No abstract

Degeneration of dopaminergic neurons causes Parkinson’s disease. Dopamine replacement therapy with L-DOPA is the best available treatment. However, patients develop L-DOPA-induced dyskinesia (LID). In the hemiparkinsonian rat, chronic L-DOPA increases rotations and abnormal involuntary movements modeling LID, via supersensitive dopamine receptors. Dopamine receptors are controlled by G protein-coupled receptor kinases (GRKs). Here we demonstrate that LID is attenuated by overexpression of GRK3 in the striatum, whereas knockdown of GRK3 by microRNA exacerbated it. Kinase-dead GRK3 and its separated RGS homology domain (RH) suppressed sensitization to L-DOPA, whereas GRK3 with disabled RH did not. RH alleviated LID without compromising anti-akinetic effect of L-DOPA. RH binds striatal Gq. GRK3, kinase-dead GRK3, and RH inhibited accumulation of ∆FosB, a marker of LID. RH-dead mutant was ineffective, whereas GRK3 knockdown exacerbated ∆FosB accumulation. Our findings reveal a novel mechanism of GRK3 control of the dopamine receptor signaling and the role of Gq in LID.

Dopamine (DA) system plays critical roles in many aspects of brain function. Abnormal dopaminergic activity is closely related to Parkinson's disease, schizophrenia, drug addiction and other neurological and psychiatric disorders. Postsynaptic density (PSD)-95, a scaffolding molecule, enriched at glutamatergic synapses, is found to have important functions in the modulation of clustering of several neurotransmitter receptor, adhesion molecules, ion channels, cytoskeletal elements and signaling molecules at postsynaptic areas. In this review we will highlight the role of PSD-95 in the interaction and regulation of DA receptors. We will also discuss the importance of PSD-95 in the regulation D1 and N-methyl-D-aspartate (NMDA) receptor functional coupling.

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.