Nucleus accumbens-specific interventions in RGS9-2 activity modulate responses to morphine.

Regulator of G protein signalling 9-2 (Rgs9-2) modulates the actions of a wide range of CNS-acting drugs by controlling signal transduction of several GPCRs in the striatum. RGS9-2 acts via a complex mechanism that involves interactions with Gα subunits, the Gß5 protein, and the adaptor protein R7BP. Our recent work identified Rgs9-2 complexes in the striatum associated with acute or chronic exposures to mu opioid receptor (MOR) agonists. In this study we use several new genetic tools that allow manipulations of Rgs9-2 activity in particular brain regions of adult mice in order to better understand the mechanism via which this protein modulates opiate addiction and analgesia. We used adeno-associated viruses (AAVs) to express forms of Rgs9-2 in the dorsal and ventral striatum (nucleus accumbens, NAc) in order to examine the influence of this protein in morphine actions. Consistent with earlier behavioural findings from constitutive Rgs9 knockout mice, we show that Rgs9-2 actions in the NAc modulate morphine reward and dependence. Notably, Rgs9-2 in the NAc affects the analgesic actions of morphine as well as the development of analgesic tolerance. Using optogenetics we demonstrate that activation of Channelrhodopsin2 in Rgs9-2-expressing neurons, or in D1 dopamine receptor (Drd1)-enriched medium spiny neurons, accelerates the development of morphine tolerance, whereas activation of D2 dopamine receptor (Drd2)-enriched neurons does not significantly affect the development of tolerance. Together, these data provide new information on the signal transduction mechanisms underlying opiate actions in the NAc.

Regulators of G protein signaling in neuropsychiatric disorders.

Regulators of G protein signaling (RGS) comprise a diverse group of about 40 proteins which determine signaling amplitude and duration via modulation of receptor/G protein or receptor/effector coupling. Several members of the RGS family are expressed in the brain, where they have precise roles in regulation of important physiological processes. The unique functions of each RGS can be attributed to its structure, distinct pattern of expression, and regulation, and its preferential interactions with receptors, Galpha subunits and other signaling proteins. Evidence suggests dysfunction of RGS proteins is related to several neuropathological conditions. Moreover, clinical and preclinical work reveals that the efficacy and/or side effects of treatments are highly influenced by RGS activity. This article summarizes findings on RGS proteins in vulnerability to several neuropsychiatric disorders, the mechanism via which RGS proteins control neuronal responses and their potential use as drug targets.