A perspective on the new mechanism of antidepressants: neuritogenesis through sigma-1 receptors.
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 Ca (2+) mobilization such that sigma-1 receptor agonists modulate Ca (2+) 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.
Takebayashi
M
M
Cellular Pathobiology Unit, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, NIH/DHHS, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Hayashi
T
T
Su
T-P
TP
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001665:Binding Sites / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy; D017480:Receptors, sigma / Q000819:agonists / Q000502:physiology*; D013256:Steroids / Q000493:pharmacokinetics; D000097605:Sigma-1 Receptor
D000928:Antidepressive Agents; D002118:Calcium; D017480:Receptors, sigma; D013256:Steroids; D000097605:Sigma-1 Receptor