Preclinical evaluation of muscarinic ligands as candidate pharmacotherapies for cocaine use disorder
Author ORCID Identifier
0009-0000-9753-5586
Defense Date
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Matthew Banks
Abstract
Cocaine Use Disorder (CUD) represents an escalating public health threat for which we lack a Food and Drug Administration (FDA) approved pharmacotherapy. An emerging pharmacotherapeutic target to treat CUD is the muscarinic acetylcholine system. Preclinical evidence suggests that activation of the M1, M4, and M5 muscarinic receptors can produce behaviorally selective reductions in cocaine self-administration in rodents. Therefore, the aim of this dissertation is to determine the efficacy of muscarinic ligands as candidate CUD pharmacotherapies using preclinical cocaine-vs-food choice and fixed-ratio cocaine self-administration procedures. There were three main findings. One, the non-selective muscarinic agonist xanomeline produced a behaviorally selective reduction in cocaine self-administration across sexes, species, pharmacological histories, behavioral histories, and operant procedures. Two, acute and repeated administration of the M1 PAM-agonist VU0364572 did not produce significant reductions in cocaine self-administration at any dose (0.32 – 10 mg/kg) evaluated. Three, both intermittent and extended cocaine access produced similar attenuation of cocaine self-administration, suggesting that behavioral economic factors, such as opening and closing a reinforcer’s economy, are likely responsible for subsequent alterations in cocaine reinforcement. In total, these data support the advancement of xanomeline to human laboratory and clinical trial experiments and the further exploration of muscarinic receptors as potential pharmacotherapeutic targets for CUD. However, the data also indicate that modifying the economic conditions around which cocaine self-administration occurs may also be an impactful mechanism by which we can reduce cocaine reinforcement.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
4-22-2026