Sleep deprivation increases A1 adenosine receptor density in the rat brain

doi:10.1016/j.brainres.2008.12.056

Brain Research

Volume 1258, 3 March 2009, Pages 53-58

https://doi.org/10.1016/j.brainres.2008.12.056 Get rights and content

Abstract

Adenosine, increasing after sleep deprivation and acting via the A₁ adenosine receptor (A₁AR), is likely a key factor in the homeostatic control of sleep. This study examines the impact of sleep deprivation on A₁AR density in different parts of the rat brain with [³H]CPFPX autoradiography. Binding of [³H]CPFPX was significantly increased in parietal cortex (PAR) (7%), thalamus (11%) and caudate-putamen (9%) after 24 h of sleep deprivation compared to a control group with an undisturbed circadian sleep-wake rhythm. Sleep deprivation of 12 h changed receptor density regionally between − 5% and + 9% (motor cortex (M1), statistically significant) compared to the circadian control group. These results suggest cerebral A₁ARs are involved in effects of sleep deprivation and the regulation of sleep. The increase of A₁AR density could serve the purpose of not only maintaining the responsiveness to increased adenosine levels but also amplifying the effect of sleep deprivation and is in line with a sleep-induced homoeostatic reorganization at the synaptic level.

Introduction

Endogenous adenosine is considered a candidate molecule for the homeostatic sleep drive, inducing sleep after prolonged wakefulness (for review see Basheer et al., 2004).

In freely moving cats, microdialysis showed accumulating adenosine levels in the cortex during prolonged wakefulness (6 h) (Porkka-Heiskanen et al., 1997). Subsequent recovery-sleep restored the adenosine concentration to baseline levels. Similar experiments have been repeated in rat with comparable results in the basal forebrain (Basheer et al., 1999, Murillo-Rodriguez et al., 2004). An artificial increase of the adenosine concentration in the basal forebrain by infusion of adenosine in cats (Portas et al., 1997) or rats (Basheer et al., 1999) increased sleep. Inhibition of equilibrative nucleoside transporters (Porkka-Heiskanen et al., 2000) resulted in electroencephalographic and behavioral effects comparable to those under sleep deprivation.

It is a matter of debate which adenosine receptor subtype mediates the sleep inducing action of adenosine. The A₁ receptor subtype (A₁AR) has the widest distribution in the central nervous system with particularly high concentrations in the cortex, cerebellum, hippocampus, striatum and thalamus (Fredholm, 1995). Selective A₁AR agonists increased the sleep drive in rats after either systemic or cerebroventricular administration (Benington et al., 1995, Schwierin et al., 1996). Inhibition of equilibrium nucleoside transporters (which in turn increased adenosine levels) had the same effect in cats, and correspondingly a selective A₁AR antagonist infused into the basal forebrain decreased sleep propensity in cats (Strecker et al., 2000). Microdialysis perfusion of A₁AR antisense oligonucleotides inhibiting the translation of A₁AR mRNA, significantly decreased nonREM sleep and increased wakefulness in rats (Thakkar et al., 2003). However, A₁AR knockout mice reacted similarly to sleep deprivation as their wild type littermates (Stenberg et al., 2003) and it has been reported that subarachnoidal infusion of the selective A_2A adenosine receptor (A_2AAR) agonist CGS21680 (Satoh et al., 1999) promoted deep sleep.

Intraperitonial injections of the A₁AR agonist CPA over 5 days significantly decreased A₁AR density in the rat cortex, suggesting desensitization (Roman et al., 2008). Since sleep deprivation increased cerebral adenosine levels it was initially hypothesized that A₁AR density might similarly decrease with deprivation. However, 3 and 6 h of total sleep deprivation increased A₁AR mRNA in the basal forebrain but not B_max or K_D values determined with [³H]DPCPX autoradiography (with and without GTP in the incubation medium) (Basheer et al., 2001). Moreover, A₁AR density in the basal forebrain increased after sleep deprivations of 12 h (10%) and 24 h (14%) (Basheer et al., 2007). In addition, rapid eye movement sleep deprivation for 48 and 96 h was reported to increase A₁AR density in cortical (15 and 20%) and subcortical (23 and 48%) areas of rat brains, as determined by [³H]L-PIA saturation binding experiments in membrane preparations. The K_D value did not change significantly (Yanik and Radulovacki, 1987).

In humans, in vivo imaging of the A₁AR with positron emission tomography and CPFPX showed an increase of A₁AR availability in cortical and subcortical regions after one night of sleep deprivation (Elmenhorst et al., 2007). These findings also did not support the hypothesis that the increase in adenosine concentration during sleep deprivation will induce receptor desensitization due to a high agonist load. Instead, they were in accord with the results of Basheer et al. (2007) who found an increase in both A₁AR mRNA and density after 12 and 24 h in the basal forebrain of the rat. The rationale of the present study was therefore to evaluate whether the widespread, particularly neocortical increase of A₁ARs observed in humans could be replicated in rats. Such a finding would extend the role of adenosine from a focal sleep modulator in the basal forebrain to, with longer durations of sleep deprivation, a ubiquitous player in sleep regulation in many parts of the brain.

