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Role of GRK6 in the addictive effect of psychostimulant drugs
Author(s) -
Li Lingyong,
Gurevich Eugenia V
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.659.14
Subject(s) - g protein coupled receptor kinase , nucleus accumbens , dopamine receptor , pharmacology , amphetamine , dopamine , dopamine receptor d2 , addiction , brain stimulation reward , g protein coupled receptor , desensitization (medicine) , receptor , neuroscience , chemistry , psychology , biology , biochemistry
The dopamine innervation of the nucleus accumbens (NAc) is the key neural substrate mediating the primary reinforcing and psychomotor stimulant effects of drugs of abuse. Psychostimulant drugs (PDS) enhance the dopamine concentration by blocking dopamine transporter and/or inducing non‐vesicular dopamine release in the brain, which increases the activity of dopamine receptors. G protein‐coupled receptor kinases (GRKs) are the key proteins regulating the signaling of G protein‐coupled receptors (GPCR) via the mechanism of homologous desensitization. The aim of the present study was to investigate the role of GRK6‐dependent GPCR desensitization in PSD addiction. Overexpression of GRK6 in NAc using lentivirus‐mediated gene transfer reduced cocaine and amphetamine‐induced conditioned place preference (CPP). The effect of down‐regulation of GRK6 in NAc on PSD‐induced CPP was also tested. To evaluate the role of GRK6 in drug craving and relapse, the drug‐induced reinstatement of CPP was performed. Our results shift the traditional focus away from receptors themselves and put the GRK/arrestin‐based receptor desensitization machinery as the main regulatory mechanisms involved in PSD reward. A pharmacological strategy based on increasing activity and/or availability of GRK6 may be a promising therapeutic approach for PSD addiction. Work supported by NIH grants NS065868 and R21DA030103.