Dysfunction of serotonergic activity and emotional responses across the light‐dark cycle in mice lacking melatonin MT 2 receptors

Melatonin (MLT) levels fluctuate according to the external light/dark cycle in both diurnal and nocturnal mammals. We previously demonstrated that melatonin MT 2 receptor knockout (MT 2 −/− ) mice show a decreased nonrapid eye movement sleep over 24 hours and increased wakefulness during the inactive (light) phase. Here, we investigated the role of MT 2 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 24 hours in MT 2 −/− mice compared with MT 2 +/+ mice.  Importantly, the physiological changes in the spontaneous firing activity of DRN 5‐HT neurons during the light/dark cycle were nullified in MT 2 −/− mice, with a higher DRN 5‐HT neural firing activity during the light phase in MT 2 −/− than in MT 2 +/+  mice. The role of MT 2 receptors over DRN 5‐HT neurons was confirmed by acute pharmacological studies in which the selective MT 2 receptors agonist UCM1014 dose dependently inhibited DRN 5‐HT activity, mostly during the dark phase. Compared with MT 2 +/+ , MT 2 −/− 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 than during the light phase in MT 2 +/+ mice, the opposite was seen in MT 2 −/− mice. No differences between MT 2 +/+ and MT 2 −/− mice were observed for depression‐like behavior in the forced swim and in the sucrose preference tests. These results suggest that MT 2 receptor genetic inactivation impacts 5‐HT neurotransmission and interferes with anxiety levels by perturbing the physiologic light/dark pattern.