Sigma receptor agonists: receptor binding and effects on mesolimbic dopamine neurotransmission assessed by microdialysis.
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ABSTRACT: BACKGROUND:Subtypes of sigma (?) receptors, ?? and ??, can be pharmacologically distinguished, and each may be involved in substance-abuse disorders. ?-Receptor antagonists block cocaine place conditioning and ?-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, ?-receptor agonist effects on mesolimbic DA are not fully characterized. METHODS:Receptor-binding studies assessed affinities of ?-receptor ligands for ?-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 ?(½)-receptor agonist DTG (1.0-5.6 mg/kg IV), and the selective ??-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 ?(½)-receptor antagonist BD 1008 (10 mg/kg intraperitoneal [IP]) and the preferential ??-receptor antagonist SN 79 (1-3 mg/kg IP), but not by the preferential ??-receptor antagonist, BD 1063 (10-30 mg/kg IP). Neither PRE-084 nor cocaine was antagonized by BD 1063 or BD 1008. CONCLUSIONS:?-Receptor agonists stimulated DA in a brain area critical for reinforcing effects of cocaine. DTG effects on DA appear to be mediated by ??-receptors rather than ??-receptors. However, DA stimulation by cocaine or PRE-084 does not likely involve ?-receptors. The relatively low potency on DA transmission of the selective ??-receptor agonist, PRE-084, and its previously reported potent reinforcing effects, suggest a dopamine-independent reinforcing pathway that may contribute to substance-abuse disorders.
SUBMITTER: Garces-Ramirez L
PROVIDER: S-EPMC3015019 | biostudies-literature | 2011 Feb
REPOSITORIES: biostudies-literature
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