title: Adenosine A(1) receptors in mouse pontine reticular formation depress breathing, increase anesthesia recovery time, and decrease acetylcholine release.
abstract: BACKGROUND
  Clinical and preclinical data demonstrate the analgesic actions of adenosine. Central administration of adenosine agonists, however, suppresses arousal and breathing by poorly understood mechanisms. This study tested the two-tailed hypothesis that adenosine A1 receptors in the pontine reticular formation (PRF) of C57BL/6J mice modulate breathing, behavioral arousal, and PRF acetylcholine release.
  
  
  METHODS
  Three sets of experiments used 51 mice. First, breathing was measured by plethysmography after PRF microinjection of the adenosine A1 receptor agonist N-sulfophenyl adenosine (SPA) or saline. Second, mice were anesthetized with isoflurane and the time to recovery of righting response (RoRR) was quantified after a PRF microinjection of SPA or saline. Third, acetylcholine release in the PRF was measured before and during microdialysis delivery of SPA, the adenosine A1 receptor antagonist 1, 3-dipropyl-8-cyclopentylxanthine, or SPA and 1, 3-dipropyl-8-cyclopentylxanthine.
  
  
  RESULTS
  First, SPA significantly decreased respiratory rate (-18%), tidal volume (-12%), and minute ventilation (-16%). Second, SPA concentration accounted for 76% of the variance in RoRR. Third, SPA concentration accounted for a significant amount of the variance in acetylcholine release (52%), RoRR (98%), and breathing rate (86%). 1, 3-dipropyl-8-cyclopentylxanthine alone caused a concentration-dependent increase in acetylcholine, a decrease in RoRR, and a decrease in breathing rate. Coadministration of SPA and 1, 3-dipropyl-8-cyclopentylxanthine blocked the SPA-induced decrease in acetylcholine and increase in RoRR.
  
  
  CONCLUSIONS
  Endogenous adenosine acting at adenosine A1 receptors in the PRF modulates breathing, behavioral arousal, and acetylcholine release. The results support the interpretation that an adenosinergic-cholinergic interaction within the PRF comprises one neurochemical mechanism underlying the wakefulness stimulus for breathing.
authors.affiliation: Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109-5615, USA.
authors.forename: George C
authors.initials: GC
authors.lastname: Gettys
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Ed
authors.initials: E
authors.lastname: Kimlin
authors.forename: Helen A
authors.initials: HA
authors.lastname: Baghdoyan
authors.forename: Ralph
authors.initials: R
authors.lastname: Lydic
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000758:Anesthesia; D000762:Anesthesia Recovery Period; D000818:Animals; D001143:Arousal / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D003216:Conditioning, Operant / Q000187:drug effects; D004563:Electrochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D008845:Microinjections; D011149:Pons / Q000187:drug effects / Q000378:metabolism*; D004856:Postural Balance / Q000187:drug effects; D043682:Receptor, Adenosine A1 / Q000187:drug effects*; D012018:Reflex / Q000187:drug effects; D012119:Respiration / Q000187:drug effects*; D012154:Reticular Formation / Q000187:drug effects / Q000378:metabolism*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D000109:Acetylcholine