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, 235 (3), 815-827

Effects of Muscarinic M 1 and M 4 Acetylcholine Receptor Stimulation on Extinction and Reinstatement of Cocaine Seeking in Male Mice, Independent of Extinction Learning

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Effects of Muscarinic M 1 and M 4 Acetylcholine Receptor Stimulation on Extinction and Reinstatement of Cocaine Seeking in Male Mice, Independent of Extinction Learning

Kevin Stoll et al. Psychopharmacology (Berl).

Abstract

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.

Figures

Fig. 1
Fig. 1. Diagram of the experimental designs
The duration of the extinction phase was determined by the subject’s behavior, and typical times are depicted (variable duration is indicated by dotted line at the end of the phase). Similarly, number of acquisition sessions was determined by the subject’s behavior. Illumination of the cue light (symbolized by white star) accompanied cocaine infusions during acquisition in all experiments, and accompanied saline infusions in all but Experiment 3.
Fig. 2
Fig. 2. Baseline behaviors in Experiment 1 and 2
Cocaine infusion earned at acquisition criteria, and saline infusions earned on the first day of extinction and at extinction criteria in Experiment 1 and 2. Ordinate: Infusions earned per 3h session. Data are group means, bars represent one s.e.m. Group sizes: pooled saline, N=26; xanomeline delayed, N=6; all others, N=8.
Fig. 3
Fig. 3. Effects of muscarinic receptor M1/M4 stimulation on extinction of previously cocaine-reinforced behavior
Number of sessions required to meet extinction criteria in Experiments 1 and 2. Data are group means, bars represent one s.e.m. Group sizes as in Fig. 2. *P<0.05, **P<0.01 vs. saline, uncensored Log-rank test.
Fig. 4
Fig. 4. Survival curves of proportion of mice meeting extinction criteria
a. Experiment 1, groups receiving saline or drug immediately after the extinction sessions. b. Experiment 2, groups receiving xanomeline delayed after or unpaired from the extinction sessions. Each symbol represents individual mice, or, when more than one mouse met criteria after the same number of sessions, 2–3 mice. Abscissa: number of sessions to meet extinction criteria; axis was truncated at 30 sessions to improve visibility (longest latency: 64 sessions, saline group). Ordinates: cumulative percentage of mice meeting criteria in each group. Group sizes as in Fig. 2.
Fig. 5
Fig. 5. Effect of post-session xanomeline in “cued” extinction
a. Cocaine intake at acquisition, and saline infusions earned on the first and last day of extinction, in Experiment 3. The “uncued” saline and xanomeline groups (Experiment 1) are included for comparison. Ordinate: infusions earned per 3h session. b. Latency to extinction in the same groups. Ordinate: number of sessions needed to meet extinction criteria. c. Survival curves showing individual events. Abscissa: number of sessions to meet extinction criteria; axis was truncated at 30 sessions for visibility (longest latency: 64 sessions, uncued saline group). Ordinates: cumulative percentage of mice meeting criteria in each group. Group sizes: pooled saline, N=26; all others, N=8.
Fig. 6
Fig. 6. Effect of xanomeline on cocaine prime-induced reinstatement of previously cocaine-reinforced responding
Infusions earned at acquisition criteria (cocaine infusions), at extinction criteria (saline infusions), and after administration of 10 mg/kg cocaine IP (saline infusions). Ordinate: Infusions earned per 3h session. Data are group means, bars represent one s.e.m. Group sizes: N=7. *P=0.01 vs. extinction paired-sample t-test, †P=0.02 vs. saline, unpaired-sample t-test.
Fig. 7
Fig. 7. Effect of xanomeline on extinction after food-reinforced responding
Food reinforcers earned and pump activations earned before and after 7 days treatment with 1.8 mg/kg/day xanomeline or saline. Ordinate: Pump activations earned per 2h session. Data are group means, bars represent one s.e.m. Group sizes: N=7.

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