Role of adenosine and wake‐promoting basal forebrain in insomnia and associated sleep disruptions caused by ethanol dependence

Abstract

J. Neurochem. (2010) 115, 782–794. Abstract Insomnia is a severe symptom of alcohol withdrawal; however, the underlying neuronal mechanism is yet unknown. We hypothesized that chronic ethanol exposure will impair basal forebrain (BF) adenosinergic mechanism resulting in insomnia‐like symptoms. We performed a series of experiments in Sprague–Dawley rats to test our hypothesis. We used Majchrowicz’s chronic binge ethanol protocol to induce ethanol dependency. Our first experiment verified the effects of ethanol withdrawal on sleep–wakefulness. Significant increase in wakefulness was observed during ethanol withdrawal. Next, we examined c‐Fos expression (marker of neuronal activation) in BF wake‐promoting neurons during ethanol withdrawal. There was a significant increase in the number of BF wake‐promoting neurons with c‐Fos immunoreactivity. Our third experiment examined the effects of ethanol withdrawal on sleep deprivation induced increase in BF adenosine levels. Sleep deprivation did not increase BF adenosine levels in ethanol dependent rats. Our last experiment examined the effects of ethanol withdrawal on equilibrative nucleoside transporter 1 and A1 receptor expression in the BF. There was a significant reduction in A1 receptor and equilibrative nucleoside transporter 1 expression in the BF of ethanol dependent rats. Based on these results, we suggest that insomnia observed during ethanol withdrawal is caused because of impaired adenosinergic mechanism in the BF.

Alcohol and Caffeine: The Perfect Storm

“…[55][56][57][58][59] The recent studies by Thakkar and coworkers strongly suggest that alcohol-induced increase in adenosine in the basal forebrain and stimulation of A 1 receptors in the cholinergic neurons of the corticopetal basal forebrain arousal system is particularly involved in the acute somnogenic effects of alcohol. [60][61][62] First, they showed with in vivo microdialysis that local perfusion of alcohol elevates significantly the extracellular concentration of adenosine in the basal forebrain. 60 Second, systemic alcohol administration reduced the activity of cholinergic cells in the basal forebrain and the bilateral microinjection of an A 1 receptor antagonist in the same brain region significantly attenuated alcohol-induced sleep.…”

Prospective and Retrospective Memory Deficits Associated with Androgenic Anabolic Steroid Use

“…NGF mediates higher brain functions such as learning and memory and the findings from this work raises the concern that persistent AAS use in humans may affect those mechanisms that lie at the core of neuronal plasticity (the brain's ability to reorganize itself by forming new neural connections across a person's life-span). Given the importance of the basal forebrain in producing acetylcholine which plays a key role in the ability of brain cells to transmit information to one another [33] and the role the hippocampus plays in memory consolidation [34], it is feasible that the memory deficits observed in previous work and in the current study may reflect damage caused to brain plasticity in humans who use AAS. However, further work on the potential interaction between persistent AAS use, brain plasticity and memory deficits in human populations is clearly needed before any firm conclusions can be reached.…”

Adenosine A1 Receptors in the Central Nervous System: Their Functions in Health and Disease, and Possible Elucidation by PET Imaging

“…Whereas most studies reported a transient increase of A 1 R agonist binding upon acute or chronic administration of ethanol, one old [95] and one recent [125] study reported decreases of A 1 R expression in some brain areas of rats. Decreased A 1 R expression in the wake-promoting basal forebrain may be related to insomnia associated with ethanol withdrawal [125].…”