Role of nucleus accumbens shell orexin in motivation for cocaine self-administration

Rutgers Biomedical/Health Sciences-Rbhs, New Brunswick NJ

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Drug addiction is a chronic disease that produces significant costs to individuals and society. While almost one million Americans suffer from cocaine use disorders, there are currently no approved pharmacotherapies for this disease. Our laboratory has implemented animal models of cocaine abuse that analyze motivation to take cocaine (behavioral economics demand curve analysis) and the propensity for cocaine relapse (cued reinstatement of extinguished cocaine seeking). I will use those behavioral methods in conjunction with DREADD chemogenetics and morpholino antisense approaches to determine the roles of orexins (hypocretins) in nucleus accumbens shell (AcbSh) in cocaine abuse. Orexins are importantly involved in the motivation for cocaine, and orexin neurons provide direct projections to AcbSh. In addition, all drugs of abuse increase dopamine signaling in this brain region, and in vitro studies found that orexin in AcbSh increases dopamine concentration. These and other findings point to a role for orexin signaling in AcbSh in cocaine abuse. However, this possibility has received little examination. The hypothesis of this proposal is that orexin in AcbSh drives cocaine demand and is necessary for cued-reinstatement of cocaine seeking behavior. Aim 1 will use pharmacology to inactivate AcbSh orexin receptors OX1R and OX2R in behavioral economics (BE) and reinstatement paradigms. Previous work with BE found that OX1R signaling is associated with cocaine demand (motivation). OX2R is more abundant in AcbSh and has been recently implicated in drug seeking. I expect that inactivation of both receptors will decrease demand and cocaine cued-reinstatement. Aim 2 will use a disconnection approach with DREADDs and morpholino antisense to confirm results in Aim 1. A hM4Di DREADD will inactivate lateral or dorsomedial hypothalamic neurons projecting to AcbSh unilaterally while morpholino antisense microinjected into the lateral hypothalamus or dorsomedial hypothalamus will downregulate orexin on the contralateral side to the DREADDs during BE and cued-reinstatement. I predict that inactivation of AcbSh- projecting lateral hypothalamic neurons in rats that receive orexin morpholino antisense in LH will result in decreased cocaine demand during BE and increased lever pressing in cued-reinstatement. This would support previous suggestions that lateral hypothalamic orexin neurons mediate reward, whereas dorsomedial orexin neurons mediate arousal. The expected results would indicate that this lateral hypothalamic orexin-AcbSh circuit drives cocaine demand and reinstatement. Together, the proposed studies will increase our understanding of the orexin system, as well as the neural circuitry underlying cocaine addiction. This fellowship will train the applicant in orexin neurobiology and in several innovative techniques in systems and behavioral neuroscience, including chemogenetic and pharmacological approaches; self-administration and behavioral economics paradigms; cannula and catheter surgeries; morpholino knockdown; and immunohistochemical techniques. These skills will be critical for the applicant to become an independent investigator in the drug addiction field.