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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Intramural Research (Z01)
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Special Emphasis Panel (CNRB)
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Nemeth-Coslett, Rosemarie V
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National Institute on Drug Abuse
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Hayashi, Teruo; Su, Tsung-Ping (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131:596-610
Cormaci, Gianfrancesco; Mori, Tomohisa; Hayashi, Teruo et al. (2007) Protein kinase A activation down-regulates, whereas extracellular signal-regulated kinase activation up-regulates sigma-1 receptors in B-104 cells: Implication for neuroplasticity. J Pharmacol Exp Ther 320:202-10
Tsai, Shang-Yi; Hayashi, Teruo; Su, Tsung-Ping (2005) Picomolar concentrations of hibernation induction delta opioid peptide [D-Ala2,D-Leu5]enkephalin increase the nerve growth factor in NG-108 cells. Synapse 57:179-81
Hayashi, Teruo; Su, Tsung-Ping (2005) The potential role of sigma-1 receptors in lipid transport and lipid raft reconstitution in the brain: implication for drug abuse. Life Sci 77:1612-24
Marrazzo, Agostino; Caraci, Filippo; Salinaro, Elisa Trovato et al. (2005) Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity. Neuroreport 16:1223-6
Hayashi, Teruo; Su, Tsung-Ping (2004) Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs 18:269-84
Peeters, Magali; Romieu, Pascal; Maurice, Tangui et al. (2004) Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine. Eur J Neurosci 19:2212-20
Takebayashi, Minoru; Hayashi, Teruo; Su, Tsung-Ping (2004) Sigma-1 receptors potentiate epidermal growth factor signaling towards neuritogenesis in PC12 cells: potential relation to lipid raft reconstitution. Synapse 53:90-103
Hayashi, Teruo; Su, Tsung-Ping (2004) Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation. Proc Natl Acad Sci U S A 101:14949-54
Stefanski, Roman; Justinova, Zuzana; Hayashi, Teruo et al. (2004) Sigma1 receptor upregulation after chronic methamphetamine self-administration in rats: a study with yoked controls. Psychopharmacology (Berl) 175:68-75

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