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An allosteric enhancer of M4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine

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Abstract

Rationale

The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M4 acetylcholine receptor subtype is centrally involved in the regulation of dopamine release in striatal areas. Consequently, striatal M4 receptors could be a novel target for modulating psychostimulant effects of cocaine.

Objectives

For the first time, we here addressed this issue by investigating the effects of a novel selective positive allosteric modulator of M4 receptors, VU0152100, on cocaine-induced behavioral and neurochemical effects in mice.

Methods

To investigate the effect of VU0152100 on the acute reinforcing effects of cocaine, we use an acute cocaine self-administration model. We used in vivo microdialysis to investigate whether the effects of VU0152100 in the behavioral studies were mediated via effects on dopaminergic neurotransmission. In addition, the effect of VU0152100 on cocaine-induced hyperactivity and rotarod performance was evaluated.

Results

We found that VU0152100 caused a prominent reduction in cocaine self-administration, cocaine-induced hyperlocomotion, and cocaine-induced striatal dopamine increase, without affecting motor performance. Consistent with these effects of VU0152100 being mediated via M4 receptors, its inhibitory effects on cocaine-induced increases in striatal dopamine were abolished in M4 receptor knockout mice. Furthermore, selective deletion of the M4 receptor gene in dopamine D1 receptor-expressing neurons resulted in a partial reduction of the VU0152100 effect, indicating that VU0152100 partly regulates dopaminergic neurotransmission via M4 receptors co-localized with D1 receptors.

Conclusions

These results show that positive allosteric modulators of the M4 receptor deserve attention as agents in the future treatment of cocaine abuse.

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Acknowledgments

The Ivan Nielsen Foundation, Aase and Einar Danielsens Foundation, Butcher Max Wørzner and wife Inger Wørzner Foundation, A.P. Møller Foundation for the Advancement of Medical Science, and Lundbeck Foundation supported the present work. We thank Birgit H. Hansen for expert technical assistance.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, Copenhagen University Hospital, 9 Blegdamsvej, 2100, Copenhagen, Denmark

    Ditte Dencker, Pia Weikop, Gunnar Sørensen, David P. D. Woldbye, Gitta Wörtwein & Anders Fink-Jensen

  2. Department of Neuroscience and Pharmacology, University of Copenhagen, 2100, Copenhagen, Denmark

    Ditte Dencker, Pia Weikop, Gunnar Sørensen, David P. D. Woldbye, Gitta Wörtwein & Anders Fink-Jensen

  3. Protein Laboratory, Department of Neuroscience and Pharmacology, University of Copenhagen, 2200, Copenhagen, Denmark

    David P. D. Woldbye

  4. Department of Public Health, Psychiatric Centre Copenhagen, University of Copenhagen, 2100, Copenhagen, Denmark

    Gitta Wörtwein

  5. Molecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Jürgen Wess

Authors
  1. Ditte Dencker
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  2. Pia Weikop
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  4. David P. D. Woldbye
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  5. Gitta Wörtwein
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  7. Anders Fink-Jensen
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Corresponding author

Correspondence to Anders Fink-Jensen.

Additional information

Ditte Dencker and Pia Weikop contributed equally to this work.

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Dencker, D., Weikop, P., Sørensen, G. et al. An allosteric enhancer of M4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine. Psychopharmacology 224, 277–287 (2012). https://doi.org/10.1007/s00213-012-2751-8

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  • DOI: https://doi.org/10.1007/s00213-012-2751-8

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