Role of wake-promoting basal forebrain and adenosinergic mechanisms in sleep-promoting effects of ethanol.
BACKGROUND
Ethanol intake has significant impact on sleep. However, the cellular substrates responsible for sleep promotion following ethanol intake are unknown. The purine nucleoside, adenosine, is responsible for mediating many neuronal and behavioral responses to ethanol. Studies performed in cell cultures suggest that ethanol inhibits equilibrative nucleoside transporter 1 to block the reuptake of adenosine resulting in increased extracellular adenosine. Adenosine also has a pivotal role in sleep regulation. Adenosine acts via A1 receptor to inhibit the wake-promoting neurons of the basal forebrain (BF) resulting in the promotion of sleep. Is ethanol-induced sleep associated with the inhibition of the BF wake-promoting neurons? Do adenosinergic mechanisms in the BF have a role in sleep-promoting effects of ethanol?


METHODS
To address these questions, we performed 3 experiments in Sprague-Dawley rats. First, we verified the effect of ethanol on sleep promotion. Second, we evaluated the effect of ethanol on c-Fos expression (a marker of neuronal activation) in the BF wake-promoting neurons and third we monitored the effects of A1 receptor blockade in the BF on ethanol-induced sleep.


RESULTS
Significant increase in non-rapid eye movement (NREM) sleep with a concomitant decrease in wakefulness was observed during the first 12 hours postethanol. REM sleep remained unaffected. Ethanol administration caused a significant decrease in the number of BF wake-promoting neurons with c-Fos immunoreactivity. Bilateral microinjections of a selective A1R receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine into the BF significantly attenuated sleep-promoting effects of ethanol.


CONCLUSIONS
These results suggest that the inhibition of BF wake-promoting neurons by adenosinergic mechanism may be responsible for the sleep promoting effects of ethanol. We believe our study is the first to investigate the cellular mechanisms responsible for the somnogenic effects of ethanol.
Thakkar
Mahesh M
MM
Harry S. Truman Memorial Veterans Hospital and Department of Neurology, University of Missouri, Columbia, Missouri, USA. thakkarmm@health.missouri.edu
Engemann
Samuel C
SC
Sharma
Rishi
R
Sahota
Pradeep
P
D000241:Adenosine / Q000378:metabolism*; D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002492:Central Nervous System Depressants / Q000097:blood / Q000494:pharmacology; D002799:Cholinergic Fibers / Q000378:metabolism; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D016548:Prosencephalon / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects* / Q000502:physiology*; D012895:Sleep, REM / Q000502:physiology; D014851:Wakefulness / Q000502:physiology*; D014970:Xanthines / Q000494:pharmacology
D058916:Adenosine A1 Receptor Antagonists; D002492:Central Nervous System Depressants; D016760:Proto-Oncogene Proteins c-fos; D043682:Receptor, Adenosine A1; D014970:Xanthines; D000431:Ethanol; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine