A Perspective on the New Mechanism of Antidepressants: Neuritogenesis Through Sigma-1 Receptors

M. Takebayashi; T. Hayashi; T.-P. Su

doi:10.1055/s-2004-832679

Pharmacopsychiatry, Table of Contents

Pharmacopsychiatry 2004; 37: 208-213
DOI: 10.1055/s-2004-832679

Original Paper

A Perspective on the New Mechanism of Antidepressants: Neuritogenesis Through Sigma-1 Receptors

M. Takebayashi¹ ^, ² , T. Hayashi¹ , T.-P. Su¹

¹Cellular Pathobiology Unit, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, USA
²present address of M. Takebayashi: Institute of Clinical Research, National Hospital, Kure Medical Center, 3-1 Aoyama, Kure 737-0023, Japan

Abstract

Sigma receptors were first described as one of the opiate receptor subtypes. Now it is well established that sigma receptors, existing as subtypes sigma-1 and sigma-2, are unique non-opioid receptors which are implicated in higher-ordered brain functions. Sigma-1 receptors have high to moderate affinities for (+)benzomorphans and also many psychotrophic drugs and neurosteroids. Sigma-1 receptor agonists and certain neurosteroids such as dehydroepiandrosterone sulfate (DHEA-S) have antidepressant-like effects in animal behavioral models of depression. The antidepressant-like effect induced by sigma-1 receptor agonists may involve intracellular Ca²⁺ mobilization such that sigma-1 receptor agonists modulate Ca²⁺ release from endoplasmic reticulum (ER) in a cytoskeletal protein-dependent manner. In addition, growth factor-induced neurite outgrowth is mediated through sigma-1 receptors, suggesting a role of antidepressants in neuroplasticity. Igmesine (JO1783), OPC-14 523 and SA4503, have recently been developed as sigma-1 agonists and are found to have antidepressant-like activity perhaps with fewer side effects. This article reviews the new potential use of sigma-1 receptor ligands in the treatment of mood disorder.

Full Text

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