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

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 (.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.

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.

• Authors: 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, Gianluigi Tanda
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 69 Issue 3 Pg. 208-17 (Feb 01 2011) ISSN: 1873-2402 [Electronic] United States
• PMID: 20950794 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• 1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine
• 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo(d)oxazol-2(3H)-one
• Benzoxazoles
• Dopamine Plasma Membrane Transport Proteins
• Ethylamines
• Ethylenediamines
• Guanidines
• Morpholines
• Piperazines
• Pyrrolidines
• Receptors, sigma
• BD 1008
• 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
• N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin
• Cocaine
• 1,3-ditolylguanidine
• Dopamine

Topics

• Animals
• Benzoxazoles (pharmacology)
• Cocaine (pharmacology)
• Dopamine (metabolism)
• Dopamine Plasma Membrane Transport Proteins (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Drug Interactions
• Ethylamines (pharmacology)
• Ethylenediamines (pharmacology)
• Guanidines (analysis, pharmacology)
• Male
• Microdialysis (methods)
• Morpholines (pharmacology)
• Nucleus Accumbens (drug effects, metabolism)
• Piperazines (pharmacology)
• Pyrrolidines (pharmacology)
• Radioligand Assay (methods)
• Rats
• Rats, Sprague-Dawley
• Receptors, sigma (agonists, antagonists & inhibitors, metabolism)
• Synaptic Transmission (drug effects)