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    Sex differences in synaptic plasticity within the reward system: the role of PKMζ and implications for opioid use disorder

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    Genre
    Thesis/Dissertation
    Date
    2023
    Author
    Knouse, Melissa cc
    Advisor
    Briand, Lisa
    Committee member
    Wimmer, Mathieu
    Parikh, Vinay
    Sutton Hickey, Ames
    Bangasser, Debra
    Kirby, Lynn
    Department
    Psychology
    Subject
    Psychology
    Neurosciences
    AMPA
    Glutamate
    Nucleus accumbens
    PKMζ
    Substance use disorder
    Synaptic plasticity
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/8600
    
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    DOI
    http://dx.doi.org/10.34944/dspace/8564
    Abstract
    Despite the fact that more men are diagnosed with substance use disorder, women escalate their drug consumption faster, exhibit higher craving during withdrawal, and have poorer treatment outcomes. Furthermore, as our cultural expectations of men and women have changed, there has been an increase in drug use in women and this increase is likely to persist. Preclinically, female rodents show stronger behavioral responses to drugs of abuse during initiation, escalation, and reinstatement of drug seeking. These behavioral differences are accompanied by alterations in structural plasticity within the mesocorticolimbic reward system. However, little is known about what functional sex differences exist in glutamate transmission in these circuits. The goal of these experiments was to determine functional sex differences in reward circuitry that may underlie behavioral sex differences in substance use disorder. We found heightened glutamate transmission in both the medial prefrontal cortex and nucleus accumbens in females compared to males. These findings corresponded with the nucleus accumbens being less plastic in females. We then investigated the role of PKMζ, a glutamatergic AMPA receptor trafficking protein, in plasticity and opioid-taking. We found PKMζ plays a role in synaptic plasticity within the nucleus accumbens and it works to blunt oxycodone-taking and motivation in a dose-dependent manner. Taken together these findings suggest there are functional sex differences at many levels within the reward system and gaining a better understanding of these differences could provide insight into improved treatments for substance use disorder.  
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