BIOLOGICAL AND BIOCHEMICAL CHARACTERIZATION OF SIGMA RECEPTORS

本项目描述了西格玛受体和配体的生化和药理学性质。神经类固醇和sigma-1受体之间的相互作用可能在生理或病理性衰老过程中具有治疗意义，特别是它们对认知功能的调节作用。为了测量内源性神经类固醇水平对sigma-1激动剂抗遗忘作用的贡献，我们今年在肾上腺切除/去势（AdX/CX）小鼠中研究了参与神经类固醇合成的关键酶的作用，以避免循环类固醇的影响。分别用三叶曲烷和非那雄胺降低和提高孕酮水平。结果表明，三洛烷增加了可用的sigma-1受体结合位点，非那雄胺减少了可用的结合位点。sigma-1激动剂PRE-084的抗遗忘作用在AdX/CX小鼠中得到促进，在三叶曲烷治疗后效果更明显。PRE-084效应被非那雄胺阻断。这些结果证实了内源性神经甾体水平调节sigma-1受体介导的学习和记忆过程，并揭示了在神经甾体中，黄体酮可能是sigma-1受体的主要调节剂。-受体；学习和记忆；neurosteroid;钙信号。

This project delineates biochemical and pharmacological properties of sigma receptors and ligands. The interaction between neurosteroids and sigma-1 receptors may be of therapeutic interest during physiological or pathological aging, particularly concerning their modulatory role on cognitive functions. To measure the contribution of endogenous neurosteroid levels to the antiamnesic effects of sigma-1 agonists, we examine this year the effects of key enzymes involved in neurosteroid synthesis, in adrenalectomized/castrated (AdX/CX) mice to avoid the effect of circulating steroids. We used trilostane and finasteride respectively to decrease and increase the progesterone level. Results indicate that the available sigma-1 receptor binding sites are increased by trilostane and decreased by finasteride. The antiamnesic effects of sigma-1 agonist PRE-084 is facilitated in AdX/CX mice and even more after trilostane treatment. The PRE-084 effect is blocked by finasteride. These results confirm that endogenous neurosteroidal levels modulate sigma-1 receptor-mediated learning and memory processes and reveal that, among neurosteroids, progesterone may be the main modulator of sigma-1 receptors. - sigma receptor; learning and memory; neurosteroid; calcium signaling.