Melatonin Receptors as Modulators of Methamphetamine-Mediated Behaviors

Abstract Drug-induced locomotor and reward-seeking behaviors, induced as a consequence of drugs of abuse, often display distinct variations across the 24-h day. This is especially well documented in mammals treated with the psychostimulant methamphetamine (METH), which triggers dysregulated dopamine release in the mesolimbic system. Time-dependent differences in the response magnitude suggest the involvement of physiological systems that govern circadian rhythms, which may be amenable to therapeutic targeting by agents aimed at treating addiction-related symptomatology. The pineal hormone melatonin signals the duration of the dark phase to brain and peripheral organs through the activation of MT 1 and/or MT 2 G protein–coupled receptor. MT 1 and/or MT 2 melatonin receptors appear to be necessary for the expression of METH-induced sensitization and reward behaviors, and may also play a role in determining the diurnal variations of these phenomena. Melatonin receptors may modulate these effects through downstream regulation of clock genes ( Per1 ) or processes (learning and memory) necessary for the sensitizing and reinforcing properties of METH and other drugs of abuse. MT 1 and/or MT 2 melatonin receptor activation appears to be a required mediator of METH actions. Hence, melatonin receptor antagonists may prove to be useful in attenuating METH abuse-related pathologies.