Sigma receptors are non-dopaminergic, non-opioid receptors which bind several neuroleptic drugs and the (+)-enantiomer of some opiate benzomorphans. The biological function of sigma binding sites has, for the most part, remained obscure and there is little data available which differentiates a true drug receptor role from a drug acceptor role. Recent biochemical studies have implicated sigma receptors in modulation of the inositol phosphate second messenger system. In addition, a variety of pharmacological, anatomical, and Physiological studies have indicated that sigma receptors are involved in neural control of movement and may be involved in drug- induced and idiopathic disorders of posture and tone. The purpose of this proposal is to further investigate the biological role of sigma receptors, with particular emphasis on biochemical systems modulated by sigma receptors and their possible involvement in motor control and the pathogenesis of dystonia. Ligands which have high affinity and selectivity for sigma receptors will be developed to use as tools in the biochemical and physiological studies. Involvement of sigma receptors in modulation of second messenger systems, protein phosphorylation, and neurotransmitter release will then be investigated. Application of sigma ligands to motor nuclei of rats will be used to investigate changes in motor behavior and electrophysiological activity. Finally, experiments will be carried out to determine the extent of sigma receptor alteration in brains of mutant dystonic rats. These studies should elucidate some of the functions of sigma receptors at both the biochemical and physiological levels. In addition, the structure-activity study should yield better ligands with which to investigate other aspects of sigma receptor biology and chemistry. The possibility that sigma receptors are involved in motor function and dysfunction suggests that sigma ligands may potentially be useful in treatment of some motor disorders.
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