Phencyclidine is a widely abused drug having dramatic hallucinogenic, intoxicant, and CNS stimulant effects. The cellular mechanisms of these effects are not yet known, but three possible sites of action have been proposed. Phencyclidine has been shown to have specific effects on a type of glutamate receptor, on a class of potassium channels, and on the sigma receptor system. The latter site of action is the least well understood but is particularly interesting because other drugs able to bind to the sigma site (e.g. N-allyl-normetazocine and cyclazocine) also have hallucinogenic effects and also because haloperidol (an important antipsychotic phenothiazine) has a very high affinity for the sigma receptor. These observations suggest that some of the psychotomimetic effects of phencyclidine may be mediated by the sigma receptor rather than the glutamate receptor or the potassium channel interactions. We are ultimately interested in studying the properties of the sigma receptor system: 1) by defining the electrophysiological effects of sigma drugs on neuronal physiology in the central nervous system, 2) by isolating the putative endogenous sigma transmitter, and 3) by identifying the role of the sigma system in the control of neurotransmission in the neocortex. This proposal describes a series of experiments designed to extend our initial observations of the effects of sigma drugs on rat hippocampal neurons in the in vitro brain slice preparation, and to extend our preliminary results which suggested that an endogenous sigma transmitter is released from nerve terminals to bind to sigma receptors in the rat hippocampus. Our specific goals during the proposed period of support are to accomplish two key tasks: we will provide a novel chemical characterization of the putative endogenous sigma factor by comparing the properties of the sigma activity in brain extracts with those released from brain slices in a calcium-dependent manner. [This information will ultimately lead to the isolation and identification of the sigma factor]. The second goal is to develop three bioassays of sigma receptor action that can be used to define the effects of sigma receptor activation, define which sigma drugs are agonists and which antagonists, and can be used to follow the purification of the endogenous sigma factor.
| Patterson, T A; Connor, M; Appleyard, S M et al. (1994) Oocytes from Xenopus laevis contain an intrinsic sigma 2-like binding site. Neurosci Lett 180:159-62 |
| Connor, M A; Chavkin, C (1992) Ionic zinc may function as an endogenous ligand for the haloperidol-sensitive sigma 2 receptor in rat brain. Mol Pharmacol 42:471-9 |
| Connor, M A; Chavkin, C (1991) Focal stimulation of specific pathways in the rat hippocampus causes a reduction in radioligand binding to the haloperidol-sensitive sigma receptor. Exp Brain Res 85:528-36 |
