Methods to Assess Melatonin Receptor-Mediated Phase-Shift and Re-entrainment of Rhythmic Behaviors in Mouse Models

The neurohormone melatonin facilitates entrainment of biological rhythms to environmental light-dark conditions as well as phase-shifts of circadian rhythms in constant conditions via activation of the MT₁ and/or MT₂ receptors expressed within the suprachiasmatic nucleus of the hypothalamus. The efficacy of melatonin and related agonists to modulate biological rhythms can be assessed using two well-validated mouse models of rhythmic behaviors. These models serve as predictive measures of therapeutic efficacy for treatment of circadian phase disorders caused by internal (e.g., clock gene mutations, blindness, depression, seasonal affective disorder) or external (e.g., shift work, travel across time zones) causes in humans. Here we provide background and detailed protocols for quantitative assessment of the magnitude and efficacy of melatonin receptor ligands in mouse circadian phase-shift and re-entrainment paradigms. The utility of these models in the discovery of novel therapeutics acting on melatonin receptors will also be discussed.