| 2021 |
Setola, Vincent |
U18Activity Code Description:
To provide support for testing, by means of a research design, the effectiveness of the transfer and application of techniques or interventions derived from a research base for the control of diseases or disorders or for the promotion of health. The project should be capable of making conclusions which are generalizable to other sites. These are usually cooperative programs between participating principal investigators, institutions, and the sponsoring Institute(s). |
Regulator of G Protein Signaling-12 (Rgs12) as a Target For Sud Therapeutics Development @ West Virginia University
For cocaine use disorder and methamphetamine use disorder, there are presently no FDA-approved medications for their treatment. These substance use disorders (SUDs) are thought to arise from persistent pathophysiologic changes in CNS synaptic transmission caused by initial exposure to these substances. Such initial exposures lead to heightened dopamine levels in the brain?s reward circuitry (a key event in establishing long-term drug-seeking behavior). We recently discovered that mice lacking expression of Regulator of G protein Signaling type-12 (RGS12) are attenuated in their normal hyperlocomotion elicited by acute cocaine or methamphetamine administration. RGS12 is the most complex member of this protein superfamily, containing five different functional domains that affect both heterotrimeric G protein-dependent and -independent signaling cascades. The Target Development Level currently assigned to RGS12 is Tbio. Without a pharmacological inhibitor to RGS12 (which would elevate this protein to the level of Tchem), we have performed genetic studies to discern the molecular functions of RGS12 within neuronal circuitry and the potential utility of reducing RGS12 function toward ameliorating disease states. We observe increased dopamine transporter (DAT) expression and dopamine uptake within the ventral striata, but not dorsal striata, of RGS12-deficient mouse strains. The most likely direct target for RGS12?s action is the presynaptic kappa opioid receptor (KOR), as activation of this GPCR is known to attenuate striatal dopaminergic tone. Given that Oprk1 (KOR) and Rgs12 mRNAs exhibit considerable overlap in their CNS expression patterns, it is likely that the increased DAT expression / function and reduced hyperlocomotion to psychostimulants exhibited by RGS12-null mice are both caused by removal of a critical negative influence on signaling downstream of KOR activation. RGS12 loss was also seen to attenuate KOR-induced conditioned place aversion (CPA) in mice. Based on our newly published data, we hypothesize that RGS12 modulates the output of dynorphin/KOR signaling both to dopamine reuptake and to behavioral responses of analgesia and aversion. To advance the Tbio target RGS12 as a novel SUD drug discovery target, we propose to test in mice whether reducing RGS12 function blunts cocaine-induced withdrawal sequelae and/or blunts the reinstatement of drug-seeking behavior after cocaine self-administration. Inhibiting RGS12 function in the adult mouse brain, by tamoxifen-induced Cre recombinase-mediated excision of Rgs12, is predicted to diminish dopamine-dependent reward upon acute re-exposure to drug, and to shape the dynorphin signaling (that is heightened during withdrawal) away from dysphoria and towards beneficial analgesia. Upon establishing proof-of-principle observations that RGS12 inhibition (via genetic means) helps to ameliorate withdrawal symptoms and blunt drug-seeking behaviors, we will be able to more robustly justify parallel high-throughput screening efforts directed towards identifying small molecule inhibitors of RGS12 biochemical activities. Alternatively, gene therapy-based approaches to decreasing RGS12 expression in SUD could be championed.
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0.943 |