Melatonin Receptors as Modulators of Methamphetamine-Mediated Behaviors

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 MT₁ and/or MT₂ G protein-coupled receptor. MT₁ and/or MT₂ 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. MT₁ and/or MT₂ 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.