2017 — 2019 |
Slosky, Lauren M |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Biased Agonism At Neurotensin Receptor 1 For the Treatment of Methamphetamine Addiction
Abstract Abuse of the highly addictive psychostimulant methamphetamine (meth) is a large and growing public health concern. Meth abuse has devastating social and economic consequences, costing the U.S. billions each year. At present, there are no effective pharmacotherapies for the treatment of meth addiction. The objective of this proposal directly addresses this unmet clinical need, as it includes the evaluation of a novel anti-abuse therapeutic strategy. Meth, like other reinforcing substances, results in aberrant activation of the mesolimbic dopamine system. Restoring dopamine normality in this system is, thus, indicated as a potential addiction treatment strategy. Restoration of dopamine signaling homeostasis may be achieved by targeting the G-protein- coupled receptor (GPCR) neurotensin receptor 1 (NTR1). The efficacy of peptide NTR1 agonists in animal models of addiction have made drug-like, small molecule NTR1 ligands highly sought-after. NTR1, like other GPCRS, signals through both G-protein- and ?-arrestin-mediated pathways. Because of the historical lack of success identifying NTR1 agonists in G protein-based assays, a large-scale screen and optimization effort was undertaken to identify small molecule NTR1 ligands in a ?-arrestin screen. We have characterized the current lead compound SBI-553 as a ?-arrestin biased NTR1 ligand, as it activates ?-arrestin without stimulating NTR1 G-protein signaling. Promising preliminary data show that SBI-553 attenuates meth-associated behaviors in mice. The objectives of this application are to elucidate the mechanism of action of ?-arrestin biased NTR1 ligands and validate their therapeutic potential in clinically relevant murine models of meth use. The central hypothesis is that ?-arrestin biased agonism at NTR1 stimulates NTR1 trafficking and signaling to attenuate the physiological and behavioral consequences of meth exposure. This hypothesis will be tested by pursuing three specific aims, using SBI-553 as a tool compound: 1) Identify the biochemical mechanism of action of ?-arrestin biased NTR1 ligands, 2) Elucidate the physiological effects of ?-arrestin biased NTR1 ligands, and 3) Elucidate the behavioral effects of ?-arrestin biased NTR1 ligands. These aims will be addressed using established GPCR trafficking and signaling assays, state-of-the-art small animal positron emission tomography (PET)/computed tomography (CT) imaging, and murine behavioral studies, including self-administration, in wild-type animals and those lacking NTR1 (NTR1-/-). Exploiting GPCR signaling bias in the treatment of disease is in its infancy, making this application both timely and novel. These studies are significant in that they will not only advance our understanding of how the NT system regulates addictive behaviors, but may also facilitate the development of novel anti-abuse agents and improve outcomes for patients struggling with chemical addiction.
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2019 — 2021 |
Slosky, Lauren M |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. |
Leveraging Functional Selectivity in the Neurotensin Receptor 1-Mediated Treatment of Addiction
Abstract: Opioid and psychostimulant addictions are large and growing public health concerns that are inadequately managed with available therapeutics. The objective of this proposal directly addresses this unmet clinical need, as it includes the evaluation of a novel anti-addiction therapeutic strategy. A shared feature of addictive drugs is their ability to induce inappropriate activation of the mesolimbic dopamine system. Restoration of dopamine signaling homeostasis may be achieved by targeting the G protein-coupled receptor (GPCR) neurotensin receptor 1 (NTR1). NTR1 modulates dopamine signaling via action at putative NTR1/dopamine receptor D2 (D2R) complexes. The efficacy of peptide or small molecule NTR1 agonists in animal models of addiction have made them highly desirable but they all have side effects. NTR1, like other GPCRs, signals through both G protein- and ?-arrestin-mediated pathways. Recently, we have developed and characterized a novel class of small molecule NTR1 ligands, typified by compound SBI-553, which activates ?-arrestin without stimulating G protein signaling. This type of functional selectivity/biased siganling presents an opportunity to produce more directed physiological action and reduce unwanted side effects. My promising initial findings suggest that SBI-553 attenuates opioid and stimulant-associated behaviors in mice without the hypotension and hypothermia characteristic of unbiased NTR1 agonism. The objectives of this application are to elucidate the mechanism by which ?-arrestin biased NTR1 ligands attenuate drug-associated behaviors and validate their therapeutic potential by integrating murine self-administration and functional neuroimaging. My central hypothesis is that selective ?-arrestin activation at NTR1 attenuates addiction-like behaviors and associated changes in regional brain metabolism through antagonism of D2R function. This hypothesis will be tested by pursuing three specific aims, using SBI-553 as a tool compound. I will first (1) K99) define the behavioral effects of ?-arrestin biased NTR1 ligands by conducting self-administration studies in genetically engineered mice. I will then (2) K99) determine the physiological effects of ?-arrestin biased NTR1 ligands using state-of-the-art small animal positron emission tomography/computed tomography (PET/CT). Finally, I will use my new training in murine self-administration and PET/CT to independently (3) R00) evaluate the contribution of D2R to the effects of ?-arrestin biased NTR1 ligands. Pursuit of these aims requires interdisciplinary training in animal models of addiction and neuroimaging to complement my previous studies in molecular biology. Therefore, I have assembled expert collaborators into an interdisciplinary mentoring committee, chaired by Drs. Marc Caron (Mentor) and Lawrence Barak (Co-Mentor). The Caron laboratory at Duke University is uniquely well-positioned to answer questions regarding biased GPCR signaling. We have developed an individualized training plan that will provide me with the scientific and professional skills required to run a productive, independent laboratory and study addiction as a brain disease, including its neurological etiology and behavioral manifestations.
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