Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY The incidence of stimulant use disorder (SUD) in the United States is on the rise. Notably, no FDA-approved medications exist to treat SUD. Cocaine and methamphetamine (METH) are the primary stimulants used by individuals with SUD. Because those stimulants exert their effects via monoamine transporters (MATs), interventions that modulate MAT function could be effective SUD treatments. Our group identified the brain- expressed protein RGS12 as being a modulator of monoamine transporters, and RGS proteins are thought to be druggable targets. Thus, my first aim (my dissertation research project) is to evaluate RGS12 inhibition as a potential treatment strategy for SUD using a mouse model of the disease. Our group discovered that mice lacking RGS12 function are resistant to the locomotor-activating effects of various stimulants, including 3,4- methylendedioxymethamphetamine (MDMA). My early dissertation work focused on understanding why RGS12- null mice are resistant to MDMA-induced hyperlocomotion. As MDMA’s primary target is the serotonin transporter (SERT), I hypothesized that SERT was dysregulated in RGS12-null mice. To test my hypothesis, I measured SERT expression and function using brain tissue from wild-type and RGS12-null mice. I discovered that, compared with wild-type mice, RGS12-null mice exhibited increases in SERT expression and function. Given that loss of RGS12 in mice is accompanied by increased expression and function of SERT (my finding) and the dopamine transporter (DAT; a previous graduate student’s finding), and because cocaine targets both SERT and DAT, I hypothesized that RGS12-null mice would be resistant to cocaine withdrawal-associated behaviors. To test my hypothesis, I assessed previously reported somatic signs of cocaine withdrawal in wild-type and RGS12-null mice. My results showed that while wild-type mice display increased grooming during cocaine withdrawal, RGS12-null mice do not. In the F99 training phase, I will continue my efforts to validate RGS12 as a target for SUD by measuring cocaine or METH intravenous self-administration (IVSA), the gold standard behavioral paradigm for modeling SUD in laboratory animals. I will determine if there are Rgs12 genotype- associated effects on the acquisition and maintenance of cocaine or METH self-administration, as well as on reinstatement of extinguished cocaine or METH self-administration. My second aim (my postdoctoral research direction) is to characterize the GPCR transcriptome in SUD-relevant circuitry, as GPCRs are excellent targets for modulating the activities of cells/circuits. In the K00 training phase, I will use retrograde tracers to label single cells that project to SUD-relevant brain regions. I will then identify, using single-cell RNA-seq, the GPCR transcriptome of labeled cells. Ideally, those data will reveal GPCRs that, upon activation or inactivation, will dampen dopamine release in the nucleus accumbens. The proposed research phases will provide me ample opportunities to learn new techniques. Additionally, the proposed training plan will help me improve my skills in presenting, writing, mentoring, teaching, and leading a laboratory group.
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