MOLECULAR MECHANISM OF PCP- AND SIGMA-DRUG ACTIONS

点击翻译按钮获取中文摘要

The objectives of this application are to investigate the roles of phencyclidine (PCP) and sigma receptors in various physiological processes, including regulation of catecholamine release, activation or inhibition of second messenger systems, and relationship to excitatory amino acid neurotransmitter systems. Although once thought to be a single receptor type due to the non-selectivity of the original drugs used to characterize sigma and PCP receptor-mediated effects, it is now clear that the two receptors are separate entities, based upon several lines of evidence including differential localization. PCP remains a major drug of abuse, although often the sensations it produces are extremely unpleasant. The unique sequelae elicited by PCP and benzomorphans, which interact with PCP and sigma receptors are markedly similar to symptoms of schizophrenia. The development of antagonists for these two receptor types could provide the basis for treatment of PCP abuse and schizophrenia. A clinically used compound thought to exert its antipsychotic properties at least partially through its antagonist action at the sigma receptor is haloperidol, originally identified as a dopamine antagonist. The association of sigma receptors with dopaminergic systems in some brain areas may factor into the "dopamine hypothesis of schizophrenia". There are at present no known antagonists for the PCP receptor, but a major advance in understanding the physiological function of this site has been its localization within the cation channel activated selectively by the excitatory amino acid NMDA. Whether this is the only location of the PCP receptor remains to be determined. The widespread localization of the two receptor types within the brain is suggestive of major significance in neurological processes, but relatively few of these have been characterized, especially those affected by sigma receptor activation. This project will concentrate on exploring the actions of the two receptor types in tissues where they have been identified and there is evidence of their activity. The P.I. has preliminary evidence suggesting that both sigma and PCP agonists inhibit the NMDA-stimulated release of radiolabeled dopamine from guinea pig striatum. Attempts will be made to separate actions mediated through the two receptor types by use of selective antagonists for sigma receptors. Results will be compared to those found for NMDA-stimulated release of radiolabeled norepinephrine from hippocampus. Radioligand binding will be used to investigate potential relationship of sigma to NMDA receptors compared to that described for PCP and NMDA receptors. Cerebellar granule or other cell cultures will be used to explore sigma and PCP receptor effects on several second messenger systems in the absence of potential complication by an intact neural network. Finally, an attempt to localize sigma and PCP receptors on interneurons or catecholaminergic terminals will be made utilizing tetrodotoxin and selective interneuron transmitter antagonists.