In contrast to heterotropic group II agonists, NAAG is a selective mGluR3 agonist (12), a fact supported by our finding that the efficacy of NAAG peptidase inhibitors in blocking PCP-induced behaviors is observed in mGluR2 knock-out mice but not in mGluR3 knockouts (26).…”

“…In contrast, a group II agonist blocked D-amphetamine-induced motor activation and increases in DA release but not electrically evoked DA release in the mPAG, bringing into question its mechanism of action (27,29). Because ZJ43 and 2-PMPA also reduce D-amphetamine-induced motor activation, 5 it will be interesting to determine if the peptidase inhibitors affect DA release in the D-amphetamine model. This demonstration of the efficacy of glutamate carboxypeptidase inhibitors in elevating NAAG levels and blocking PCPinduced increases in glutamate release suggests that their mechanisms of action in the behavioral studies may reside in part or wholly within the mPFC and NAc because these areas have previously been implicated in the behavioral effects of PCP.…”

“…Subsequent studies demonstrated that PCP increases extracellular levels of glutamate and dopamine in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) (1), presumably as a result of decreased activation of NMDA receptors on GABAergic interneurons. Excess glutamate activation of AMPA receptors appears to be involved in the effects of PCP because an AMPA antagonist blocks the behavioral effects of PCP in animal models (2)(3)(4)(5). As a result, the glutamate theory of schizophrenia supports the development of drugs that reduce PCP-induced glutamate release as novel antipsychotic therapies.…”

Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model

“…Furthermore, a common preclinical model of schizophrenia involving transient blockade of N-methyl-D-aspartate receptors (NMDARs) with repeated administration of NMDAR antagonists during a critical period of adolescent development induces profound and lasting deficits in LTD at synapses from the hippocampus to PFC (Ghoshal and Conn, 2015;Thomases et al, 2014). This has been postulated to contribute to the increased activity of PFC neurons observed following phencyclidine (PCP) treatment in rodents (Katayama et al, 2007;Suzuki et al, 2002;Thomases et al, 2014;Wang et al, 2007) as well as the subsequent behavioral changes associated with negative and cognitive symptoms in the disorder (Neill et al, 2010(Neill et al, , 2014.…”