Sigma receptors, a novel class of putative neurotransmitter receptors, have been extensively characterized in binding studies, but relatively less is known about their functions in the central nervous system. Indeed, establishment of the function of these sites would greatly strengthen the argument that they serve as a signalling mechanism in the brain. Previous work and work from the investigators laboratories has supported the hypothesis that one function of sigma receptors is to regulate dopamine neurotransmission. The study of sigma-dopamine interactions is important for several reasons: (1) dopamine activity has been hypothesized to be involved in the expression of schizophrenic symptoms, (2) the motor side effects of antipsychotic drug treatment, such as tardive dyskinesia may be related to alterations in dopamine neurotransmission, (3) antipsychotic drugs that produce tardive dyskinesia, such as haloperidol, have high affinity for both dopamine and sigma receipts, (4) sigma ligands have been shown to affect dopamine neurotransmission. The proposed studies will analyze the role of sigma receptors in dopamine neurotransmission within the nigrostriatal system. These studies will address the nature of the interaction from three perspectives: (1) behavioral, using the rat turning model, (2) neurochemical, using microdialysis with electrochemical detection to measure in vivo dopamine release; and (3) electrophysiological, with measurements of firing rate and pattern following administration of sigma ligands. The proposed studies aims to elucidate the sites and mechanisms of action of sigma ligands within the nigrostriatal dopamine system. The proposed research examines the effects of putative sigma antagonists and the possibility of interactions between sigma and NMDA receptors in the nigrostriatal system These issues will be addressed in both cell body and terminal regions by examining the effects of dopamine and NMDA antagonists, and the effects of sigma ligands on NMDA-evoked changes in physiology or neurochemistry. The results of these experiments may provide a better understanding of the role of sigma receptors as a signalling mechanism within the nigrostriatal system and the possible mechanisms by which sigma-active antipsychotics produce movement disorders.
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