Section snippets

Results

The results of the effect of sleep deprivation on A₁AR binding of [³H]CPFPX are given in Table 1, and relative regional changes are depicted in Fig. 1. A representative autoradiogram of [³H]CPFPX binding of a rat of the 12 h control group is shown in Fig. 2. The analysis of the data by two-way ANOVA showed that the means of the factors ‘group’ and ‘region’ are significantly different (F₍_3,276) = 267.12; p < 0.0001 and F₍_9,276) = 12.95; p < 0.0001, respectively) which is specified by the results from

Discussion

The results of the present study suggest that sleep deprivation for 24 h produces an increase of A₁AR density in cortical and subcortical regions of the rat brain.

This finding is consistent with an increase of A₁ARs in the basal forebrain (12 h, 10%; 24 h, 14%) established in a subset analysis in some of the animals reported here (Basheer et al., 2007). The results of the present study enlarge and extend these previous findings significantly, because 12 and 24 h of total sleep deprivation

Animals

Thirty-two male Sprague Dawley rats (250–350 g) were used. Rats were housed in a 12 h light/dark cycle (light on 7:00 AM to 7:00 PM), at 23 ± 1 °C with access to food and water ad libitum; treatment was according to the Association for Accreditation of Laboratory Animal Care and Use Committee as Boston VA Healthcare system, Harvard University and US National Institute of Health. In a subset of these animals (n = 24) an analysis of A₁AR density changes in the basal forebrain has been performed and

Acknowledgments

Sabine Wilms, Markus Cremer and Ramkumar Karthikeyan are gratefully acknowledged for excellent technical assistance and Marcus Holschbach for providing Tritium labeled CPFPX.

This work was supported by the Department of Veterans Affairs Medical Research Service Award to RB, the National Institute of Mental Health (NIMH39683) to RWM, the Heinrich Hertz Foundation of the Ministry of Science and Technology, North-Rhine Westfalia, Germany to DE and the German Federal Ministry of Education and

References (24)

BasheerR. et al.
Adenosine and behavioral state control: adenosine increases c-Fos protein and AP1 binding in basal forebrain of rats
Brain Res. Mol. Brain Res.
(1999)
BasheerR. et al.
Adenosine and sleep-wake regulation
Prog. Neurobiol.
(2004)
BeningtonJ.H. et al.
Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation
Brain Res.
(1995)
McCarleyR.W.
Neurobiology of REM and NREM sleep
Sleep Med.
(2007)
Murillo-RodriguezE. et al.
The diurnal rhythm of adenosine levels in the basal forebrain of young and old rats
Neuroscience
(2004)
Porkka-HeiskanenT. et al.
Brain site-specificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study
Neuroscience
(2000)
PortasC.M. et al.
Role of adenosine in behavioral state modulation: a microdialysis study in the freely moving cat
Neuroscience
(1997)
RomanV. et al.
Repetitive stimulation of adenosine A1 receptors in vivo: changes in receptor numbers, G-proteins and A1 receptor agonist-induced hypothermia
Brain Res.
(2008)
SchwierinB. et al.
Effects of N6-cyclopentyladenosine and caffeine on sleep regulation in the rat
Eur. J. Pharmacol.
(1996)
StreckerR.E. et al.
Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state
Behav. Brain Res.
(2000)

TononiG. et al.

Sleep function and synaptic homeostasis

Sleep Med. Rev.

(2006)

YanikG. et al.

REM sleep deprivation up-regulates adenosine A1 receptors

Brain Res.

(1987)

Cited by (60)

