Morgane Thomsen1, Brian S Fulton, S Barak Caine. 1. Alcohol and Drug Abuse Research Center, McLean Hospital/Harvard Medical School, Belmont, MA, USA, mthomsen@mclean.harvard.edu.
Abstract
RATIONALE: 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.
RATIONALE: 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: Julia N Heinrich; John A Butera; Tikva Carrick; Angela Kramer; Dianne Kowal; Tim Lock; Karen L Marquis; Mark H Pausch; Mike Popiolek; Shaiu-Ching Sun; Eugene Tseng; Albert J Uveges; Scott C Mayer Journal: Eur J Pharmacol Date: 2009-01-11 Impact factor: 4.432
Authors: Morgane Thomsen; P Jeffrey Conn; Craig Lindsley; Jürgen Wess; Joon Y Boon; Brian S Fulton; Anders Fink-Jensen; S Barak Caine Journal: J Pharmacol Exp Ther Date: 2009-12-08 Impact factor: 4.030
Authors: H E Shannon; K Rasmussen; F P Bymaster; J C Hart; S C Peters; M D Swedberg; L Jeppesen; M J Sheardown; P Sauerberg; A Fink-Jensen Journal: Schizophr Res Date: 2000-05-05 Impact factor: 4.939
Authors: Morgane Thomsen; Andrew C Barrett; Paul Butler; S Stevens Negus; S Barak Caine Journal: J Pharmacol Exp Ther Date: 2017-05-04 Impact factor: 4.030
Authors: C E Van Skike; S E Maggio; A R Reynolds; E M Casey; M T Bardo; L P Dwoskin; M A Prendergast; K Nixon Journal: Prog Neuropsychopharmacol Biol Psychiatry Date: 2015-11-12 Impact factor: 5.067