Author ORCID Identifier
https://orcid.org/0000-0001-9044-7698
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Matthew L. Banks
Abstract
In recent years, there has been a sharp increase in the number of cocaine-related overdose deaths, a concerning trend given the current lack of Food and Drug Administration-approved pharmacotherapies for cocaine use disorder. Pharmacological manipulations targeting dopamine have been shown to modulate cocaine-maintained behavior; however, there has been no success in developing effective treatment strategies for cocaine use disorder. Thus, there is a need for basic research into the mechanisms of cocaine’s reinforcing effects to improve our understanding of cocaine reinforcement towards identifying novel therapeutic targets. The goal of this dissertation was to selectively manipulate the mesocorticolimbic dopamine pathway using DREADDs and evaluate the role of this pathway in the neurobiology of cocaine reinforcement using a translationally relevant cocaine-vs-food choice procedure.
Accordingly, the first portion of this dissertation used a high throughput locomotor assay to evaluate the pharmacology of DREADDs as tools and three DREADD agonists. The effects of DCZ, CNO, and C21 were evaluated in TH:Cre female and male rats pre- and post-intra-VTA Gq DREADD virus injection and compared to locomotor effects produced by d-amphetamine to empirically determine the appropriate agonist and doses to use in the second portion of this dissertation. There were four main findings. First, d-amphetamine significantly increased locomotor activity in the absence and presence of VTA Gq DREADDs, suggesting expression of the receptors did not alter amphetamine’s effects. Second, no DREADD agonist dose tested significantly altered locomotor activity prior to Gq DREADD virus injection, demonstrating a degree of behavioral selectivity. Third, DCZ was more potent to increase locomotor activity compared to CNO or C21 post-DREADD virus injection. Lastly, DCZ maintained elevated locomotor activity in a subset of rats over the 2hr locomotor sessions, supporting selection of DCZ for use in further studies.
The second portion of this dissertation evaluated the effects of acute and chronic activation or inactivation of the mesocorticolimbic dopamine pathway on cocaine reinforcement using a cocaine-vs-food choice procedure in female and male rats that has shown translational utility in modelling clinical aspects of behavioral misallocation between drugs and alternative nondrug reinforcers. There were three main findings. First, acute and continuous DCZ treatment prior to VTA Gq or Gi DREADD expression had no significant effect on cocaine choice, confirming and extending the results of the first portion of this dissertation. Second, acute activation of VTA dopaminergic neurons significantly increased cocaine choice, while acute inactivation had no effect. Third, continuous activation of VTA dopaminergic neurons had no effect on cocaine choice, suggesting potential tolerance to DCZ effects on Gq DREADDs.
Overall, these results suggest activation of a subset of VTA dopaminergic neurons is sufficient to increase cocaine’s relative reinforcing effectiveness, but inactivation of a subset of VTA dopaminergic neurons is insufficient to alter cocaine’s relative reinforcing effectiveness. Because of the low Gi DREADD expression profile, interpretation of the Gi DREADD results is difficult regarding whether there was insufficient expression to modulate VTA dopaminergic neurons or dampening VTA dopaminergic neuron activity does not alter cocaine choice. Lastly, this dissertation also provides evidence for both the utility and potential limitations of chemogenetic tools in behavioral neuroscience research.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-7-2024