Rationale Stimulating muscarinic M /M receptors can blunt reinforcing and other effects of cocaine. A hallmark of addiction is 1 4 continued drug seeking/craving after abstinence and relapse. Objectives We tested whether stimulating M and/or M receptors could facilitate extinction of cocaine seeking, and whether this 1 4 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 M /M receptor- 1 4 preferring agonist xanomeline, the M receptor-selective allosteric agonist VU0357017, the M receptor-selective positive 1 4 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 M +M receptors significantly expedited extinction from 17.2 sessions to 8.3 using xanomeline or 7.8 using 1 4 VU0357017 + VU0152100. VU0357017 alone and VU0152100 alone did not significantly modify rates of extinction (12.6 and 14.6 sessions).
Psychopharmacology – Springer Journals
Published: Dec 18, 2017
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