Elsevier

Neuroscience

Volume 79, Issue 1, 28 April 1997, Pages 225-235
Neuroscience

Role of adenosine in behavioral state modulation: a microdialysis study in the freely moving cat

https://doi.org/10.1016/S0306-4522(96)00640-9Get rights and content

Abstract

There is considerable evidence to suggest that the activity of forebrain and mesopontine cholinergic neurons is intimately involved in electroencephalographic arousal. Furthermore, our previous in vitro investigation suggested that both cholinergic systems are under a powerful tonic inhibitory control by endogenous adenosine. We thus examined the in vivo effect, on electrographically defined behavioral states, of microdialysis perfusion of adenosine into the cholinergic zones of the substantia innominata of the basal forebrain and the laterodorsal tegmental nucleus of freely moving cats. Localized perfusion of adenosine into either the basal forebrain or the laterodorsal tegmental nucleus caused a marked alteration in sleep–wake architecture. Adenosine (300 μM) perfused into either the basal forebrain or laterodorsal tegmental nucleus produced a dramatic decrease in waking, to about 50% of the basal level. Perfusion into the basal forebrain resulted in a significant increase in rapid eye movement sleep, while slow wave sleep was unchanged. In contrast, adenosine perfusion into the laterodorsal tegmental nucleus produced an increase of both slow wave sleep and rapid eye movement sleep, the magnitude of which were proportional to the decrease in waking. Electroencephalographic power spectral analysis showed that adenosine perfusion into the basal forebrain increased the relative power in the delta frequency band, whereas higher frequency bands (theta, alpha, beta and gamma) showed a decrease.

These data strongly support the hypothesis that adenosine might play a key role as an endogenous modulator of wakefulness and sleep. The decrease in wakefulness may be directly related to the inhibition of cholinergic neurons of the basal forebrain and the laterodorsal tegmentum. The increase in rapid eye movement sleep is a novel but robust effect whose origin, at present, is uncertain.

The observation that local perfusion of adenosine into either the basal forebrain or the laterodorsal tegmental nucleus dramatically decreases wakefulness suggests that these areas might represent a major site of action of the xanthine stimulants (adenosine antagonists) found in coffee and tea.

Section snippets

Experimental procedures

Adult cats (3–3.5 kg, n=12) were pre-anesthetized with a mixture of ketamine hydrochloride (100 mg/ml) and acepromazine maleate (10 mg/ml) at a dose of 0.1 ml/kg (i.p.). This treatment allowed an intravenous catheter to be inserted into the forelimb so that sodium pentobarbital (30 mg/kg, i.v.) could be fractionally administered to obtain and maintain deep surgical anesthesia. Cats were then stereotaxically implanted with electrodes to record EEG, electro-oculogram and electromyogram (EMG). In

Histology

In nine of the 10 cases described here as BF perfusion, the probe tip was found to be located within the SI. A typical photomicrograph of a coronal section of the cat BF (approximately A 15)[5]illustrating the area of perfusion in the SI is shown in Fig. 1a. In one animal the tip of the probe was localized to the cholinergic zone of the septum, including the DBB. For each of the six cases described as LDT perfusion, the probe tip was found to be located within the LDT, as shown in the

Discussion

These data provide evidence that adenosine, through local actions within the cholinergic nuclei of the LDT or the BF, strongly decreases waking. These data further support the hypothesis that adenosine acts as an endogenous modulator of behavioral state, as originally postulated by Radulovacki,[35]and more specifically, is consistent with the hypothesis that adenosine-mediated inhibition localized to the cholinergic arousal centers decreases waking, thus providing a link between cellular

Conclusion

We have demonstrated that local adenosine perfusion into the BF or LDT resulted in a significant decrease in waking. We suggest that this decrease most probably results from a direct inhibition of cholinergic neurons. However, as neither the LDT nor the BF is a homogeneous neuronal population, a greater understanding of the effects of adenosine on non-cholinergic neurons in these two regions is required to substantiate this hypothesis. Moreover, adenosine acts to reduce glutamate transmission

References (60)

  • J.S Lin et al.

