title: Methylxanthines do not affect rhythmogenic preBötC inspiratory network activity but impair bursting of preBötC-driven motoneurons.
abstract: Clinical stimulation of preterm infant breathing with methylxanthines like caffeine and theophylline can evoke seizures. It is unknown whether underlying neuronal hyperexcitability involves the rhythmogenic inspiratory active pre-Bötzinger complex (preBötC) in the brainstem or preBötC-driven motor networks. Inspiratory-related preBötC interneuronal plus spinal (cervical/phrenic) or cranial hypoglossal (XII) motoneuronal bursting was studied in newborn rat en bloc brainstem-spinal cords and brainstem slices, respectively. Non-respiratory bursting perturbed inspiratory cervical nerve activity in en bloc models at >0.25mM theophylline or caffeine. Rhythm in the exposed preBötC of transected en bloc preparations was less perturbed by 10mM theophylline than cervical root bursting which was more affected than phrenic nerve activity. In the preBötC of slices, even 10mM methylxanthine did not evoke seizure-like bursting whereas >1mM masked XII rhythm via large amplitude 1-10Hz oscillations. Blocking A-type γ-aminobutyric (GABAA) receptors evoked seizure-like cervical activity whereas in slices neither XII nor preBötC rhythm was disrupted. Methylxanthines (2.5-10mM), but not blockade of adenosine receptors, phosphodiesterase-4 or the sarcoplasmatic/endoplasmatic reticulum ATPase countered inspiratory depression by muscimol-evoked GABAA receptor activation that was associated with a hyperpolarization and input resistance decrease silencing preBötC neurons in slices. The latter blockers did neither affect preBötC or cranial/spinal motor network bursting nor evoke seizure-like activity or mask corresponding methylxanthine-evoked discharges. Our findings show that methylxanthine-evoked hyperexcitability originates from motor networks, leaving preBötC activity largely unaffected, and suggest that GABAA receptors contribute to methylxanthine-evoked seizure-like perturbation of spinal motoneurons whereas non-respiratory XII motoneuron oscillations are of different origin.
authors.affiliation: Department of Physiology, Faculty of Medicine & Dentistry, 750 Medical Sciences Building, University of Alberta, Edmonton T6G 2H7, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Panaitescu
authors.forename: J
authors.initials: J
authors.lastname: Kuribayashi
authors.forename: A
authors.initials: A
authors.lastname: Ruangkittisakul
authors.forename: V
authors.initials: V
authors.lastname: Leung
authors.forename: M
authors.initials: M
authors.lastname: Iizuka
authors.forename: K
authors.initials: K
authors.lastname: Ballanyi
mesh_terms: D000818:Animals; D002110:Caffeine / Q000009:adverse effects; D001239:Inhalation / Q000502:physiology*; D007395:Interneurons / Q000187:drug effects* / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D012125:Respiratory Center / Q000187:drug effects* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D013806:Theophylline / Q000009:adverse effects; D014970:Xanthines / Q000009:adverse effects*
chemical_list: D011963:Receptors, GABA-A; D014970:Xanthines; C008514:methylxanthine; D002110:Caffeine; D013806:Theophylline
keywords: 3,7-dimethyl-1-propargylxanthine; 8-cyclopentyl-1,3-dipropylxanthine; C(4); CPA; DMPX; DPCPX; Hepes; IRCs; P; PDE4; RTN; SERCA; T; VRC; apnea of prematurity; cyclopiazonic acid; endoplasmic/sarcoplasmic reticulum ATPase; epilepsy; fourth cervical; hydroxyethyl piperazineethanesulfonic acid; ictal respiratory changes; network oscillations; pFRG; parafacial respiratory group; phosphodiesterase-4; postnatal day; pre-Bötzinger complex; preBötC; retrotrapezoid nucleus; rhythm generation; seizures; thoracic; ventral respiratory column