Melatonin-mediated attenuation of fluphenazine-induced hypokinesia in C57BL/6 mice is dependent on the light/dark phase

Our aims were to assess the effect of melatonin on fluphenazine-induced hypokinesia during the light (ZT 9.5–10.5) and dark (ZT 17.5–18.5) phases in mice lacking endogenous pineal melatonin (C57BL/6 mouse), and to investigate the effects of the manipulation of environmental lighting in mice with a targeted deletion of the MT1 melatonin receptor. In both knockout (C57KO MT1) and wild type (C57WT) mice, fluphenazine (1 mg/kg) induced hypokinesia during the light phase (C57WT: M=105, SEM=31.2 s, n = 31; C57 MT1KO:M=118, SEM = 32.6 s, n = 29). During the light phase melatonin (10 mg/kg, sc) significantly reduced hypokinesia in both genotypes (C57WT: M=33.1, SEM=8.4 s; C57 MT1KO: M=33.3, SEM=13.0 s). In the dark, fluphenazine did not induce a substantial hypokinesia in either C57WT or C57 MT1KO mice. Manipulating the lightning environment during testing, experiments conducted during the light phase in a dark environment served to abolish the hypokinetic effect of fluphenazine in all groups regardless of melatonin treatment. Conversely, experiments conducted during the dark phase in a light environment showed mice to have hypokinetic effects by fluphenazine treatment in both C57WT (M=98.4, SEM=20.2 s) and C57 MT1KO (M=40.4 SEM=9.5 s) groups. These data suggest that fluphenazine-induced hypokinesia is more pronounced under light than dark conditions, and that melatonin is only able to counteract hypokinesia during the light phase. Importantly, our data suggest that the effect of melatonin on hypokinesia was not solely mediated by the MT1 melatonin receptor in the C57BL/6 mouse, leaving the possible activation of MT2 receptor as the mechanism of action which is regulated by the light/dark environment.