Pharmaceuticals 2011, 4, 880-914; doi:10.3390/ph4060880 OPEN ACCESS pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Review A Role for Sigma Receptors in Stimulant Self Administration and Addiction Jonathan L. Katz *, Tsung-Ping Su, Takato Hiranita, Teruo Hayashi, Gianluigi Tanda, Theresa Kopajtic and Shang-Yi Tsai Psychobiology and Cellular Pathobiology Sections, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA * Author to whom correspondence should be addressed; E-Mail:
[email protected]. Received: 16 May 2011; in revised form: 11 June 2011 / Accepted: 13 June 2011 / Published: 17 June 2011 Abstract: Sigma1 receptors (σ1Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs.