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, 7 (3), 238-45

Adenosine and Sleep

Affiliations

Adenosine and Sleep

Theresa E Bjorness et al. Curr Neuropharmacol.

Abstract

Over the last several decades the idea that adenosine (Ado) plays a role in sleep control was postulated due in large part to pharmacological studies that showed the ability of Ado agonists to induce sleep and Ado antagonists to decrease sleep. A second wave of research involving in vitro cellular analytic approaches and subsequently, the use of neurochemical tools such as microdialysis, identified a population of cells within the brainstem and basal forebrain arousal centers, with activity that is both tightly coupled to thalamocortical activation and under tonic inhibitory control by Ado. Most recently, genetic tools have been used to show that Ado receptors regulate a key aspect of sleep, the slow wave activity expressed during slow wave sleep. This review will briefly introduce some of the phenomenology of sleep and then summarize the effect of Ado levels on sleep, the effect of sleep on Ado levels, and recent experiments using mutant mouse models to characterize the role for Ado in sleep control and end with a discussion of which Ado receptors are involved in such control. When taken together, these various experiments suggest that while Ado does play a role in sleep control, it is a specific role with specific functional implications and it is one of many neurotransmitters and neuromodulators affecting the complex behavior of sleep. Finally, since the majority of adenosine-related experiments in the sleep field have focused on SWS, this review will focus largely on SWS; however, the role of adenosine in REM sleep behavior will be addressed.

Figures

Fig. (1)
Fig. (1)
Raw electroencephalograph and electromyography examples of waking, SWS, and REM sleep from a C57/BL6 mouse. EEG signals were recorded from screw electrodes overlying the cortex, while EMG signals were recorded from panel electrodes from the dorsal neck muscle. Each trace shows a 10 sec epoch. The y-axis is set at 250 µv.
Fig. (2)
Fig. (2)
A. Indirect A1R -mediated modulation SWA. Projections from the brainstem reticular formation cholinergic arousal center to the thalamus and from basal forebrain cholinergic arousal center to the cortex and thalamus mediate the cholinergic tone. During waking, cholinergic tone is high, resulting in a desynchronized, high frequency cortical EEG (middle trace), as is monoaminergic tone (not shown). During REM sleep only cholinergic tone is high in association with a desynchronized EEG, similar to that observed during waking. The desynchronized activity is due in part to the cholinergically induced depolarization of thalamic and cortical neurons facilitating synaptically responsive non-bursting spiking patterns (bottom trace). During SWS, cholinergic tone is decreased due, in part to increased adenosine mediated inhibition of cholinergic center arousal neurons. The emergence of synchronized, low frequency cortical EEG (middle trace) requires this decreased activity in the cholinergic arousal centers of the forebrain and brainstem, allowing hyperpolarization of thalamic and cortical neurons. This is a necessary condition for burst-pause oscillatory firing of thalamic and cortical neurons (bottom trace). The thalamic neuron recordings were made in vitro, under control, waking-like conditions (bottom left) and in the presence of adenosine to approximate SWS-like conditions (modified with permission from [42]). B. Activation of A1Rs can directly facilitate SWA. Ado hyperpolarizes thalamic and cortical neurons by increasing potassium conductance through the GIRK channel and by decreasing the Ih current, which facilitates burst-pause firing at the expense of single spikes [42]. Both these changes also reduce cell conductance at the threshold for burst generation providing an additional facilatory effect on bursting. These effects may be synchronized by the thalamocortical- thalamo-reticular circuits to generate the high amplitude SWA observed during sleep.
Fig. (3)
Fig. (3)
Pre-synaptic effect of adenosine on glutamatergic activity. During cellular activity, adenosine is released from neurons and glia. This adenosine feeds back onto pre-synaptic neurons to inhibit glutamate release via A1Rs. This inhibition of an excitatory compound reduces neural activity.

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