Regulators of G-protein signaling 2 and 4 differentially regulate cocaine-induced rewarding effects

There is a need to identify new therapeutic targets for the treatment of cocaine addiction due to the rise in cocaine abuse and deaths due to cocaine overdose. Regulator of G protein signaling (RGS) proteins such as RGS2 and RGS4 are widely distributed in brain regions that play a role in drug reward. Importantly, RGS2 and RGS4 negatively regulate G-protein coupled receptor signaling pathways of monoaminergic neurotransmitters that play a role in the rewarding effects of cocaine by enhancing the rate of hydrolysis of Gα-bound guanine nucleotide triphosphate. Thus, the objective of this study was to investigate the effects of cocaine on conditioned place preference (CPP) and locomotor activity in mice that lacked either RGS2 or RGS4 (i.e. knockout (KO) mice) and their wildtype (WT) littermates. Moreover recent studies have reported influence of sex on RGS functioning and hence studies were conducted in both male and female mice. Cocaine-induced CPP was attenuated in male, but not female RGS4 KO mice compared to respective RGS4 WT mice. Cocaine-induced CPP was not influenced by deletion of RGS2 in either male or female mice. Similarly, cocaine-induced locomotor activity was not influenced by deletion of either RGS2 or RGS4 irrespective of sex. Together, the data indicate that the rewarding effects of cocaine were attenuated in the absence of RGS4 expression, but not in the absence of RGS2 expression in a sex-dependent manner. Importantly, these data suggest that RGS4 can serve as a potential target for medications that can be used to treat cocaine addiction. The primary finding of this study was that knockout of regulator of G-protein signaling 4 (RGS4) attenuated the rewarding effects of cocaine in male, but not in female mice. Cocaine-induced conditioned place preference (CPP) was not influenced by presence or absence of RGS2 irrespective of sex. Additionally, cocaine-induced increase in locomotor activity was not influenced by presence or absence of either RGS2 or RGS4. Together, these data suggest that RGS4, but not RGS2 plays a role in the rewarding effects of cocaine in a sex-dependent manner. [Display omitted] •Rewarding effects of cocaine were observed in all wildtype (WT) mice (RGS2 WT and RGS4 WT) irrespective of genotype or sex.•Rewarding effects of cocaine were attenuated in male, but not in female mice lacking RGS4 (RGS4 KO).•Presence or absence of RGS2 did not influence the rewarding effects of cocaine irrespective of sex.•RGS2 or RGS4 play no