Elsevier

Neuroscience

Volume 99, Issue 3, 16 August 2000, Pages 507-517
Neuroscience

Brain site-specificity of extracellular adenosine concentration changes during sleep deprivation and spontaneous sleep: an in vivo microdialysis study

https://doi.org/10.1016/S0306-4522(00)00220-7Get rights and content

Abstract

Previous data suggested that increases in extracellular adenosine in the basal forebrain mediated the sleep-inducing effects of prolonged wakefulness. The present study sought to determine if the state-related changes found in basal forebrain adenosine levels occurred uniformly throughout the brain. In vivo microdialysis sample collection coupled to microbore high-performance liquid chromatography measured extracellular adenosine levels in six brain regions of the cat: basal forebrain, cerebral cortex, thalamus, preoptic area of hypothalamus, dorsal raphe nucleus and pedunculopontine tegmental nucleus. In all these brain regions extracellular adenosine levels showed a similar decline of 15 to 20% during episodes of spontaneous sleep relative to wakefulness. Adenosine levels during non-rapid eye movement sleep did not differ from rapid eye movement sleep. In the course of 6 h of sleep deprivation, adenosine levels increased significantly in the cholinergic region of the basal forebrain (to 140% of baseline) and, to a lesser extent in the cortex, but not in the other regions. Following sleep deprivation, basal forebrain adenosine levels declined very slowly, remaining significantly elevated throughout a 3-h period of recovery sleep, but elsewhere levels were either similar to, or lower than, baseline.

The site-specific accumulation of adenosine during sleep deprivation suggests a differential regulation of adenosine levels by as yet unidentified mechanisms. Moreover, the unique pattern of sleep-related changes in basal forebrain adenosine level lends strong support to the hypothesis that the sleep-promoting effects of adenosine, as well as the sleepiness associated with prolonged wakefulness, are both mediated by adenosinergic inhibition of a cortically projecting basal forebrain arousal system.

Section snippets

Experimental animals and surgery

Adult male cats were housed under constant temperature, with ad libitum access to food and water. Under pentobarbital anesthesia, animals were surgically implanted with electrodes for recording electroencephalogram, electrooculogram, electromyogram and ponto-geniculate-occipital waves for determination of behavioral state. In each subject, four to six intracerebral guide cannulae (CMA 10 guide, CMA/Microdialysis, Stockholm, Sweden) were implanted above the target sites for later insertion of

Control experiments

Immediately after the probe insertion the extracellular adenosine concentrations were high, but declined spontaneously to the basal level within 6 h; mean concentration in sample was 32.8±3.0 nmol/l (mean±S.E.M., n=10 probes in the BF and the thalamus) (Fig. 1A). Adenosine concentrations were also measured on four consecutive days from two samples collected each day during wakefulness (n=10 probes in the BF). There was no significant difference in the basal adenosine concentrations between the

Adenosine levels during sleep deprivation and recovery sleep

The present study has extended our description of the state-related changes in extracellular adenosine levels measured previously only in the BF and thalamus to four additional brain areas in order to determine if the earlier findings were site-specific.29 Perhaps the most important present finding is that, during prolonged wakefulness, extracellular adenosine accumulated in a site-specific manner. In the BF (n=8) adenosine levels rose steadily and monotonically during each of the 6 h of sleep

Conclusions

During natural sleep–wake cycles the changes in extracellular adenosine concentrations were similar in all brain areas studied: wakefulness>non-REM=REM sleep. During 6 h of sleep deprivation, adenosine levels increased significantly in the BF and, to a lesser extent in the cortex, but not in any other subcortical structures tested to date. This site-specific accumulation of adenosine during sleep deprivation indicates the existence of physiological regulation of adenosine levels, by as yet

Acknowledgements

This work was supported by the National Institute of Mental Health (NIMH 39683) and the Department of Veterans Affairs Medical Research Service Awards to RES and RWM. We thank Dr Dag Stenberg and Dr Mahesh Thakkar for helpful consultations in the course of the work, Drs Carl Olson and P. Shiromani for anatomical consultation, Lynda Dauphin for histological work and running the experiments with us, and Kara Rebello, Russell Delgiacco, and Rachel Aronson for technical assistance.

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