Wednesday, April 2, 2025
4/2/2025
Regulation of Methamphetamine-Induced Behaviors by the Neurotensin Receptor 1 - PROJECT SUMMARY Methamphetamine (meth) addiction is a large and growing public health concern that is inadequately managed with available therapeutics. This proposal addresses this need by furthering our understanding of a promising new anti-addiction therapeutic strategy. Meth induces inappropriate dopamine (DA) release from neurons of the mesolimbic DA pathway. Restoration of DA signaling homeostasis may be achieved by targeting the G protein- coupled receptor (GPCR) neurotensin receptor 1 (NTSR1). NTSR1 modulates DA signaling via action at putative NTSR1/D2 DA receptor complexes. The efficacy of peptide NTSR1 agonists in animal models of meth use have made clinically useful, small molecule NTSR1 ligands highly desirable. NTSR1, like other GPCRs, signals through both G protein- and β-arrestin-mediated pathways. Recently, we developed and characterized a novel class of small molecule NTSR1 ligands, typified by compound SBI-553, which activate β-arrestin without stimulating G protein signaling. This type of functional selectivity or biased signaling presents an opportunity to produce more directed physiological action and reduce unwanted side effects. Promising data suggests that SBI- 553 attenuates the reinforcing effects of meth in mice without the hypotension and hypothermia characteristic of balanced NTSR1 ligands. At present, the mechanisms by which β-arrestin-biased NTSR1 ligands block meth effects are unclear and the cell type(s) on which β-arrestin-biased NTSR1 ligands act on is unknown. The objectives of this application are to elucidate the molecular mechanism by which β-arrestin-biased NTSR1 ligands achieve β-arrestin recruitment to the NTSR1 and to identify the cell type(s) in the nucleus accumbens (NAc) at which they act to attenuate meth-induced behaviors. My central hypothesis is that is that β-arrestin- biased NTSR1 ligands stimulate receptor-β-arrestin association via a G protein-independent, GPCR kinase 2 (GRK2)-dependent mechanism and attenuate meth-induced behaviors via action on D2-expressing medium spiny neurons (MSNs) in the NAc core. I will test this hypothesis by pursuing two aims, using SBI-553 as a tool compound. I will first (1) elucidate the biochemical mechanism by which NTSR1 ligands recruit β-arrestin, using recently developed GRK- and G protein-subtype-specific-null cells. I will then (2) identify the cell type on which NTSR1 ligands act in the NAc to attenuate meth addiction-like behaviors, visualizing NTSR1-expressing cells in and projecting to the NAc using virally-mediated fluorophore expression and assessing the ability of SBI-553 to attenuate meth-induced locomotion and conditioned place preference in mice lacking NTSR1 selectivity in D2 MSNs. Pursuit of these aims requires interdisciplinary training in molecular biology and systems neuroscience. Therefore, I have assembled expert collaborators into an interdisciplinary mentoring committee, led by Drs. Lauren Slosky (Sponsor) and Kevin Wickman (Co-Sponsor). Together, we have crafted an individualized training plan that will provide me with the foundational scientific and professional skills necessary to reach my long-term goal of running an independent laboratory and studying the neurobiological basis of addiction.
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