Phencyclidine (PCP) is a major clinical psychotogenic agent and drug of abuse. PCP and other dissociative anesthetics (e.g. ketamine) induce their unique behavioral effects by blocking neurotransmission mediated at the N-methyl-D-aspartate (NMDA)-type glutamate receptor. In addition to the main agonist binding site for glutamate, the NMDA receptor complex contains multiple co-agonist/modulatory sites, including a strychnine-insensitive glycine binding site. In rodents, stimulation of the glycine site reverses PCP-induced hyperactivity, whereas in humans glycine and similar agents (e.g. D-serine) ameliorate PCP psychosis-like symptoms of schizophrenia. In CNS, glycine and D-serine levels in the immediate vicinity of NMDA receptors are maintained at low, subsaturating doses by the action of colocalized amino acid transporters. Over the past grant cycle, we have demonstrated that inhibitors of glycine transport significantly antagonized neurochemical effects of PCP, both in vitro and in vivo. Further, we have demonstrated the existence of novel transporters which may serve as additional treatment targets, as well as significant interactions between NMDA and GABA-B systems. Finally, we have shown that subchronic PCP administration induces persistent neurophysiological and neuroanatomical changes that may account for chronic cognitive deficits following prolonged abuse and may also serve as an animal model for investigating similar deficits in schizophrenia. Over the upcoming project cycle, we will continue to investigate effects of subchronic continuous treatment and compare these effects with those obtained following subchronic intermittnet or acute perinatal treatment. Neurochemical, neurophysiological and neuroanatomic paradigms will be used to compare consequences of persistent exposure to NMDA antagonists to deficits observed in schizophrenia, as well as the ability of NMDA/glycine-site agonists to reverse these changes. Plain Language: Schizophrenia and substance abuse are both major public health concerns. This project seeks to develop new understandings of effects of drugs of abuse such as PCP and Ketamine in the brain, and seeks to develop new treatments for schizophrenia by searching for drugs that counteract the effect of PCP and ketamine in rodents.
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