A<sub>1</sub>Receptor and Adenosinergic Homeostatic Regulation of Sleep-Wakefulness: Effects of Antisense to the A<sub>1</sub>Receptor in the Cholinergic Basal Forebrain

Thakkar, Mahesh; Winston, Stuart; McCarley, Robert W.

doi:10.1523/jneurosci.23-10-04278.2003

Cited by 159 publications

(116 citation statements)

References 49 publications

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…The negative correlation between the sleep-loss-dependent decreases in A 1 AR availability and increase in N3 in the first sleep cycle of recovery sleep seemingly contradicts animal findings on the involvement of the adenosinergic system in the homeostatic regulation of sleep (24)(25)(26)46). This negative correlation-similar to the correlations for the cognitive performance impairments and sleepiness-is most likely because of a wake-dependent increase of adenosine release/concentration, outweighing the homeostatic upregulation of A 1 AR, and thus leaving fewer sites available for binding with the PET receptor ligand.…”

Section: Discussionmentioning

confidence: 81%

See 1 more Smart Citation

Recovery sleep after extended wakefulness restores elevated A ₁ adenosine receptor availability in the human brain

Elmenhorst

Hennecke

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Adenosine and functional A 1 adenosine receptor (A 1 AR) availability are supposed to mediate sleep-wake regulation and cognitive performance. We hypothesized that cerebral A 1 AR availability after an extended wake period decreases to a well-rested state after recovery sleep. [ 18 F]CPFPX positron emission tomography was used to quantify A 1 AR availability in 15 healthy male adults after 52 h of sleep deprivation and following 14 h of recovery sleep. Data were additionally compared with A 1 AR values after 8 h of baseline sleep from an earlier dataset. Polysomnography, cognitive performance, and sleepiness were monitored. Recovery from sleep deprivation was associated with a decrease in A 1 AR availability in several brain regions, ranging from 11% (insula) to 14% (striatum). A 1 AR availabilities after recovery did not differ from baseline sleep in the control group. The degree of performance impairment, sleepiness, and homeostatic sleep-pressure response to sleep deprivation correlated negatively with the decrease in A 1 AR availability. Sleep deprivation resulted in a higher A 1 AR availability in the human brain. The increase that was observed after 52 h of wakefulness was restored to control levels during a 14-h recovery sleep episode. Individuals with a large increase in A 1 AR availability were more resilient to sleep-loss effects than those with a subtle increase. This pattern implies that differences in endogenous adenosine and A 1 AR availability might be causal for individual responses to sleep loss.S leep loss is known to impair almost every aspect of cognition, such as learning (1), long-term memory consolidation (2), attention and psychomotor vigilance (PVT) (3), and executive functions (4), including decision making (5) and emotional control (6). Sleep deprivation further typically alters the frequency distribution of the waking electroencephalogram (EEG) as an indicator of alertness corresponding to cognitive performance (7). However, large interindividual differences exist in the degree of cognitive performance decline during sleep deprivation (3). In a trait-like process, some individuals keep high-level performance during sustained wakefulness, whereas others suffer from severe performance loss (3). The neuro-molecular mechanisms in the brain responsible for these different vulnerabilities are still largely unknown. Caffeine, commonly consumed for fighting fatigue, promotes wakefulness via adenosine receptor antagonism. It seems likely that the adenosinergic system is a neurochemical link between performance and sleep (8). Adenosine is contributing to the homeostatic process of sleep-wake regulation (for review, see refs. 9-12). As has been shown in cats and rats, extracellular adenosine concentration fluctuates rhythmically in many brain regions, such as the basal forebrain, increasing during wakefulness and decreasing during sleep: it thereby induces sleep after wake extension and is in turn restored to baseline levels after recovery sleep (13). For additional information on adenosine, see...

show abstract

Section: Discussionmentioning

confidence: 81%

“…Moreover, A 1 AR mRNA was shown to increase in the basal forebrain under sleep restriction (11). Inhibiting the A 1 AR mRNA translation in rats decreased nonrapid eye-movement sleep and increased wakefulness (26). An up-regulation of A 1 AR density in the human and in the rat brain in response to acute sleep loss (10,27,28) has been shown.…”

mentioning

confidence: 94%

Recovery sleep after extended wakefulness restores elevated A ₁ adenosine receptor availability in the human brain

Elmenhorst

Hennecke

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In one study, adenosine, acting via the A 1 receptor, stimulated calcium release in cholinergic but not noncholinergic neurons (Basheer et al, 2002). In the second study, perfusion of adenosine A 1 receptor antisense into the BF reduced non-REM sleep and EEG delta power (Thakkar et al, 2003b). Neither study investigated whether sleep was changed after lesion of the BF cholinergic neurons, which left open the possibility raised by both studies that A 1 receptors on noncholinergic neurons could affect sleep.…”

Section: Discussionmentioning

confidence: 99%

Adenosine and Sleep Homeostasis in the Basal Forebrain

et al. 2006

View full text Add to dashboard Cite

It is currently hypothesized that the drive to sleep is determined by the activity of the basal forebrain (BF) cholinergic neurons, which release adenosine (AD), perhaps because of increased metabolic activity associated with the neuronal discharge during waking, and the accumulating AD begins to inhibit these neurons so that sleep-active neurons can become active. This hypothesis grew from the observation that AD induces sleep and AD levels increase with wake in the basal forebrain, but surprisingly it still remains untested. Here we directly test whether the basal forebrain cholinergic neurons are central to the AD regulation of sleep drive by administering 192-IgGsaporin to lesion the BF cholinergic neurons and then measuring AD levels in the BF. In rats with 95% lesion of the BF cholinergic neurons, AD levels in the BF did not increase with 6 h of prolonged waking. However, the lesioned rats had intact sleep drive after 6 and 12 h of prolonged waking, indicating that the AD accumulation in the BF is not necessary for sleep drive. Next we determined that, in the absence of the BF cholinergic neurons, the selective adenosine A 1 receptor agonist N6-cyclohexyladenosine, administered to the BF, continued to be effective in inducing sleep, indicating that the BF cholinergic neurons are not essential to sleep induction. Thus, neither the activity of the BF cholinergic neurons nor the accumulation of AD in the BF during wake is necessary for sleep drive.

