Role of Wake‐Promoting Basal Forebrain and Adenosinergic Mechanisms in Sleep‐Promoting Effects of Ethanol

Abstract

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 three 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 first 12 hours post- ethanol. 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. CONCLUSION 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.

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.…”

“…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. 61 In relation to anxiety, several studies have shown the involvement of A 1 receptors. A 1 receptor knockout mice display enhanced anxiety, 63 and the anxiogenic effects of caffeine have been generally attributed to blockade of A 1 receptors, although a role of A 2A receptors cannot be discarded.…”

Nicotine Infusion in the Wake‐Promoting Basal Forebrain Enhances Alcohol‐Induced Activation of Nucleus Accumbens

“…Neuronal activation is indicated by induction of c-Fos (Thakkar et al, 2010; Shiromani et al, 1992; Morgan and Curran, 1991; McKenna et al, 2009). Thus, activation of NAc was examined by monitoring c-Fos expression with immunohistochemistry (IH).…”

“…Rats were divided in four groups: ACSF+W, EtOH, NiC and NiC+EtOH. ACSF (500 nl/side) was bilaterally microinjected into the BF of ACSF+W and EtOH group, whereas nicotine [75 pmol (equivalent to 11 ng nicotine free base)/500 nl/side] was bilaterally microinjected into the BF of the NiC and NiC+EtOH groups as described previously (Thakkar et al, 2008a, 2010). In brief, the rat was gently swaddled in a towel.…”

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

“…A recent study in rodents showed that ethanol promotes non-REM sleep but does not affect REM sleep. The somnogenic effect of ethanol is related to adenosine inhibition of wake-promoting neurons in the basal forebrain via A 1 R. Bilateral microinjections of the selective A 1 R antagonist DPCPX in this area reduce the effect of ethanol on non-REM sleep [113]. A study in which ethanol was administered to mice, either alone or in combination with selective AR agonists and antagonists, and animals were tested for anxiety in the elevated plus-maze, has indicated that activation of A 1 R also mediates the anxiolytic effect of ethanol [114].…”