Xanomeline treatment attenuates cocaine self-administration in rats and nonhuman primates

The lack of an FDA-approved pharmacotherapy to combat cocaine use disorder (CUD) is an ongoing and urgent public health challenge. Emerging evidence suggests that the muscarinic acetylcholine system modulates mesolimbic dopamine release and thus may serve as a suitable target for novel CUD medicatio...

Full description

Saved in:
Bibliographic Details
Published in:Neuropharmacology Vol. 281; p. 110686
Main Authors: Marsh, Samuel A., Heslep, Nicholas, Paronis, Carol A., Bergman, Jack, Negus, S. Stevens, Banks, Matthew L.
Format: Journal Article
Language:English
Published: England Elsevier Ltd 15.12.2025
Subjects:
Animals
Choice Behavior - drug effects
Cocaine - administration & dosage
Cocaine choice
Cocaine-Related Disorders - drug therapy
Conditioning, Operant - drug effects
Dopamine Uptake Inhibitors - administration & dosage
Female
Macaca mulatta
Male
Muscarinic Agonists - pharmacology
Muscarinic receptors
Nonhuman primates
Pharmacotherapy
Rats
Rats, Sprague-Dawley
Self Administration
Xanomeline
Rats
Pharmacotherapy
Xanomeline
Cocaine choice
Muscarinic receptors
Nonhuman primates
ISSN:0028-3908, 1873-7064, 1873-7064
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The lack of an FDA-approved pharmacotherapy to combat cocaine use disorder (CUD) is an ongoing and urgent public health challenge. Emerging evidence suggests that the muscarinic acetylcholine system modulates mesolimbic dopamine release and thus may serve as a suitable target for novel CUD medications. The M1/M4-preferring muscarinic agonist xanomeline was recently approved by the Food and Drug Administration for schizophrenia management, and a previous study in male rats suggested that xanomeline treatment attenuated cocaine self-administration in a cocaine-vs-food choice procedure. The present study was conducted to further examine xanomeline treatment effectiveness on cocaine self-administration in male and female rats and nonhuman primates. Both male and female rats and monkeys were trained to self-administer cocaine during daily behavioral sessions. Repeated xanomeline treatment significantly decreased cocaine choice in rats similar to both pharmacological (amphetamine maintenance) and non-pharmacological (increasing alternative reinforcer value) positive controls. In separate groups of monkeys, acute xanomeline pretreatment decreased cocaine-vs-food choice in three out of four monkeys and selectively decreased cocaine-, but not food-maintained responding, under a multiple schedule of cocaine and food reinforcement in three out of four monkeys. Overall, the consistent effectiveness of xanomeline to reduce IV cocaine self-administration in both rodents and nonhuman primate supports its further evaluation as a CUD medication in humans. [Display omitted] •Xanomeline treatment attenuated cocaine choice in male and female rats.•Acute xanomeline treatment decreased cocaine SA in 7 out of 8 monkeys.•Xanomeline effects were similar to amphetamine maintenance in rats.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0028-3908
1873-7064
1873-7064
DOI:10.1016/j.neuropharm.2025.110686