Differential role of G protein signaling regulator RGS7 on rewarding effects of opioids and psychostimulants

Abstract

The endogenous opioid system is critical for natural reward responses that drive positive behavioral reinforcement, as well as the reinforcing effects associated with addictive substances, such as morphine. The rewarding and reinforcing properties of many drugs of abuse depend on the activation of the m‐opioid receptor (MOR). MOR is a G‐protein coupled receptor whose signaling efficiency is controlled by the regulator of G‐protein signaling (RGS) proteins. In vitro studies have demonstrated that RGS7, a member of the R7 family of RGS proteins, negatively regulates MOR signaling via inhibitory G‐proteins of the Gi/o class. Co‐labeling studies performed in the CNS show that RGS7 and MOR are co‐expressed in the same neuronal population. However, the impact of RGS7 on MOR signaling in vivo is unknown. This study utilizes both genetic and viral approaches to ablate RGS7 both globally and in specific neuronal populations to determine the contribution of RGS7 in reward‐related behaviors. Global RGS7 knockout mice display enhanced morphine‐induced conditional place preference (CPP) and increased locomotor activity in response to morphine. Conditional elimination of RGS7 in striatal neurons results in similar enhancement of morphine‐induced reward in the CPP test. Using an operant self‐administration task these conditional RGS7 knockout mice also displayed increase active lever pressing, as well as a vertically shifted dose‐response profile of morphine‐intake. Together this suggests that RGS7 modulates the reinforcing properties of morphine. To investigate the impact RGS7 has on morphine‐induced alteration in neuronal excitability and plasticity of glutamatergic synapse, electrophysiology approaches were applied to those mice that underwent morphine self‐administration. It was found that RGS7 exerted its effects by controlling morphine‐induced changes in excitability of medium spiny neurons in the nucleus accumbens (NAc) and gating the compositional plasticity of AMPA and NMDA receptors. We further studied the role of RGS7 in reward‐related behaviors in response to other drugs of abuse, such as psychostimulants. Interestingly, mice lacking RGS7 KO exhibit similar responses to cocaine‐induced CPP as their wild‐type littermates. Overall, the results show that RGS7 in the NAc specifically control the rewarding and reinforcing effects of opioids but not of psychostimulants.Support or Funding InformationThis work was supported by the National Institutes of Health Grants DA026405, DA036082, and DA036596 and by the Canadian Institutes of Health Research (CIHR) Fellowship.