The use of illicit drugs by over twenty millions individuals in the United States negatively impacts both the economy and allocation of medical resources. Drugs of abuse can interfere with the brain's dopamine reward system, leading to a model in which drug taking and drug seeking behaviors are considered pathologies of the central nervous system. When viewed in the perspective of a disease, drug abuse becomes treatable with pharmacological therapies that seek to restore dopamine signaling to normal. The endogenous hormone ghrelin, which regulates food intake, appears to be one of the strongest modulators of CNS dopamine signaling underlying reward, and thus ghrelin receptors may be prime targets for antagonizing addictive behaviors. The GHSR1a ghrelin receptor, like typical G protein coupled receptors (GPCRs), signals through two pathways, one regulated by G-proteins and the other by -arrestin (arr) proteins. Each signaling arm is thus a potential target for pharmacological regulation by either classical ligands or the newly recognized class of functionally selective biased ligands. However, the signaling events by which GHSR1a mediates the response to drugs of abuse and the relative contribution of arr, which may be important to the modulation of dopaminergic circuit plasticity, have not been well detailed. Our NIDA (National Institute on Drug Abuse) sponsored P30 Center has a program in place to identify and characterize small molecule GPCR ligands useful for understanding and treating drug abuse. We believe the GHSR1a presents an outstanding pharmacological target for treating addiction and that arr signaling will play an important role in modulating dopaminergic signaling to this end. To test our hypotheses we have two specific aims: 1. Characterize GHSR1a signal transduction pathways using a model cell system. We will (a) determine the contribution arr versus G protein to GHSR1a trafficking and signaling, (b) modify molecular determinants underlying the interaction between GHSR1a and arrs, (c) evaluate arr versus G protein signaling bias and (d) establish a high throughput and secondary screens to identify arr/G protein biased ligands;2. Determine the role of arrs in GHSR1a-mediated behaviors using an animal model. We will establish in wild-type and arr2 knockout (arr2KO) mice that pharmacological suppression and/or activation of GHSR1a produces a change in the behavioral responses to cocaine while determining the role of arr2 in these responses. These studies from a basic research perspective will assess the importance of arrs to ghrelin receptor regulation of reward seeking behavior;providing in cell and animal models a framework for investigating classical ghrelin receptor ligands as well as identifying and characterizing functionally selective ones. These studies will also provide a paradigm for future comparative investigations with arr1KO mice and dopamine receptor subtype KO mice. Altogether, our studies from a clinical perspective lay crucial groundwork for the expeditious and safe pharmacological exploitation of ghrelin signaling to reduce drug use and drug-seeking behaviors.
This proposal will characterize the role of beta-arrestin proteins in ghrelin receptor modulation of the dopamine rewarding system of the brain. It will provide a scientific rationale for pharmacologic targeting of ghrelin receptors by classical and biased functionally selective small molecules in order to treat drug abuse and addictive behaviors.
|Toth, Krisztian; Slosky, Lauren M; Pack, Thomas F et al. (2018) Ghrelin receptor antagonism of hyperlocomotion in cocaine-sensitized mice requires ?arrestin-2. Synapse 72:|