Sigma receptor agonists: Receptor binding and effects on mesolimbic dopamine neurotransmission assessed by microdialysis

Linda Garcs-Ramrez, Jennifer L. Green, Takato Hiranita, Theresa A. Kopajtic, Maddalena Mereu, Alexandra M. Thomas, Christophe Mesangeau, Sanju Narayanan, Christopher R. McCurdy, Jonathan L. Katz, Gianluigi Tanda

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Background: Subtypes 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. Methods: Receptor-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. Results: Cocaine (.11.0 mg/kg intravenous [IV]), the nonselective σ1/2-receptor agonist DTG (1.05.6 mg/kg IV), and the selective σ1-receptor agonist PRE-084 (.3210 mg/kg IV) dose-dependently increased DA to ∼275%, ∼150%, and ∼160% maxima, respectively. DTG-induced stimulation of DA was antagonized by the nonselective σ1/2-receptor antagonist BD 1008 (10 mg/kg intraperitoneal [IP]) and the preferential σ2-receptor antagonist SN 79 (13 mg/kg IP), but not by the preferential σ1-receptor antagonist, BD 1063 (1030 mg/kg IP). Neither PRE-084 nor cocaine was antagonized by BD 1063 or BD 1008. Conclusions: σ-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.

Original languageEnglish (US)
Pages (from-to)208-217
Number of pages10
JournalBiological Psychiatry
Volume69
Issue number3
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

Keywords

  • Abuse liability
  • addiction
  • cocaine
  • dopamine microdialysis
  • nucleus accumbens
  • reinforcing effects
  • sigma receptors

ASJC Scopus subject areas

  • Biological Psychiatry

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