Dysfunction of serotonergic activity and emotional responses across the light-dark cycle in mice lackingmelatonin MT2 receptors.

Abstract

Melatonin (MLT) levels fluctuate according to the external light/dark cycle in both diurnal and nocturnal mammals. We previously demonstrated that melatoninMT2 receptor knockout (MT2 -/- ) mice show a decreased nonrapid eyemovement sleep over 24hours and increased wakefulness during the inactive (light) phase. Here, we investigated the role of MT2 receptors in physiological light/dark cycle fluctuations in the activity of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons and anxiety- and depression-like behavior. We found that the 5-HT burst-firing activity was tonically reduced across the whole 24hours in MT2 -/- mice compared with MT2 +/+ mice. Importantly, the physiological changes in the spontaneous firing activity of DRN 5-HT neurons during the light/dark cycle were nullified in MT2 -/- mice, with a higher DRN 5-HT neural firing activity during the light phase in MT2 -/- than in MT2 +/+ mice. The role of MT2 receptors over DRN 5-HT neurons was confirmed by acute pharmacological studies in which the selective MT2 receptors agonist UCM1014 dose dependently inhibited DRN 5-HT activity, mostly during the dark phase. Compared withMT2 +/+ , MT2 -/- mice displayed an anxiety-like phenotype in the novelty-suppressed feeding and in the light/dark box tests; while anxiety levels in the light/dark box test were lower during the dark thanduring the light phase inMT2 +/+ mice, the opposite was seen in MT2 -/- mice. No differences between MT2 +/+ and MT2 -/- mice were observed for depression-like behavior in the forced swim and in the sucrose preference tests. These results suggest that MT2 receptor genetic inactivation impacts 5-HT neurotransmission and interferes with anxiety levels by perturbing thephysiologic light/dark pattern.