Regulators Of G‐Protein Signaling 2 And 4 Differentially Regulate the Rewarding Effects of Nicotine and Cocaine

Addiction to nicotine and cocaine is a major cause of preventable premature morbidity and mortality. The reinforcing effects of nicotine and cocaine are primarily mediated by increasing dopamine in the mesolimbic reward pathway. The effects of neurotransmitters like dopamine in this pathway are mediated by G protein‐coupled receptors (GPCRs). Interestingly, regulator of G protein‐signaling (RGS) proteins negatively regulate the functioning of GPCRs. In this study we specifically focused on the role of RGS2 and RGS4, which are extensively distributed in the mesolimbic reward pathway. This study evaluated the effects of RGS2 and RGS4 in the rewarding effects of nicotine (0.5 mg/kg; s.c.; base) and cocaine (15 mg/kg; i.p.) using conditioned place preference procedure (CPP) in mice lacking either RGS2 (i.e. RGS2 KO) or RGS4 (RGS4 KO) and their wildtype counterparts. Because a role of sex has been reported in the effects mediated by different RGS proteins, both male and female mice lacking either RGS2 or RGS4 were studied while assessing the rewarding effects of cocaine and nicotine. Cocaine and nicotine‐induced CPP was observed in all wildtype mice irrespective of genotype and sex. Cocaine‐induced rewarding effects were attenuated in male RGS4 KO mice, but not male RGS2 KO mice compared to respective saline controls. In contrast, nicotine‐induced rewarding effects were attenuated in male RGS2 KO mice, but not in male RGS4 KO mice compared to respective saline controls. Interestingly, knockout of either RGS2 or RGS4 in female mice had no effect on nicotine or cocaine‐induced rewarding effects, respectively. Thus, these data suggest both genotype and sex‐dependent differential effects of RGS2 and RGS4 in the rewarding effects of nicotine and cocaine. Clinically, the data support a role for targeting RGS2 and RGS4 for the treatment nicotine and cocaine addiction, respectively. Support or Funding Information This work was supported by a Bower, Bennett and Bennett grant awarded to Dr. Manoranjan S. D’Souza by the Raabe College of Pharmacy, Ohio Northern University (ONU), Ada, Ohio.