• Linda Garcés-Ramírez, Jennifer L Green, Takato Hiranita, Theresa A Kopajtic, Maddalena Mereu, Alexandra M Thomas, Christophe Mesangeau, Sanju Narayanan, Christopher R McCurdy, Jonathan L Katz, and Gianluigi Tanda.
• Psychobiology Section, Medication Discovery Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland, USA.
• Biol. Psychiatry. 2011 Feb 1; 69 (3): 208-17.

BackgroundSubtypes of sigma (σ) receptors, σ₁ and σ₂, can be pharmacologically distinguished, and each may be involved in substance-abuse disorders. σ-Receptor antagonists block cocaine place conditioning and σ-receptor agonists are self-administered in rats that previously self-administered cocaine. Self-administration of abused drugs has been related to increased dopamine (DA) neurotransmission, however, σ-receptor agonist effects on mesolimbic DA are not fully characterized.MethodsReceptor-binding studies assessed affinities of σ-receptor ligands for σ-receptor subtypes and the DA transporter; effects on DA transmission in the rat nucleus accumbens shell were assessed using in vivo microdialysis.ResultsCocaine (.1-1.0 mg/kg intravenous [IV]), the nonselective σ(½)-receptor agonist DTG (1.0-5.6 mg/kg IV), and the selective σ₁-receptor agonist PRE-084 (.32-10 mg/kg IV) dose-dependently increased DA to ∼275%, ∼150%, and ∼160% maxima, respectively. DTG-induced stimulation of DA was antagonized by the nonselective σ(½)-receptor antagonist BD 1008 (10 mg/kg intraperitoneal [IP]) and the preferential σ₂-receptor antagonist SN 79 (1-3 mg/kg IP), but not by the preferential σ₁-receptor antagonist, BD 1063 (10-30 mg/kg IP). Neither PRE-084 nor cocaine was antagonized by BD 1063 or BD 1008.Conclusionsσ-Receptor agonists stimulated DA in a brain area critical for reinforcing effects of cocaine. DTG effects on DA appear to be mediated by σ₂-receptors rather than σ₁-receptors. However, DA stimulation by cocaine or PRE-084 does not likely involve σ-receptors. The relatively low potency on DA transmission of the selective σ₁-receptor agonist, PRE-084, and its previously reported potent reinforcing effects, suggest a dopamine-independent reinforcing pathway that may contribute to substance-abuse disorders.Published by Elsevier Inc.

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