Rationale: Stimulating muscarinic M1/M4 receptors can blunt reinforcing and other effects of cocaine. A hallmark of addiction is continued drug seeking/craving after abstinence and relapse.
Objectives: We tested whether stimulating M1 and/or M4 receptors could facilitate extinction of cocaine seeking, and whether this was mediated via memory consolidation.
Methods: Experimentally naïve C57BL/6J mice were allowed to acquire self-administration of intravenous cocaine (1 mg/kg/infusion) under a fixed-ratio 1 schedule of reinforcement. Then, saline was substituted for cocaine until responding extinguished to ≤30% of cocaine-reinforced responding. Immediately after each extinction session, mice received saline, the M1/M4 receptor-preferring agonist xanomeline, the M1 receptor-selective allosteric agonist VU0357017, the M4 receptor-selective positive allosteric modulator VU0152100, or VU0357017 + VU0152100. In additional experiments, xanomeline was administered delayed after the session or in the home cage before extinction training began. In the latter group, reinstatement of responding by a 10-mg/kg cocaine injection was also tested.
Results: Stimulating M1 + M4 receptors significantly expedited extinction from 17.2 sessions to 8.3 using xanomeline or 7.8 using VU0357017 + VU0152100. VU0357017 alone and VU0152100 alone did not significantly modify rates of extinction (12.6 and 14.6 sessions). The effect of xanomeline was fully preserved when administered delayed after or unpaired from extinction sessions (7.5 and 6.4 sessions). Xanomeline-treated mice showed no cocaine-induced reinstatement.
Conclusions: These findings show that M1/M4 receptor stimulation can decrease cocaine seeking in mice. The effect lasted beyond treatment duration and was not dependent upon extinction learning. This suggests that M1/M4 receptor stimulation modulated or reversed some neurochemical effects of cocaine exposure.
Keywords: Abuse; Addiction; C57BL/6; Cholinergic; Extinction; Mouse; Preclinical; Psychostimulant; Relapse.