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Circadian rhythms of behavior and physiology are regulated by a hypothalamic master oscillator (the suprachiasmatic nucleus, SCN) and, at the molecular level, are timed by the cyclical transcription of a set of canonical “clock genes”.1 Every autonomously circadian mammalian cell is host to a transcriptional-translational negative feedback loop. Mutations in or deletions of the genes involved result in circadian defects or, in some cases, arrhythmicity.2 Unexpectedly, methamphetamine, when made freely available in the drinking water of mice, is capable of driving circadian rhythms of locomotor behavior in the absence of both the SCN3,4 and, as we have recently demonstrated, several of the canonical clock genes.5 These and other facts suggest the existence of a separate methamphetamine sensitive circadian oscillator (MASCO).
The implied existence of an entirely independent circadian oscillator poses several difficult and important questions: (1) Where is it located? (2) Which genes are involved in its generation? (3) How does it interact with the known circadian oscillators in the SCN and peripheral organs? (4) What are its effects on health, particularly on dopaminergic neurons and the response to drugs of abuse? At the moment we know almost nothing about the first two of these questions. On the basis of very incomplete understanding we can speculate about the third and the fourth.
When both MASCO and the SCN are present, they interact in the control of locomotor behavior. In intact mice, methamphetamine administration changes the phase angle of entrainment to a light: dark cycle and in some cases produces a separate, long period rhythm that “beats” with the 24 h light entrained component which is presumably the output of the SCN.4,6 Similarly, in constant conditions methamphetamine administration can produce two activity components which come together and separate repeatedly (Fig. 1).4,6
Of course, the mechanism that underlies MASCO did not evolve in response to environmental methamphetamine and we are currently unable to observe it in its “native state” (i.e., in the absence of drug). We believe that it may have arisen in response to periodic rewarding stimuli in the environment4,7 and is perhaps related to the food entrainable oscillator (FEO) with which it shares some properties.7,8 We suspect that MASCO oscillates in the absence of drug and that under those conditions it is closely coupled with the SCN and therefore its output is covert. Addition of methamphetamine may loosen this coupling or increase MASCO's amplitude, or both, enabling it independently to regulate some fraction of locomotor output.
If our supposition is correct and MASCO (and perhaps FEO) is part of a system designed to predict the recurrence of rewarding stimuli in the environment then it is likely to play an important role in many reward mediated behaviors including, but not limited to, drug abuse and addiction. There is evidence for circadian rhythms in responsiveness to drugs of abuse9-11 and it is possible that these rhythms are regulated by the coupled action of MASCO and the SCN. Individual variations in the relative strength of these two oscillators or their coupling might explain some of the individual variation in the propensity for drug abuse, addiction, or relapse. The phase relationship between MASCO and other circadian rhythms could also be important in the sensitivity to drugs of abuse. For example, the temporal relationship between a rhythm of responsiveness to the rewarding properties of a drug and the rhythm of its breakdown in the liver could drastically modulate its physiological and psychological effects.
The finding that MASCO is an independent circadian oscillator, which does not employ the canonical circadian molecular feedback loop,5,12 opens the door for further investigations of the site and molecular basis of this oscillator. Such research is likely to inform our understanding of drug abuse and addiction. Likewise, existing knowledge of the neural circuitry of drug abuse will drive research on MASCO. Studies of the interaction between biological rhythms and drugs of abuse are likely to result in significant advances for both fields.
This work was supported by NIH Conte Center grant 1P50MH074924 (M.M.) and F32DA024542 (J.M.).