title: Acute and chronic effects of the M1/M4-preferring muscarinic agonist xanomeline on cocaine vs. food choice in rats.
abstract: BACKGROUND
  We previously showed that the M1/M4-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 M1 or M1/M4 subtypes would be less limited by undesired effects and can achieve higher efficacy.
authors.affiliation: Alcohol and Drug Abuse Research Center, McLean Hospital/Harvard Medical School, Belmont, MA, USA, mthomsen@mclean.harvard.edu.
authors.forename: Morgane
authors.initials: M
authors.lastname: Thomsen
authors.forename: Brian S
authors.initials: BS
authors.lastname: Fulton
authors.forename: S Barak
authors.initials: SB
authors.lastname: Caine
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy / Q000503:physiopathology; D002755:Choice Behavior / Q000187:drug effects* / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005518:Food Preferences / Q000187:drug effects* / Q000502:physiology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000819:agonists / Q000378:metabolism; D043588:Receptor, Muscarinic M4 / Q000819:agonists / Q000378:metabolism; D012054:Reinforcement, Psychology; D012646:Self Administration; D013830:Thiadiazoles / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D018765:Dopamine Uptake Inhibitors; D018721:Muscarinic Agonists; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4; D013830:Thiadiazoles; C075257:xanomeline; D003042:Cocaine