Binding experiments suggest the presence of sigma binding sites that are distinct from any known brain neurotransmitter receptor or other drug binding site. These sites are unique in binding with high affinity both antipsychotic drugs and the unnatural (+)-enantiomers of opiates. Recent developments indicate the presence of at least two subtypes of the sigma receptor, termed sigma-1 and sigma-2. Sigma binding is found in many brain areas, particularly in brainstem regions associated with movement, including various cranial nerve nuclei, the red nucleus, cerebellum and the dopamine-rich substantia nigra. An investigation of the role of sigma receptors in the nigros-triatal dopamine system is timely and important for several reasons: 1) Dopamine is hypothesized to be involved in schizophrenia and the motor side effects of antipsychotic drugs. Consequently, understanding the role of sigma receptors in modulating dopamine may have implications for antipsychotic drug therapy. 2) The relationship between sigma receptors and antipsychotic drug therapy takes on added significance from the high to moderate affinity of typical antipsychotic drugs for sigma receptors. This implies that typical antipsychotic drugs could affect dopamine systems though both dopaminergic and sigmaergic mechanisms. 3) New compounds, some with subnanomolar affinities, possess a high degree of selectivity for sigma receptors; these compounds apparently remove previous impediments associated with the use of weak and nonselective sigma ligands. 4) Novel irreversible sigma compounds have been developed that may provide additional pharmacological tools for elucidating the biological role of sigma receptors in modulating dopamine function. 5) Preliminary data indicate that certain sigma compounds produce extremely potent dopamine-mediated effects on behavior. Based on these considerations we propose to investigate the behavioral, neurochemical and electrophysiological consequences of sigma receptor activation in the nigrostriatal dopamine system. These experiments focus on both functional and pharmacological questions. The main functional question is to establish the sites of action of sigma ligands within the nigrostriatal dopamine system. The pharmacological studies aim to establish the role of sigma receptors in the actions of sigma- ligands. This will be accomplished by determining the correlation between the potency of sigma ligands in these systems and their binding to sigma-1 and sigma-2 receptors. The other approach will be to use irreversible sigma ligands to investigate their possible utilization as sigma antagonists. Establishing a clear connection between sigma receptors and nigrostriatal dopamine function may have implications for the mechanisms of the cognitive and motor actions antipsychotic drugs.

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National Institute of Mental Health (NIMH)
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Brown University
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