Investigating Regulator of G protein Signaling 12 (RGS12) as a Potential Target for Cocaine Use Disorder Therapeutics

James Lamp*, Allison White, and Vincent Setola

West Virginia University School of Medicine, Cellular and Integrative Physiology Program, West Virginia University, Morgantown, WV 26506

Presentation Category: Oral-Science & Technology (Oral Presentation #31)

Student’s Major: Neuroscience

Cocaine is the most-used illegal psychostimulant in the United States today. As a result of its widespread usage, cocaine use disorder (CUD) is the third most common drug-related disorder in the world after alcoholism and opioid use disorder. Currently, there is no approved pharmacological method for helping persons with CUD achieve and sustain abstinence, so identifying potential treatments for CUD is an important unmet medical need. Cocaine exerts its effects on the brain by blocking the reuptake of synaptic dopamine and serotonin through the dopamine transporter (DAT) and the serotonin transporter (SERT), respectively. Our group recently discovered that mice lacking the Regulator of G protein Signaling 12 (RGS12) protein exhibit blunted locomotor responses to cocaine and to other psychostimulants that target DAT and SERT (e.g., amphetamine, MDMA). Further, mice lacking RGS12 exhibit increased expression and function of DAT and SERT, the primary molecular targets through which cocaine blocks dopamine and serotonin reuptake. Based on these findings, we sought to address whether the absence of RGS12 in mice affects behavioral features associated with cocaine withdrawal. To do so, we treated wild-type and Rgs12 knockout mice with a twelve-day regimen of cocaine that has been shown to result in somatic signs (e.g., digging, grooming, rubbing) of withdrawal. We hypothesized that the insensitivity of mice lacking RGS12 to the locomotor-stimulating effects of cocaine may indicate a resistance to withdrawal from the drug. If correct, our hypothesis would suggest that pharmaceuticals targeting RGS12 might be effective treatments for persons with CUD.

Funding: The project described was supported by grant number T32 GM132494 from NIH NIGMS (AW) and grant number U18 DA052497 from NIH NIDA (VS).

Program/mechanism supporting research/creative efforts: WVU's Research Apprenticeship Program (RAP) & accompanying HONR 297-level course