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LY2033298, a positive allosteric modulator at muscarinic M4 receptors, enhances inhibition by oxotremorine of light-induced phase shifts in hamster circadian activity rhythms

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Abstract

Rationale

Entrainment of circadian rhythms to the light–dark cycle is essential for restorative sleep, and abnormal sleep timing is implicated in central nervous system (CNS) disorders like depression, schizophrenia, and Alzheimer's disease. Many transmitters, including acetylcholine, that exerts its actions via muscarinic receptors modulate the suprachiasmatic nucleus, the master pacemaker.

Objectives

Since positive allosteric modulators of muscarinic M4 receptors are candidates for treatment of mood and cognitive deficits of CNS disorders, it is important to evaluate their circadian actions.

Materials and methods

The effects of intraperitoneally applied muscarinic agents on circadian wheel-running rhythms were measured employing hamsters, a model organism for studying activity rhythms.

Results

Systemic administration of the muscarinic receptor agonist oxotremorine (0.01–0.04 mg/kg) inhibited light-induced phase delays and advances of hamster circadian wheel-running rhythms. The M4 positive allosteric modulator, LY2033298 (10–40 mg/kg), had no effect on light-induced phase shifts when administered alone, yet significantly enhanced (at 20 mg/kg) the inhibitory influence of oxotremorine on light-induced phase delays. In addition, the muscarinic receptor antagonist, scopolamine, which was without effect on light-induced phase shifts when administered alone (0.001–0.1 mg/kg), antagonized (at 0.1 mg/kg) the inhibitory effect of oxotremorine and LY2033298 on light-induced phase delays.

Conclusions

These results are the first to demonstrate that systemically applied muscarinic receptor agonists modulate circadian activity rhythms, and they also reveal a specific role for M4 receptors. It will be of importance to evaluate circadian actions of psychotropic drugs acting via M4 receptors, since they may display beneficial properties under pathological conditions.

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Authors and Affiliations

  1. Department of Biology, Valdosta State University, Valdosta, GA, 31602, USA

    Robert L. Gannon

  2. CNS Unit, IDRS, 125 chemin de ronde, 78290, Croissy sur Seine, Paris, France

    Mark J. Millan

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  1. Robert L. Gannon
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  2. Mark J. Millan
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Correspondence to Robert L. Gannon.

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Gannon, R.L., Millan, M.J. LY2033298, a positive allosteric modulator at muscarinic M4 receptors, enhances inhibition by oxotremorine of light-induced phase shifts in hamster circadian activity rhythms. Psychopharmacology 224, 231–240 (2012). https://doi.org/10.1007/s00213-012-2743-8

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  • DOI: https://doi.org/10.1007/s00213-012-2743-8

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