Acute and chronic effects of the M1/M4-preferring muscarinic agonist xanomeline on cocaine vs. food choice in rats

• Published in: Psychopharmacology Vol. 231; no. 3; pp. 469 - 479
• Main Authors: Thomsen, Morgane, Fulton, Brian S., Caine, S. Barak
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2014
• Subjects: Animals; Behavior, Addictive - drug therapy; Behavior, Addictive - physiopathology; Biomedical and Life Sciences; Biomedicine; Choice Behavior - drug effects; Choice Behavior - physiology; Cocaine - administration & dosage; Conditioning, Operant - drug effects; Conditioning, Operant - physiology; Dopamine Uptake Inhibitors - administration & dosage; Dose-Response Relationship, Drug; Food Preferences - drug effects; Food Preferences - physiology; Male; Muscarinic Agonists - pharmacology; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry; Pyridines - pharmacology; Rats, Sprague-Dawley; Receptor, Muscarinic M1 - agonists; Receptor, Muscarinic M1 - metabolism; Receptor, Muscarinic M4 - agonists; Receptor, Muscarinic M4 - metabolism; Reinforcement (Psychology); Self Administration; Thiadiazoles - pharmacology; Time Factors; Self-administration; Xanomeline; Muscarinic; Choice; Addiction; Rats; Cocaine
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-013-3256-9

Rationale We previously showed that the M 1 /M 4 -preferring muscarinic agonist xanomeline can acutely attenuate or eliminate cocaine self-administration in mice. Objective Medications used to treat addictions will arguably be administered in (sub)chronic or repeated regimens. Tests of acute effects often fail to predict chronic effects, highlighting the need for chronic testing of candidate medications. Methods Rats were trained to lever press under a concurrent FR5 FR5 schedule of intravenous cocaine and food reinforcement. Once baseline behavior stabilized, the effects of 7 days once-daily injections of xanomeline were evaluated. Results Xanomeline pretreatment dose-dependently (1.8–10 mg/kg/day) shifted the dose-effect curve for cocaine rightward (up to 5.6-fold increase in A 50 ), with reallocation of behavior to the food-reinforced lever. There was no indication of tolerance, rather effects grew over days. The suppression of cocaine choice appeared surmountable at high cocaine doses, and xanomeline treatment did not significantly decrease total-session cocaine or food intake. Conclusions In terms of xanomeline's potential for promoting abstinence from cocaine in humans, the findings were mixed. Xanomeline did produce reallocation of behavior from cocaine to food with a robust increase in food reinforcers earned at some cocaine/xanomeline dose combinations. However, effects appeared surmountable, and food-maintained behavior was also decreased at some xanomeline/cocaine dose combinations, suggesting clinical usefulness may be limited. These data nevertheless support the notion that chronic muscarinic receptor stimulation can reduce cocaine self-administration. Future studies should show whether ligands with higher selectivity for M 1 or M 1 /M 4 subtypes would be less limited by undesired effects and can achieve higher efficacy.