Author ORCID Identifier
https://orcid.org/0000-0002-3237-394X
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Dr. Javier González-Maeso, PhD
Abstract
Opioid use disorder (OUD), like other substance use disorders (SUD), is characterized by maladaptive behavioral allocation away from other rewarding aspects of life following prolonged use, as well as large rates of relapse. While pharmacotherapies exist for OUD, they tend to only target the opioid receptors rather than the underlying mechanisms behind the maladaptive behaviors. Serotonin (5-hydroxytryptamine; 5-HT) is involved in modulation of cravings and regulation of motivational reward-related behaviors, thought to be due to a top-down processing method of external and internal stimuli. Serotonin 2A receptors (5-HT2AR) are widespread throughout the brain and most densely populate layer V pyramidal neurons in the cortex. These cortical pyramidal neurons project to several subcortical regions, including the nucleus accumbens (NAc), which is a main area associated with drug abuse. 5-HT2ARs are the main target of classical psychedelics, which produce alterations in processes related to cognition, perception and sensory processing via activation of these receptors. These compounds may possess the ability to alter behaviors associated with reward-related behaviors, such as context-related motivation, which plays a large part in substance use disorders. The present work has focused on the assessment of two structurally different psychedelics in their ability to unpair drug-context interactions in an oxycodone (OXY)-induced conditioned place preference (CPP) model. Psilocybin (PSI), prodrug of psilocin, activates a variety of serotonin and other receptors, whereas 2,5-dimethoxy-4-iodoamphetamine (DOI), is more selective for 5-HT2 receptors. Interestingly, both psychedelics acutely produce increase head twitch response with females having increased acute responses compared to males, but only PSI was able to produce a decrease in OXY-induced CPP in male wild-type mice. In the CPP model the effects of PSI were not seen in global knockouts of the 5-HT2AR, but when utilizing cre-recombinase viral vector delivery in knockout mice which allows for assessment of specific expression of 5-HT2AR, it was found that rescue of 5-HT2ARs in a subset of pyramidal neurons that express 5-HT2AR and project to the NAc rescued the effects of PSI on OXY-induced CPP. This suggests there is a modulation of the cortico-striatal reward circuit, potentially influencing the incentive to action and rewarding effects of opioids in this model.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-9-2024