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KAPPA OPIOID RECEPTOR AVAILABILITY, SOCIAL RANK, AND COCAINE SELF-ADMINISTRATION IN FEMALE AND MALE MONKEYS

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title
KAPPA OPIOID RECEPTOR AVAILABILITY, SOCIAL RANK, AND COCAINE SELF-ADMINISTRATION IN FEMALE AND MALE MONKEYS
author
Johnson, Bernard Nevin
abstract
Cocaine use disorder (CUD) persists as a worldwide public health problem for which there is no FDA-approved pharmacotherapy. A gap in the literature and the main goal of the research described in this dissertation is to extend decades of study involving primate social behavior with intravenous cocaine self-administration (SA) and noninvasive brain imaging of the dopamine system using positron emission tomography (PET), to an opposing neurobiological system, the dynorphin/kappa opioid receptor (KOR) system.Towards that goal, Aim I (Chapter II) utilized PET imaging with a KOR radiotracer, [11C]EKAP, to obtain baseline measures of KOR availability and assess the relationship between KOR availability and social rank in cocaine-naïve male and female monkeys. There were significant interactions between sex and social rank in [11C]EKAP binding potential (BP) in 12/15 brain regions; the lowest receptor availability across all regions of interest were observed in dominant females and subordinate males, the two most vulnerable phenotypes to cocaine reinforcement based on previous studies. Aim II (Chapter III) examined acquisition of cocaine reinforcement in the monkeys that were characterized in Aim I. Subordinate females acquired cocaine SA at xiv significantly lower doses than their dominant counterparts under a fixed‑ratio (FR) schedule of reinforcement. These findings contrast with previous work from our laboratory showing a direct relationship between social rank and vulnerability to cocaine reinforcement (Nader et al. 2012), perhaps due to the differences in duration of social housing experience. In socially housed male monkeys, I extended the examination of acquisition of cocaine reinforcement to include the context of an alternative, non-drug, reinforcer (cocaine vs. food choice). Consistent with what we had noted previously using FR schedules of reinforcement (Morgan et al. 2002), subordinate male monkeys were more vulnerable to cocaine reinforcement compared with dominant male monkeys. Aim III (Chapter IV) examined the effects of chronic cocaine exposure and subsequent time off from cocaine on the KOR system. Longitudinal PET imaging studies found significant interactions between condition (baseline, 100 mg/kg of cocaine, and 30-days off cocaine), sex, and social rank in [11C]EKAP BP in 7/15 brain regions. These interactions were associated with increases in KOR availability following cocaine SA and after 30-days off from cocaine in dominant females. In a subset of monkeys, no differences were observed in [11C]EKAP binding between 30- and 100-days off from cocaine. Together, the research presented in this dissertation describe the neurobiology of the KOR system associated with social status, sex, and with the vulnerability and the long-term consequences of the reinforcing effects of cocaine in a unique nonhuman primate model of drug abuse and help identify mechanisms to aid in the development of preclinical personalized-medicine strategies for CUD.
subject
Cocaine
Cynomolgus Monkey
Kappa Opioid Receptor
PET Imaging
Sex Differences
Social Rank
contributor
Nader, Michael A (advisor)
Solingapuram Sai, Kiran K (committee member)
Czoty, Paul W (committee member)
Gould, Robert W (committee member)
date
2024-05-23T08:36:13Z (accessioned)
2024-05-23T08:36:13Z (available)
2024 (issued)
degree
Physiology and Pharmacology (discipline)
identifier
http://hdl.handle.net/10339/109417 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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