Segment 9

NREM: Adenosine

Neurobiology of Sleep and Wakefulness

Learning Points & Defining Behavioral States Historical Overview: Brainstem & Forebrain Wakefulness and REM Sleep (Monoamines,

Acetylcholine & GABA, Hypocretin/Orexin) NREM Sleep: GABA, Adenosine Summary

Sleepiness Across the Day: MSLT

modied from Carskadon & Dement, Neurosci Biobehav Rev 11:307-317, 1987

Adenosine and Sleep The adenosine receptor

antagonist caffeine is used worldwide to increase wakefulness and improve performance on psychomotor tasks (Sebastio and Ribeiro, Handb Exp Pharmacol 193:471-534, 2009)

Adenosine and Sleep ICV adenosine decreases wakefulness

and increases NREM sleep (Virus et al., Neuropharmacology 22:1401-1404, 1983)

Adenosine delivered to the preoptic area of the anterior hypothalamus decreases wakefulness and induced NREM sleep ( Ticho and Radulovacki, Pharmacol Biochem Behav 40:33-40, 1991)

Adenosine and Sleep The sleep-inducing

effects of adenosine are mediated by A1 and A2A adenosine receptors (Porkka-Heiskanen et al., Sleep Med Rev 6:321-332, 2002; Basheer et al., Prog Neurobiol 73:379-396, 2004)

Caffeine blocks A1 and A2A receptors

Adenosine and NREM Sleep Endogenous adenosine

levels in basal forebrain increase during prolonged wakefulness and decrease during recovery sleepPorkka-Heiskanen et al., 1997Science 276:1265-1268 Ad

enos

ine (%

of ho

ur 2)

Prolonged

WakingRecovery

Adenosine and Sleep The sleep deprivation-induced increase

in adenosine levels is specific to the basal forebrain Adenosine levels do not increase in the

thalamus, dorsal raphe, PPT, or preoptic area/anterior hypothalamus after sleep deprivation ( Porkka-Heiskanen et al., Neuroscience 99:507-517, 2000)

Sleep Deprivation Induced Increase in Adenosine Levels is Site Specific

Porkka-Heiskanen et al., Neuroscience 99:507-517, 2000

Preoptic area

Basal forebrain

CortexThalamus

PPTDorsal raph

By what mechanisms might an accumulation of basal forebrain adenosine increase sleep? Adenosine inhibits all cholinergic and

some non-cholinergic (putatively GABAergic) basal forebrain neurons (Arrigoni et al., Neuroscience 140:403-413, 2006)

Adenosine disinhibits GABAergic sleep-active VLPO neurons (Chamberlin et al., Neuroscience 119:913-918, 2003; Morairty et al., ibid 123:451-457, 2004)

Adenosine Increases Sleep by Activating A1 Receptors in the Prefrontal Cortex (PFC)

(Van Dort et al., J Neurosci 29:871, 2009)

Prefrontal Cortex

Adenosine in Prefrontal Cortex Inhibits ACh Release and Slows the EEG

Van Dort et al., J Neurosci 29:871-881, 2009

Adenosine in Prefrontal Cortex Decreases Wakefulness

Van Dort et al., J Neurosci 29:871-881, 2009

Adenosine Promotes Sleep Adenosine A1 receptors in mouse

prefrontal cortex comprise part of a descending system that inhibits wakefulness (Van Dort et al., J Neurosci 29:871-881, 2009)