The abuse of phencyclidine (PCP) and ketamine remain important public health problems. In previous years of this project, we have shown that PCP-like drugs functioned as antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor to produce behavioral effects in animals that are relevant to their abuse potential. Our work so far leaves unresolved whether or not all glutamate and NMDA antagonists may have PCP-like abuse-related effects. This is particularly important because various glutamate antagonists have potential as medications for neurological and behavioral disorders, including as treatments for drug tolerance and dependence. There are two closely-related goals of this project: 1) To further define the cellular site(s) of action for the abuse-related effects of NMDA antagonists by focusing primarily on which modulatory and structural subtype(s) (i.e. NR2A, NR2B, NR2C or NR2D) are most important. 2) To further refine our battery of animal tests for abuse potential assessment to produce more distinctive profiles for glutamate antagonists from different classes. We propose to compare the behavioral pharmacology of NMDA antagonists that act at various sites on the NMDA receptor complex as well as NMDA receptor subtype selective agents using well-validated animal test procedures useful for predicting abuse-related effects. We will also evaluate other nonNMDA glutamatergic compounds, such as agonists and antagonists for the metabotropic glutamate receptor, to further confirm the hypothesis that only NMDA glutamate antagoists have PCP-like effects. Glutamate antagonists will be compared using a) drug discrimination in rats and rhesus monkeys using NMDA antagonists as training drugs, b) intravenous drug self-administration in rhesus monkeys using a progressive-ratio procedure, and c) threshold determinations for electrical brain stimulation reward in rats. We will continue our series of studies relating to current problems arising from the abuse of PCP and ketamine. We plan to study a new abused formulation of PCP referred to as """"""""illy"""""""" that contains formalin and to study combinations of ketamine with drugs commonly encountered in the club drug scene. The proposed research is important for understanding PCP/ketamine abuse and for developing safe medications. The presence of PCP-like side effects and abuse liability will seriously limit the therapeutic usefulness of glutamate antagonists, so knowing how to predict them from animal studies is essential.
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