Bipolar mania and epilepsy pathophysiology and treatment may converge in purine metabolism: A new perspective on available evidence
2023, Neuropharmacology
Decreased ATPergic signaling is an increasingly recognized pathophysiology in bipolar mania disease models. In parallel, adenosine deficit is increasingly recognized in epilepsy pathophysiology. Under-recognized ATP and/or adenosine-increasing mechanisms of several antimanic and antiseizure therapies including lithium, valproate, carbamazepine, and ECT suggest a fundamental pathogenic role of adenosine deficit in bipolar mania to match the established role of adenosine deficit in epilepsy. The depletion of adenosine-derivatives within the purine cycle is expected to result in a compensatory increase in oxopurines (uric acid precursors) and secondarily increased uric acid, observed in both bipolar mania and epilepsy. Cortisol-based inhibition of purine conversion to adenosine-derivatives may be reflected in observed uric acid increases and the well-established contribution of cortisol to both bipolar mania and epilepsy pathology. Cortisol-inhibited conversion from IMP to AMP as precursor of both ATP and adenosine may represent a mechanism for treatment resistance common in both bipolar mania and epilepsy. Anti-cortisol therapies may therefore augment other treatments both in bipolar mania and epilepsy. Evidence linking (i) adenosine deficit with a decreased need for sleep, (ii) IMP/cGMP excess with compulsive hypersexuality, and (iii) guanosine excess with grandiose delusions may converge to suggest a novel theory of bipolar mania as a condition characterized by disrupted purine metabolism. The potential for disease-modification and prevention related to adenosine-mediated epigenetic changes in epilepsy may be mirrored in mania. Evaluating the purinergic effects of existing agents and validating purine dysregulation may improve diagnosis and treatment in bipolar mania and epilepsy and provide specific targets for drug development.
Spontaneous attentional failures reflect multiplicative interactions of chronic sleep loss with acute sleep loss and circadian misalignment
2023, Sleep Health
Acute and chronic sleep loss and circadian timing interact such that, depending on their combination, small or very large performance decrements are observed in tasks of attention. Here, we tested whether such nonlinear interactions extend to a physiological measure of spontaneous visual attentional failures, indicating a fundamental principle of sleep-wake regulation.
Nine healthy volunteers completed an in-laboratory 3-week forced desynchrony protocol consisting of 12 consecutive 42.85-hour cycles with a sleep-wake ratio of 1:3.3. The protocol induced increasing chronic sleep loss, while extended wake (32.85 hours) and sleep episodes (10 hours) occurred at multiple circadian phases. Attentional failure rate was quantified from continuous electrooculograms (number of 30-second epochs with slow eye movements/h of wakefulness) as a function of time since scheduled wake (acute sleep loss), week of study (chronic sleep loss), and circadian (melatonin) phase.
During the first ∼8 hours awake, attentional failure rate was low, irrespective of the week. During the following wake hours, attentional failure rate increased steadily but at a faster rate in weeks 2 and 3 compared to week 1. The effects of acute and chronic sleep loss on attentional failure rate were magnified during the biological night compared to the biological day.
A single extended sleep episode can only temporarily reverse attentional impairment associated with chronic sleep loss. Multiplicative effects of acute and chronic sleep loss—further amplified during the biological night—substantiate the interaction of 2 homeostatic response mechanisms and caution against underestimating their disproportionate combined impact on performance, health, and safety.
Cerebral A<inf>1</inf> adenosine receptor availability in female and male participants and its relationship to sleep
2021, NeuroImage
The neuromodulator adenosine and its receptors are mediators of sleep-wake regulation which is known to differ between sexes. We, therefore, investigated sex differences in A₁ adenosine receptor (A₁AR) availability in healthy human subjects under well-rested conditions using [¹⁸F]CPFPX and positron emission tomography (PET). [¹⁸F]CPFPX PET scans were acquired in 50 healthy human participants (20 females; mean age ± SD 28.0 ± 5.3 years). Mean binding potential (BP_ND; Logan's reference tissue model with cerebellum as reference region) and volume of distribution (V_T) values were calculated in 12 and 15 grey matter brain regions, respectively. [¹⁸F]CPFPX BP_ND was higher in females compared to males in all investigated brain regions (p < 0.025). The largest differences were found in the pallidum and anterior cingulate cortex, where mean BP_ND values were higher by 29% in females than in males. In females, sleep efficiency correlated positively and sleep latency negatively with BP_ND in most brain regions. V_T values did not differ between sexes. Sleep efficiency correlated positively with V_T in most brain regions in female participants. In conclusion, our analysis gives a first indication for potential sex differences in A₁AR availability even under well-rested conditions. A₁AR availability as measured by [¹⁸F]CPFPX BP_ND is higher in females compared to males. Considering the involvement of adenosine in sleep-wake control, this finding might partially explain the known sex differences in sleep efficiency and sleep latency.
Of adenosine and the blues: The adenosinergic system in the pathophysiology and treatment of major depressive disorder
2021, Pharmacological Research
Citation Excerpt :
