Thomsen Morgane, Fulton Brian S, Caine S Barak
Alcohol and Drug Abuse Research Center, McLean Hospital/Harvard Medical School, Belmont, MA, USA,
Psychopharmacology (Berl). 2014 Feb;231(3):469-79. doi: 10.1007/s00213-013-3256-9. Epub 2013 Aug 31.
We previously showed that the M1/M4-preferring muscarinic agonist xanomeline can acutely attenuate or eliminate cocaine self-administration in mice.
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.
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.
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.
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.
我们之前表明，偏好M1/M4的毒蕈碱激动剂占诺美林可在小鼠中急性减弱或消除可卡因自我给药行为。
用于治疗成瘾的药物可以说是以（亚）慢性或重复给药方案进行给药的。急性效应测试往往无法预测慢性效应，这凸显了对候选药物进行慢性测试的必要性。
训练大鼠在静脉注射可卡因和食物强化的同时FR5 FR5时间表下按压杠杆。一旦基线行为稳定，评估每日一次注射占诺美林7天的效果。
占诺美林预处理呈剂量依赖性（1.8 - 10毫克/千克/天）将可卡因的剂量效应曲线向右移动（A50增加高达5.6倍），行为重新分配到食物强化杠杆。没有耐受性迹象，相反，效应在数天内增强。在高可卡因剂量下，对可卡因选择的抑制似乎是可克服的，并且占诺美林治疗并未显著降低可卡因或食物的总摄入量。
就占诺美林在人类中促进戒除可卡因的潜力而言，研究结果喜忧参半。占诺美林确实使行为从可卡因重新分配到食物，在某些可卡因/占诺美林剂量组合下获得的食物强化物显著增加。然而，效应似乎是可克服的，并且在某些占诺美林/可卡因剂量组合下，食物维持的行为也减少了，这表明临床实用性可能有限。尽管如此，这些数据支持慢性毒蕈碱受体刺激可减少可卡因自我给药的观点。未来的研究应表明，对M1或M1/M4亚型具有更高选择性的配体是否受不良影响的限制较小，并且可以实现更高的疗效。
