Author ORCID Identifier

https://orcid.org/0000-0002-4936-8688

Semester

Fall

Date of Graduation

2023

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Stanley Hileman

Committee Member

Vincent Setola

Committee Member

A. Courtney DeVries

Committee Member

Eric Kelley

Committee Member

Bernard Schreurs

Committee Member

William Stauber

Abstract

Stimulant use disorder is a psychiatric illness that is characterized by repeated use of stimulant drugs despite harm to the user. There are currently no Federal Drug Administration (FDA)- approved medications for stimulant use disorder, and the number of stimulant use-associated deaths have increased over the past decade. Given the prevalence of and lack of treatments for stimulant use disorder, there is an urgent need to identify new drug targets and treatments for this illness. Our group is investigating Regulator of G protein Signaling-12 (RGS12) as one such potential drug target for stimulant use disorder. Mice lacking RGS12 are insensitive to the locomotor-stimulating effects of cocaine at low-to-moderate doses. Dopamine transporter (DAT) levels are also increased in the ventral striatum of RGS12-null mice. We therefore hypothesize that RGS12-null mice clear extracellular monoamines more efficiently than wild-type mice, making them less sensitive to the physiological and behavioral effects of cocaine. To test this hypothesis and to understand RGS12’s role in modulating monoamine neurotransmission, we had two aims: 1) Determine the effect of RGS12 loss on serotonin (SERT) and norepinephrine (NET) transporter levels and uptake/release function, and 2) Investigate the effect of RGS12 loss on other cocaine-related behaviors using intravenous self-administration (IVSA) and cocaine withdrawal assays. We found that RGS12-null mice display elevated SERT levels and uptake function in some brain regions while NET levels were unaffected in RGS12-null mice. We then conducted IVSA studies to evaluate acquisition and extinction of volitional cocaine intake in wild-type and RGS12-null mice. While the rate of acquisition is similar in wild-type and RGS12-null mice, RGS12-null mice administer more infusions of cocaine (0.5 mg/kg/infusion) than wild-type mice. Further, RG12-null mice have an upward-shifted dose-response curve (0.01–3 mg/kg/infusion) compared with wild-type mice. Next, progressive ratio (PR) breakpoint studies were conducted to determine if the motivation for cocaine taking differs between wild-type and RGS12-null mice. There was no difference in breakpoint at 0.25, 0.5, or 1 mg/kg, suggesting that motivation for cocaine intake is similar in wild-type and RGS12-null mice. During the extinction phase of IVSA, wild-type mice maintained elevated active lever responses for the 10-day extinction period while RGS12-null mice significantly reduced active lever responses by day 10. Separate experiments were conducted to determine whether RGS12-null mice experience less severe symptoms of cocaine withdrawal. Cocaine or vehicle was administered to wild-type and RGS12-null mice for 12 days (t.i.d., 5–20 mg/kg per injection), and somatic signs of cocaine withdrawal were recorded six hours following the last injection. Wild-type mice withdrawn from cocaine administration displayed increased grooming events compared with their saline-injected counterparts. In contrast, cocaine-withdrawn RG12-null mice displayed no differences in grooming behavior compared with RGS12-null mice treated with saline, indicating that loss of RGS12 protects against at least one feature of cocaine withdrawal. Collectively, these data provide evidence that inhibition of RGS12 may be a viable treatment strategy to aid in the cessation of cocaine use. However, future studies will be required to evaluate the efficacy, safety, and clinical utility of RGS12 inhibition in the context of stimulant use disorder.

Embargo Reason

Publication Pending

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