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The Clock Gene Rev-Erbα Regulates Methamphetamine Actions on Circadian Timekeeping in the Mouse Brain
Nora L Salaberry1, Maria Mateo1, Jorge Mendoza2
1CNRS UPR-3212, Institute of Cellular and Integrative Neurosciences, 5 rue Blaise Pascal, 67084, Strasbourg, Cedex, France.
Abstract:
Circadian rhythms are strongly affected by drugs. In rodents, chronic methamphetamine (METH) intake changes circadian activity rhythms, mainly by altering light synchronization that generates the expression of a free-running rhythm with a period longer than 24 h and a second behavioral component that is independent of the main suprachiasmatic (SCN) clock. Although a number of clock genes do not appear to be involved in the effects of METH on circadian behavior, the molecular clockwork controlling these changes is still unclear. Therefore, we investigated the role of the clock gene Rev-Erbα in METH-induced behavioral and molecular responses using knockout mice and their wild-type littermates. Chronic intake of METH alters period circadian behavior of wild-type mice. However, in mice lacking the clock gene Rev-Erbα METH had no effect on their behavioral rhythms. Furthermore, PER2 bioluminescence rhythms in two extra-SCN brain oscillators, the dorsomedial hypothalamus and the habenula, were altered by METH in wild type but not in KO mice. Together, the present results implicate Rev-Erbα in the modulation of the circadian responses to METH and may provide a better comprehension into the mechanisms underlying circadian alterations provoked by drug addiction.
Insights
Methamphetamine (METH) disrupts circadian rhythms by altering light synchronization. The clock gene Rev-Erbα is crucial for these METH-induced behavioral changes, as its absence prevents rhythm alterations.
Area of Science:
- Neuroscience
- Chronobiology
- Pharmacology
Background:
- Circadian rhythms, regulated by the suprachiasmatic nucleus (SCN), govern physiological processes.
- Drug addiction, particularly methamphetamine (METH) use, significantly disrupts these rhythms.
- The molecular mechanisms underlying METH's impact on circadian behavior remain incompletely understood.
Purpose of the Study:
- To investigate the role of the clock gene Rev-Erbα in mediating behavioral and molecular adaptations to chronic METH exposure.
- To elucidate the involvement of Rev-Erbα in extra-SCN circadian oscillators affected by METH.
Main Methods:
- Utilized Rev-Erbα knockout (KO) mice and their wild-type littermates.
- Administered chronic methamphetamine (METH) to assess behavioral rhythm changes.
- Measured PER2 bioluminescence rhythms in brain regions outside the SCN.
Main Results:
- Chronic METH intake altered circadian activity rhythms in wild-type mice.
- METH had no significant effect on behavioral rhythms in Rev-Erbα knockout mice.
- METH altered PER2 bioluminescence rhythms in the dorsomedial hypothalamus and habenula of wild-type mice, but not in KO mice.
Conclusions:
- The clock gene Rev-Erbα plays a critical role in modulating circadian responses to chronic methamphetamine exposure.
- These findings suggest Rev-Erbα is a key component in the neural circuitry affected by METH-induced circadian disruption.
- Understanding Rev-Erbα's function may offer insights into the neurobiological underpinnings of drug addiction and associated circadian dysregulation.
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