Dissertation
Elucidating the neural pathways mediating the extinction and reinstatement of cocaine seeking
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2025
DOI: 10.25820/etd.008205
Abstract
Prior studies indicate the infralimbic cortex (IL) and prelimbic cortex (PL) regulate the inhibition vs. promotion, respectively, of cocaine seeking. As subregions of the rodent medial prefrontal cortex, the IL and PL are uniquely positioned to regulate drug-seeking behavior via distinct afferent and efferent projections. Thus, the present work sought to elucidate the specific projections to and from the IL and PL that may contribute to their opposing influences on cocaine seeking. Utilizing optogenetic and chemogenetic manipulations, connections between the IL, PL, nucleus accumbens shell (NAshell), and amygdala were investigated for their role in the extinction and reinstatement of cocaine seeking. Additionally, the present work analyzed drug-taking behavior between female and male rats, utilizing a large sample size from data pooled across numerous experiments.
Results from the present work indicate IL projections to the NAshell and amygdala are necessary for the encoding and retention of cocaine extinction learning. These results expand on our laboratory’s previous work that identified a role for IL activity in the 20 seconds immediately following an unreinforced lever press for the encoding of cocaine extinction learning. Contrasting with fear conditioning literature, inhibition of BLA projections to the IL or PL had no effect on extinction or reinstatement of cocaine seeking. Analysis of female and male drug-taking behavior during 2-hour, FR1 cocaine self-administration revealed males took more cocaine and acquired the task in fewer sessions than females. Altogether, findings from the present work further our understanding of the neural mechanisms involved in cocaine-seeking behaviors.
Details
- Title: Subtitle
- Elucidating the neural pathways mediating the extinction and reinstatement of cocaine seeking
- Creators
- Alexa Ryan Cohill-Milanick
- Contributors
- Ryan T LaLumiere (Advisor)John H Freeman (Committee Member)Isabel A Muzzio (Committee Member)Jason J Radley (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Psychology
- Date degree season
- Autumn 2025
- DOI
- 10.25820/etd.008205
- Publisher
- University of Iowa
- Number of pages
- xvi, 141 pages
- Copyright
- Copyright 2025 Alexa Ryan Cohill-Milanick
- Language
- English
- Date submitted
- 08/29/2025
- Description illustrations
- illustrations, graphs, tables
- Description bibliographic
- Includes bibliographical references (pages 119-132).
- Public Abstract (ETD)
- Relapse rates are extremely high for individuals with substance use disorder. However, some individuals remain abstinent for extended periods of time, suggesting there are competing motivations over drug seeking. Thus, elucidating the neural mechanisms that promote vs. suppress drug seeking will provide background knowledge for improving translational advances. Of particular interest are the infralimbic and prelimbic cortices, subregions of the rodent medial prefrontal cortex, which regulate the inhibition and promotion, respectively, of cocaine seeking. However, it remains largely unknown how specific projections to and from these regions influence dichotomous roles over cocaine seeking. To investigate these neural mechanisms, rats were first trained to press a lever to self-administer cocaine. Then, as a form of inhibitory learning, all consequences of the lever press were removed and rats decreased, or extinguished, lever pressing. Finally, an aspect of self-administration was reintroduced and rats reinstated, or increased, lever pressing, which serves as a measure of drug seeking. The present work inhibited infralimbic projections to key downstream regions, the nucleus accumbens shell and amygdala, during early extinction training, resulting in impaired cocaine extinction learning. Thus, without manipulation, these pathways are critical for such learning. In contrast, basolateral amygdala projections to the infralimbic or prelimbic cortex had no effect on the extinction or reinstatement of cocaine seeking. The present work also identified sex differences in cocaine-taking behaviors, with males taking more cocaine and acquiring the task more quickly than females. These results highlight the specificity of neural mechanisms involved in cocaine-seeking behavior.
- Academic Unit
- Psychological and Brain Sciences
- Record Identifier
- 9985134848202771
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