ATP and the purine type 2 X7 receptor affect sleep

• Published in: Journal of applied physiology (1985) 2010-11, Vol.109 (5), p.1318-1327
• Main Authors: KRUEGER, James M, TAISHI, Ping, DE, Alok, DAVIS, Christopher J, WINTERS, Bradley D, CLINTON, James, SZENTIRMAI, Eva, ZIELINSKI, Mark R
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Adenosine Triphosphate - metabolism; Animals; Biological and medical sciences; Brain; Brain Waves; Cells; Circadian Rhythm; Cytokines; Electroencephalography; Electromyography; Fundamental and applied biological sciences. Psychology; Humans; Interleukin-1 - administration & dosage; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Physiology; Purinergic P2 Receptor Agonists - administration & dosage; Purinergic P2 Receptor Antagonists - administration & dosage; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2X7 - drug effects; Receptors, Purinergic P2X7 - genetics; Receptors, Purinergic P2X7 - metabolism; Recombinant Proteins - administration & dosage; RNA, Messenger - metabolism; Signal Transduction - drug effects; Sleep; Sleep - drug effects; Sleep deprivation; Sleep Deprivation - metabolism; Sleep Deprivation - physiopathology; Somatosensory Cortex - drug effects; Somatosensory Cortex - metabolism; Somatosensory Cortex - physiopathology
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.00586.2010

Sleep is dependent upon prior brain activities, e.g., after prolonged wakefulness sleep rebound occurs. These effects are mediated, in part, by humoral sleep regulatory substances such as cytokines. However, the property of wakefulness activity that initiates production and release of such substances and thereby provides a signal for indexing prior waking activity is unknown. We propose that extracellular ATP, released during neuro- and gliotransmission and acting via purine type 2 (P2) receptors, is such a signal. ATP induces cytokine release from glia. Cytokines in turn affect sleep. We show here that a P2 receptor agonist, 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP), increased non-rapid eye movement sleep (NREMS) and electroencephalographic (EEG) delta power while two different P2 receptor antagonists, acting by different inhibitory mechanisms, reduced spontaneous NREMS in rats. Rat P2X7 receptor protein varied in the somatosensory cortex with time of day, and P2X7 mRNA was altered by interleukin-1 treatment, by sleep deprivation, and with time of day in the hypothalamus and somatosensory cortex. Mice lacking functional P2X7 receptors had attenuated NREMS and EEG delta power responses to sleep deprivation but not to interleukin-1 treatment compared with wild-type mice. Data are consistent with the hypothesis that extracellular ATP, released as a consequence of cell activity and acting via P2 receptors to release cytokines and other sleep regulatory substances, provides a mechanism by which the brain could monitor prior activity and translate it into sleep.