Moreover, it has been recently demonstrated that astroglial A1R activation is necessary for the sustained antidepressant-like effects following 12, but not 72, hours of sleep deprivation, such that these effects are absent in A1R KO mice [238,239]. Furthermore, in line with this, there is evidence that sleep deprivation leads to a rapid upregulation of A1R, in both humans [255] and animals [256–258]. Like sleep deprivation, ECT is known to have rapid and pronounced antidepressant effects.
Major depressive disorder (MDD) is the foremost cause of global disability, being responsible for enormous personal, societal, and economical costs. Importantly, existing pharmacological treatments for MDD are partially or totally ineffective in a large segment of patients. As such, the search for novel antidepressant drug targets, anchored on a clear understanding of the etiological and pathophysiological mechanisms underpinning MDD, becomes of the utmost importance.
The adenosinergic system, a highly conserved neuromodulatory system, appears as a promising novel target, given both its regulatory actions over many MDD-affected systems and processes. With this goal in mind, we herein review the evidence concerning the role of adenosine as a potential player in pathophysiology and treatment of MDD, combining data from both human and animal studies.
Altogether, evidence supports the assertions that the adenosinergic system is altered in both MDD patients and animal models, and that drugs targeting this system have considerable potential as putative antidepressants. Furthermore, evidence also suggests that modifications in adenosine signaling may have a key role in the effects of several pharmacological and non-pharmacological antidepressant treatments with demonstrated efficacy, such as electroconvulsive shock, sleep deprivation, and deep brain stimulation. Lastly, it becomes clear from the available literature that there is yet much to study regarding the role of the adenosinergic system in the pathophysiology and treatment of MDD, and we suggest several avenues of research that are likely to prove fruitful.
Enhanced adenosine A<inf>1</inf> receptor and Homer1a expression in hippocampus modulates the resilience to stress-induced depression-like behavior
2020, Neuropharmacology
Citation Excerpt :
Each line had a unique expression pattern, due to the random integration site of the transgene into the founder mouse genome. In this study, we have selected two founder mouse lines with identical levels of A1R increase in the cortex, comparable to the upregulation induced by seizures or sleep deprivation in mice and humans (Biber et al., 2008; Elmenhorst et al., 2007, 2009; Vanore et al., 2001). However, both lines have distinct pattern of transgenic expression in the hippocampus altering their depression- and anxiety-like behavior.
Resilience to stress is critical for the development of depression. Enhanced adenosine A₁ receptor (A₁R) signaling mediates the antidepressant effects of acute sleep deprivation (SD). However, chronic SD causes long-lasting upregulation of brain A₁R and increases the risk of depression. To investigate the effects of A₁R on mood, we utilized two transgenic mouse lines with inducible A₁R overexpression in forebrain neurons. These two lines have identical levels of A₁R increase in the cortex, but differ in the transgenic A₁R expression in the hippocampus. Switching on the transgene promotes robust antidepressant and anxiolytic effects in both lines. The mice of the line without transgenic A₁R overexpression in the hippocampus (A1Hipp-) show very strong resistance towards development of stress-induced chronic depression-like behavior. In contrast, the mice of the line in which A₁R upregulation extends to the hippocampus (A1Hipp+), exhibit decreased resilience to depression as compared to A1Hipp-. Similarly, automatic analysis of reward behavior of the two lines reveals that depression resistant A1Hipp-transgenic mice exhibit high sucrose preference, while mice of the vulnerable A1Hipp + line developed stress-induced anhedonic phenotype. The A1Hipp + mice have increased Homer1a expression in hippocampus, correlating with impaired long-term potentiation in the CA1 region, mimicking the stressed mice. Furthermore, virus-mediated overexpression of Homer1a in the hippocampus decreases stress resilience. Taken together our data indicate for first time that increased expression of A₁R and Homer1a in the hippocampus modulates the resilience to stress-induced depression and thus might potentially mediate the detrimental effects of chronic sleep restriction on mood.
Adenosine A<inf>2A</inf> receptor as potential therapeutic target in neuropsychiatric disorders
2019, Pharmacological Research
Adenosine A_2A receptor (A_2AR) is a G-protein coupled receptor that regulates several important functions in the central nervous system. Large amount of preclinical data suggests that the A_2AR could represent a target for the development of new therapeutic strategies for different neuropsychiatric conditions. In this review we will recapitulate and discuss the most relevant studies on the role of A_2ARs in neurodegenerative, neurodevelopmental and psychiatric diseases, which led to suggest a therapeutic use of A_2AR agonists in certain diseases (Niemann-Pick disease, autism-spectrum disorders, schizophrenia) and A_2AR antagonists in others (Alzheimer’s disease, Parkinson’s disease, attention-deficit hyperactivity disorder, fragile X syndrome, depression, anxiety). Moreover, we will try to analyze which are the main obstacles to the conduction of clinical trials with A_2AR ligands for the treatment of neuropsychiatric disease.

View all citing articles on Scopus

¹: Fax: +49 0 2461 612820.

View full text

Research ReportSleep deprivation increases A1 adenosine receptor density in the rat brain

Abstract

Introduction

Section snippets

Results

Discussion

Animals

Acknowledgments

Brain Res. Mol. Brain Res.

Prog. Neurobiol.

Brain Res.

Sleep Med.

Neuroscience

Neuroscience

Neuroscience

Brain Res.

Eur. J. Pharmacol.

Behav. Brain Res.

Sleep Med. Rev.

Brain Res.

Research Report
Sleep deprivation increases A₁ adenosine receptor density in the rat brain