Date Approved

4-2022

Document Type

Dissertation

Degree Name

PhD in Cell & Molecular Biology

Department

Cell Biology and Neuroscience

College

Graduate School of Biomedical Sciences, Virtua Health College of Medicine & Life Sciences of Rowan University

First Advisor

Jessica Loweth, PhD

Committee Member 1

Daniel Manvich, PhD

Committee Member 2

Daniel Chandler, PhD

Committee Member 3

Barry Waterhouse, PhD

Committee Member 4

Debra Bangasser, PhD

Subject(s)

Cocaine-Related Disorders, Substance-Related Disorders, Estrous Cycle, Conditioning, Operant, Receptor, Metabotropic Glutamate 5, Sex Differences, Models, Animal, Behavior and Behavior Mechanisms

Disciplines

Behavior and Behavior Mechanisms | Cell Biology | Disease Modeling | Laboratory and Basic Science Research | Medical Cell Biology | Medical Molecular Biology | Medicine and Health Sciences | Molecular and Cellular Neuroscience | Substance Abuse and Addiction

Abstract

Cocaine use disorder is a chronic, relapsing brain disease. Sex and ovarian hormones are known to influence cocaine addiction liability and relapse vulnerability. However, little is known regarding the cellular and synaptic mechanisms contributing to sex differences in relapse vulnerability, including how these measures are influenced by hormonal fluctuations. To investigate sex differences in relapse vulnerability we use a rodent model of cocaine craving and relapse called the incubation model in which cue-induced seeking progressively increases or “incubates” during the first month of withdrawal from extended-access cocaine self-administration. Using this model, we have recently shown that females in the estrus stage of the cycle (Estrus Females) show enhanced incubated cue-induced craving compared to both females in all other stages of the cycle (Non-Estrus Females) and Males. One region known to play a critical role in driving cue-induced drug seeking behavior is the basolateral amygdala (BLA). However, less is known regarding the effects of cocaine exposure on BLA excitatory synaptic transmission. To investigate this, we conducted ex vivo whole-cell patch clamp recordings and western blots in adult male and female Sprague-Dawley rats following 2-3 weeks of withdrawal from extended-access cocaine administration or drug-naïve controls from BLA pyramidal neurons. Our data indicate sex differences and estrous cycle effects in glutamate receptor expression and BLA excitatory synaptic transmission during the first month of withdrawal from extended-access cocaine self-administration. Additionally, we wanted to identify a translationally relevant therapeutic target that may be contributing to the estrous cycle-dependent changes in incubated cocaine craving that we have observed. We focused on metabotropic glutamate receptor 5 (mGlu5) as studies have shown that mGlu5-dependent transmission plays a critical role in mediating the reinforcing properties of cocaine, including estrogen-dependent changes in behavioral responding to the drug. To investigate mGlu5’s role in the BLA, we conducted western blots to assess changes in mGlu5 expression in the BLA and behavioral studies to determine whether the BLA is a key site of action through which mGlu5 inhibition reduces enhanced incubated craving in Estrus Female. Together these findings lay the groundwork for understanding the mechanisms driving sex differences in incubated cue-induced cocaine craving.

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