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Contribution of both M1 and M4 receptors to muscarinic agonist-mediated attenuation of the cocaine discriminative stimulus in mice

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Abstract

Rationale

We previously showed that muscarinic agonists with M1 and/or M4 receptor affinities attenuated cocaine discrimination and self-administration in wild-type mice but not in M1/M4 double-knockout mice.

Objective

This study aims to elucidate the respective contributions of M1 and M4 receptors to this effect.

Methods

Knockout mice lacking either the M1 subtype (M −/−1 ) or the M4 subtype (M −/−4 ) and wild-type mice were trained to discriminate 10 mg/kg cocaine from saline. Muscarinic ligands were tested for modulation of cocaine discrimination: xanomeline (M1/M4-preferring agonist), VU0357017 (M1-selective partial agonist), 77-LH-28-1 (M1 agonist), and BQCA (M1-selective positive allosteric modulator).

Results

Xanomeline produced rightward shifts in the cocaine dose–effect curve in all three genotypes, but most robustly in wild-type mice. VU0357017 produced rightward shifts in the cocaine dose–effect curve in wild-type and M −/−4 mice, but not in M −/−1 mice. Response rates were suppressed by xanomeline in wild-type and M −/−1 but not in M −/−4 mice and were unaltered by VU0357017. 77-LH-28-1 and BQCA also showed evidence of attenuating cocaine’s discriminative stimulus, but at doses that suppressed responding or had other undesirable effects. Intriguingly, both VU0357017 and 77-LH-28-1 exhibited U-shaped dose–effect functions in attenuating cocaine discrimination. None of the drugs substituted for the cocaine stimulus.

Conclusions

Attenuation of the cocaine stimulus by VU0357017 depended upon M1 receptors, and full effects of xanomeline depended upon both M1 and M4 receptors. Therefore M1-selective agonists and mixed M1/M4 agonists may be promising leads for developing medications that block cocaine’s effects.

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Disorders (J.W.), by the Molecular Libraries Probe Production Centers Network (U54MH084659, P.J.C and C.W.L.), and by a grant from the National Institutes on Drug Abuse (DA027825, M.T.). All procedures were carried out in accordance with the Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (National Research Council 2003) and US laws. We thank Joon Y. Boon for technical assistance.

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Authors and Affiliations

  1. Alcohol and Drug Abuse Research Center, McLean Hospital/Harvard Medical School, Belmont, MA, USA

    Morgane Thomsen, Jeffrey E. Wessell, Brian S. Fulton & S. Barak Caine

  2. Vanderbilt Program in Drug Discovery, Vanderbilt Specialized Chemistry Center (Molecular Libraries Probe Production Centers Network; MLPCN), Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

    Craig W. Lindsley & P. Jeffrey Conn

  3. Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Jürgen Wess

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  1. Morgane Thomsen
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  2. Craig W. Lindsley
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  3. P. Jeffrey Conn
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  4. Jeffrey E. Wessell
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  5. Brian S. Fulton
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  6. Jürgen Wess
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  7. S. Barak Caine
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Correspondence to Morgane Thomsen.

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Thomsen, M., Lindsley, C.W., Conn, P.J. et al. Contribution of both M1 and M4 receptors to muscarinic agonist-mediated attenuation of the cocaine discriminative stimulus in mice. Psychopharmacology 220, 673–685 (2012). https://doi.org/10.1007/s00213-011-2516-9

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