Phencyclidine (PCP), also known as angel dust, is an important drug of abuse in the United States. In addition to producing profound changes in behavior, PCP disrupts neuroendocrine function and affects body temperature. These changes not only participate in the acute and chronic drug effects, but also can be used to provide information on the underlying mechanisms of drug action. Although there is a large volume of information on the neurochemical basis of PCP-induced changes in behavior, little is known about the neurochemical mechanisms mediating the effects of PCP on neuroendocrine function and body temperature. The overall goal of the proposed studies is to define the role of N-methyl-D-aspartate (NMDA) and monoaminergic systems in the effects of PCP on the hypothalamic-pituitary-adrenal (HPA) axis and body temperature. The proposed studies will characterize the effects of both competitive NMDA antagonists and glycine antagonists in order to determine whether stimulation of the HPA axis and changes in body temperature are general properties of compounds that inhibit NMDA receptor-mediated neurotransmission. Interactions between the various binding sites on the NMDA receptor also will be assessed by determining whether competitive antagonists and glycine antagonists can reduce the effects of PCP and MK- 801 on the HPA axis and body temperature. The role of monoaminergic systems in producing some of the effects of PCP and MK-801 on neuroendocrine function and body temperature will be evaluated by using selective monoaminergic receptor antagonists. Knowledge of the fundamental mechanisms of action by which the effects of PCP are manifested is imperative in order to develop strategies with which to prevent and possibly treat the sequelae of this important drug of abuse. The proposed studies also will generate new information on the effects of inhibiting NMDA receptor-mediated neurotransmission. As the NMDA receptor is thought to play a major role in development, learning and memory, seizure and mental disorders as well as neurotoxicity, studying the effects of PCP and its interactions with NMDA receptors may lead to new and important information outside of the area of drug abuse that could increase our understanding of the etiology and the treatment of neurological and mental disorders.
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