Haloperidol-induced hypokinesia in rats is differentially affected by the light/dark phase, age, and melatonin

It has been well established that the striatal dopaminergic system is compromised with aging, namely D2 receptor function. Also well documented is the age related decline of the neurohormone, melatonin, in both humans and nonhuman animals. What has not been well studied is the possible interaction between the D2 receptor system and the age related decline in melatonin with its unmistakable pattern of synthesis and release exclusively during the dark phase. We tested the effect of the D2 antagonist, haloperidol (1.0 mg/kg ip), in adolescent (2 mo old) and adult rats (10 mo old) in the light (ZT3) and dark phases (ZT 15) in rats kept in a 12 L/12D cycle and the effect of exogenous melatonin (15 mg/kg ip/day x 4 days for a total of 60 mg/kg) on D2 antagonism. Using the bar test, measuring the extrapyramidal side-effect of hypokinesia, we report haloperidol to work differentially depending on both age and phase. Adult rats experienced the effect of the D2 antagonist in both the light and dark phases, while younger rats did not show hypokinetic affects in the dark. By manipulated lighting, we were able to restore the effect of haloperidol in younger rats in the dark phase. We also found ameliorating effects of melatonin lessening time on the bar after treatment with haloperidol, however, this effect was only found in older rats. These data demonstrate the importance of the light/dark cycle and age in the susceptibility of extrapyramidal effects with use of drugs that target D2 receptor function.