Melatonin has been implicated in attenuating an organism's response to drugs of abuse, like cocaine and nicotine. We used melatonin receptor knockout mice to characterize the role of melatonin receptors in regulating nicotine response over the 24-h circadian cycle.

Normal C3H mice have greater nicotine-induced hypothermia and locomotor depression in the light phase than in the dark phase of the circadian cycle. Melatonin 1a knockouts and their wild-type littermates had attenuated response to nicotine, but no significant variation between the light and dark phases. Melatonin 1a knockouts and the wild-types self-administer significantly less nicotine.

Melatonin 1a1b knockouts have increased sensitivity to nicotine, no consistent variation between the light and dark phases, and increased voluntary oral nicotine consumption. Males in the mutant genotypes had increased sensitivity to nicotine compared to females. We conclude that melatonin receptors modulate the physiological response to nicotine, especially in the dark phase of the circadian cycle.