title: Adenosine and the homeostatic control of sleep: effects of A1 receptor blockade in the perifornical lateral hypothalamus on sleep-wakefulness.
abstract: The orexinergic neurons of the lateral hypothalamus (LH) are critical for wakefulness [McCarley RW (2007) Neurobiology of REM and NREM sleep. Sleep Med 8:302-330]. Recent evidence suggests that adenosine (AD), a homeostatic sleep factor, may act via A1 receptor (A1R) to control orexinergic activity and regulate sleep-wakefulness [Thakkar MM, Winston S, McCarley RW (2002) Orexin neurons of the hypothalamus express adenosine A1 receptors. Brain Res 944:190-194; Liu ZW, Gao XB (2006) Adenosine inhibits activity of hypocretin/orexin neurons via A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. J Neurophysiol]. To evaluate the role of AD in the orexinergic LH and its influences on sleep-wakefulness, we designed two experiments in freely behaving rats: First, we bilaterally microinjected 1,3-dipropyl-8-phenylxanthine (DPX) (1.5 pmol and 15 pmol), a selective A1R antagonist into the LH during the light cycle and examined its effect on spontaneous sleep-wakefulness. Second, we performed 6 h of sleep deprivation. Thirty minutes before the animals were allowed to enter recovery sleep, 15 pmol of DPX was bilaterally microinjected into the LH and its effects on recovery sleep were monitored. Microinjection of DPX into the orexinergic LH produced a significant increase in wakefulness with a concomitant reduction in sleep, both during spontaneous bouts of sleep-wakefulness and during recovery sleep. Local administration of DPX into the LH produced a significant increase in the latency to non-REM sleep during recovery sleep. However, total slow wave (delta) activity during non-REM sleep phase of recovery sleep remained unaffected after DPX treatment. This is the first study that implicates endogenous adenosine to have a functional role in controlling orexinergic tone and influencing the homeostatic regulation of sleep-wakefulness.
authors.affiliation: Department of Neurology, University of Missouri, Harry S. Truman Veteran's Memorial Hospital, 800 Hospital Drive, Columbia, MO 65201-5297, USA. thakkarmm@health.missouri.edu
authors.forename: M M
authors.initials: MM
authors.lastname: Thakkar
authors.forename: S C
authors.initials: SC
authors.lastname: Engemann
authors.forename: K M
authors.initials: KM
authors.lastname: Walsh
authors.forename: P K
authors.initials: PK
authors.lastname: Sahota
mesh_terms: D000241:Adenosine / Q000494:pharmacology / Q000502:physiology*; D058916:Adenosine A1 Receptor Antagonists; D000704:Analysis of Variance; D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D003700:Delta Rhythm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis / Q000502:physiology*; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008845:Microinjections / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D043682:Receptor, Adenosine A1 / Q000502:physiology*; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D012892:Sleep Deprivation / Q000503:physiopathology; D013997:Time Factors; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology*; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D014970:Xanthines; C049140:1,3-dipropyl-8-phenylxanthine; D000241:Adenosine