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Neuropharmacology. 2014 Nov;86:228-40. doi: 10.1016/j.neuropharm.2014.07.016. Epub 2014 Aug 10.

Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism.

Author information

1
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand; Integrative Neuroscience Section, National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA.
2
Medical University Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Waehringerstrasse 13a, A-1090 Vienna, Austria.
3
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
4
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
5
Integrative Neuroscience Section, National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA.
6
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
7
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, USA.
8
Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.
9
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: sramamoorthy@vcu.edu.

Abstract

Salvinorin A (SalA), a selective κ-opioid receptor (KOR) agonist, produces dysphoria and pro-depressant like effects. These actions have been attributed to inhibition of striatal dopamine release. The dopamine transporter (DAT) regulates dopamine transmission via uptake of released neurotransmitter. KORs are apposed to DAT in dopamine nerve terminals suggesting an additional target by which SalA modulates dopamine transmission. SalA produced a concentration-dependent, nor-binaltorphimine (BNI)- and pertussis toxin-sensitive increase of ASP(+) accumulation in EM4 cells coexpressing myc-KOR and YFP-DAT, using live cell imaging and the fluorescent monoamine transporter substrate, trans 4-(4-(dimethylamino)-styryl)-N-methylpyridinium) (ASP(+)). Other KOR agonists also increased DAT activity that was abolished by BNI pretreatment. While SalA increased DAT activity, SalA treatment decreased serotonin transporter (SERT) activity and had no effect on norepinephrine transporter (NET) activity. In striatum, SalA increased the Vmax for DAT mediated DA transport and DAT surface expression. SalA up-regulation of DAT function is mediated by KOR activation and the KOR-linked extracellular signal regulated kinase-½ (ERK1/2) pathway. Co-immunoprecipitation and BRET studies revealed that DAT and KOR exist in a complex. In live cells, DAT and KOR exhibited robust FRET signals under basal conditions. SalA exposure caused a rapid and significant increase of the FRET signal. This suggests that the formation of KOR and DAT complexes is promoted in response to KOR activation. Together, these data suggest that enhanced DA transport and decreased DA release resulting in decreased dopamine signalling may contribute to the dysphoric and pro-depressant like effects of SalA and other KOR agonists.

KEYWORDS:

Dopamine transporter; Dysphoric; Kappa opioid receptor; Pro-depressant; Salvinorin A; Serotonin transporter; Trafficking

PMID:
25107591
PMCID:
PMC4188751
DOI:
10.1016/j.neuropharm.2014.07.016
[Indexed for MEDLINE]
Free PMC Article

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