show abstract

“…Behavioral state data was acquired and digitized using the Harmonie software (Stellate Systems, Montreal, Canada and sleep-wakefulness was visually scored in 10 sec epochs as (1) Wakefulness, (which included both active and quiet wakefulness) determined by the presence of low amplitude, high frequency desynchronized EEG with the concomitant presence of active muscle tone; (2) non-REM sleep; determined by the presence of low frequency, high amplitude, synchronized EEG with low EMG tone; and (3) REM sleep, determined by complete absence of muscle tone along with desynchronized EEG (Thakkar et al, 2003). The effect of THIP on the sleep-wakefulness was analyzed by repeated measure ANOVA followed by Bonferoni's test (EZAnalyze Ver 3.0. http://www.ezanalyze.com).…”

Section: Analysis Of Behavioral Statesmentioning

confidence: 99%

Effect of microdialysis perfusion of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol in the perifornical hypothalamus on sleep–wakefulness: Role of δ-subunit containing extrasynaptic GABAA receptors

2008

View full text Add to dashboard Cite

Gaboxadol or 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP) is a selective agonist for the δ-subunit containing extrasynaptic GABA A receptors that will soon enter the U.S. market as a sleep aid (Winsky-Sommerer et al., 2007). Numerous studies have shown that systemic administration of THIP reduces wakefulness and increases sleep both in humans and rats (Lancel and Langebartels, 2000;Walsh et al., 2007). However, it is yet unclear where in the brain THIP acts to promote sleep. Since the perifornical lateral hypothalamus (PFH) contains orexin neurons and orexin neurons are critical for maintenance of arousal (McCarley, 2007), we hypothesized that THIP may act on PFH neurons to promote sleep. To test our hypothesis, we used reverse microdialysis to perfuse THIP unilaterally into the PFH and studied its effects on sleep-wakefulness during the light period in freely behaving rats. Microdialysis perfusion of THIP (100 µM) into the PFH produced a significant reduction in wakefulness with a concomitant increase in nonREM sleep as compared to ACSF perfusion. REM sleep was unaffected. This is the first study implicating the δ-subunit containing extrasynaptic GABA A receptors in PFH in control of sleep-wakefulness in freely behaving rats. KeywordsOrexin/hypocretin; perifornical hypothalamus; THIP; reverse microdialysisThe γ-aminobutyric acid (GABA) system is closely linked with the regulation of sleepwakefulness. Thus, it is not surprising that pharmacological landscape for treatment of various sleep disorders including insomnia have been dominated by agents that activate GABA A receptors . Classical synaptic GABA transmission results in phasic inhibition that is mainly mediated by γ2 subunits containing postsynaptic GABA A receptors (Rudolph and Mohler, 2006;Ebert et al., 2006;Olsen et al., 2007), In contrast, tonic inhibition is mainly mediated by δ subunit containing "extrasynaptic" GABA A receptors (Olsen et al.,Correspondence: Mahesh Thakkar, Harry Truman Memorial Veteran's Hospital, Columbia, MO., Department of Neurology, University of Missouri, 800 Hospital Drive, Columbia, MO, 65201, Ph. (573) 814 6000 ext 53697, Email: thakkarmm@health.missouri.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 2007). These "extrasynaptic" GABA A receptors have a higher affinity for GABA and slower rates of desensitization and deactivation than do the classical synaptic receptors. NIH Public AccessThe GABA A agonist THIP selectively activates extrasynaptic GABA A receptors (WinskySommerer et al., 2007). Systemic administration of THIP induces sleep in rats and humans (...

show abstract

A₁Receptor and Adenosinergic Homeostatic Regulation of Sleep-Wakefulness: Effects of Antisense to the A₁Receptor in the Cholinergic Basal Forebrain

Cited by 159 publications

References 49 publications

Recovery sleep after extended wakefulness restores elevated A ₁ adenosine receptor availability in the human brain

Recovery sleep after extended wakefulness restores elevated A ₁ adenosine receptor availability in the human brain

Adenosine and Sleep Homeostasis in the Basal Forebrain

Effect of microdialysis perfusion of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol in the perifornical hypothalamus on sleep–wakefulness: Role of δ-subunit containing extrasynaptic GABAA receptors

Contact Info

Product

Resources

About

A1Receptor and Adenosinergic Homeostatic Regulation of Sleep-Wakefulness: Effects of Antisense to the A1Receptor in the Cholinergic Basal Forebrain

Cited by 159 publications

References 49 publications

Recovery sleep after extended wakefulness restores elevated A 1 adenosine receptor availability in the human brain

Recovery sleep after extended wakefulness restores elevated A 1 adenosine receptor availability in the human brain

Adenosine and Sleep Homeostasis in the Basal Forebrain

Effect of microdialysis perfusion of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol in the perifornical hypothalamus on sleep–wakefulness: Role of δ-subunit containing extrasynaptic GABAA receptors

Contact Info

Product

Resources

About

A₁Receptor and Adenosinergic Homeostatic Regulation of Sleep-Wakefulness: Effects of Antisense to the A₁Receptor in the Cholinergic Basal Forebrain

Recovery sleep after extended wakefulness restores elevated A ₁ adenosine receptor availability in the human brain

Recovery sleep after extended wakefulness restores elevated A ₁ adenosine receptor availability in the human brain