    A critical role of the posterior hypothalamus in the mechanisms of wakefulness determined by microinjection of muscimol in freely moving cats

    Brain Res.

    (1989)
  • R.W McCarley et al.

    Brain stem modulation and REM sleep

    Sem. Neurosci.

    (1995)
  • N Quan et al.

    Microdialysis: a system for localized drug delivery into the brain

    Brain Res. Bull.

    (1989)
  • M Radulovacki et al.

    Caffeine produces REM sleep rebound in rats

    Brain Res.

    (1980)
  • P.B Reiner et al.

    Physiological evidence for subpopulations of cortically projecting basal forebrain neurons in the anesthetized rat

    Neuroscience

    (1987)
  • S.A Rivkees et al.

    Immunohistochemical detection of A1 adenosine receptors in rat brain with emphasis on localization in the hippocampal formation, cerebral cortex, cerebellum, and basal ganglia

    Brain Res.

    (1995)
  • T Roehrs et al.

    Effects of theophylline on nocturnal sleep and daytime sleepiness/alertness

    Chest

    (1995)
  • K Semba et al.

    Organization of central cholinergic systems

    Prog. Brain Res.

    (1989)
  • M Steriade et al.

    Projections of cholinergic and non-cholinergic neurons of the brainstem core to relay and associational thalamic nuclei in the cat and macaque monkey

    Neuroscience

    (1988)
  • L.W Swanson et al.

    Evidence for a projection from the lateral preoptic area and substantia innominata to the “mesencephalic locomotor region” in the rat

    Brain Res.

    (1984)
  • R Szymusiak et al.

    Sleep-related neuronal discharge in the basal forebrain of cats

    Brain Res.

    (1986)
  • R Szymusiak et al.

    Sleep–waking discharge of basal forebrain projection neurons in cats

    Brain Res. Bull.

    (1989)
  • M Thakkar et al.

    Effect of rapid eye movement sleep deprivation on 5′-nucleotidase in the brain

    Neurosci. Lett.

    (1996)
  • S.R Ticho et al.

    Role of adenosine in sleep and temperature regulation in the preoptic area of rats

    Pharmac. Biochem. Behav.

    (1991)
  • R.M Virus et al.

    The effects of adenosine and 2′-deoxycoformycin on sleep and wakefulness in rats

    Neuropharmacology

    (1983)
  • N.J Woolf et al.

    Cholinergic systems in the rat brain: III. Projections from the pontomesencephalic tegmentum to the thalamus, tectum, basal ganglia, and basal forebrain

    Brain Res. Bull.

    (1986)
  • G Yanik et al.

    The dose–response effects of caffeine on sleep in rats

    Brain Res.

    (1987)
  • G Yanik et al.

    REM sleep deprivation up-regulates adenosine A1 receptors

    Brain Res.

    (1987)
  • T Zetterstrom et al.

    Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre

    Neurosci. Lett.

    (1982)
  • H.A Baghdoyan et al.

    Simultaneous pontine and basal forebrain microinjections of carbachol suppress REM sleep

    J. Neurosci.

    (1993)
  • Cited by (184)

    • Astrocyte-neuron circuits in epilepsy

      2023, Neurobiology of Disease
    • Trihexyphenidyl increases delta activity in non-rapid eye movement sleep without impairing cognitive function in rodent models

      2022, Neuropharmacology
      Citation Excerpt :

      It suggested that BF cholinergic neurons might be suppressed during sleep rebound. It fits with the observation that, microinjection of adenosine, a neuromodulator to inhibit BF cholinergic neurons, produced a dramatic decrease in wakefulness by 50% (Portas et al., 1997). It is still lacking of evidence if BF cholinergic neurons are suppressed or activated in chronic sleep insufficiency condition.

    View all citing articles on Scopus
    View full text