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

Melatonin (MLT) levels fluctuate according to the external light/dark cycle in both diurnal and nocturnal mammals. We previously demonstrated that melatonin MT₂ receptor knockout (MT₂ ^-/- ) 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 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 24 hours 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 with MT₂ ^+/+ , 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 than during the light phase in MT₂ ^+/+ 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 the physiologic light/dark pattern.

MT2 receptors; UCM1014; anxiety; light/dark cycle; melatonin; serotonin.