Acute ethanol modulates glutamatergic and serotonergic phase shifts of the mouse circadian clock in vitro.
Alcohol abuse is associated with sleep problems, which are often linked to circadian rhythm disturbances. However, there is no information on the direct effects of ethanol on the mammalian circadian clock. Acute ethanol inhibits glutamate signaling, which is the primary mechanism through which light resets the mammalian clock in the suprachiasmatic nucleus (SCN). Glutamate and light also inhibit circadian clock resetting induced by nonphotic signals, including 5-HT. Thus, we investigated the effects of acute ethanol on both glutamatergic and serotoninergic resetting of the mouse SCN clock in vitro. We show that ethanol dose-dependently inhibits glutamate-induced phase shifts and enhances serotonergic phase shifts. The inhibition of glutamate-induced phase shifts is not affected by excess glutamate, glycine or d-serine, but is prevented by excess brain-derived neurotrophic factor (BDNF). BDNF is known to augment glutamate signaling in the SCN and to be necessary for glutamate/light-induced phase shifts. Thus, ethanol may inhibit glutamate-induced clock resetting at least in part by blocking BDNF enhancement of glutamate signaling. Ethanol enhancement of serotonergic phase shifts is mimicked by treatments that suppress glutamate signaling in the SCN, including antagonists of glutamate receptors, BDNF signaling and nitric oxide synthase. The combined effect of ethanol with these treatments is not additive, suggesting they act through a common pathway. Our data indicate further that the interaction between 5-HT and glutamate in the SCN may occur downstream from nitric oxide synthase activation. Thus, acute ethanol disrupts normal circadian clock phase regulation, which could contribute to the physiological and psychological problems associated with alcohol abuse.
Prosser
R A
RA
Department of Biochemistry and Cellular and Molecular Biology, Walters Life Sci Building M407, University of Tennessee, Knoxville, TN 37996, USA. rprosser@utk.edu
Mangrum
C A
CA
Glass
J D
JD
D020268:Alcohol-Induced Disorders, Nervous System / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000009:adverse effects; D021081:Chronobiology Disorders / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000009:adverse effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D009924:Organ Culture Techniques; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D012893:Sleep Wake Disorders / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D002492:Central Nervous System Depressants; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D012701:Serotonin; D000431:Ethanol; D018698:Glutamic Acid; D052248:Nitric Oxide Synthase Type I