Effects of Ramelteon and Triazolam in a Mouse Genetic Model of Early Morning Awakenings

Abstract

The onset of the daily wheel running bout precedes dark onset by several hours in the early runner genetic variant of mice. Here, we test the hypothesis that timed daily administration of a melatonin agonist, ramelteon, or a benzodiazepine, triazolam, normalizes the timing of daily wheel-running rhythms in early runner mice. The daily profiles of wheel-running activity of early runner mice were monitored continuously in a 12:12 light/dark cycle. Wheel running was assessed before, during and after timed daily oral administration of saline vehicle (n = 12), ramelteon (10 mg/kg, n = 12), or triazolam (1 mg/kg, n = 12). The timing of wheel-running rhythms relative to the light/dark cycle was used as a measure of the timing of wake onset. Under baseline conditions, early runner mice entrained to a light/dark cycle at an advanced phase, approximately 3 h before dark onset, on average. Triazolam, but not ramelteon, suppressed wheel-running acutely when administered just prior to the time at which wheel-running onset had occurred under baseline conditions. On a washout day under a light/dark cycle subsequent to one week of once daily administration, the onset of wheel-running was delayed relative to baseline in both ramelteon-treated mice and triazolam-treated mice. In constant dark subsequent to a second week of once daily administration, the onset of wheel-running activity was not affected by either compound. Thus, ramelteon and triazolam caused a shift in the timing of wheel-running rhythms in an LD cycle but did so without long-term effects on the functioning of the circadian clock.