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Impact of Ampakine CX‐717 on Diaphragm EMG Activity and Breathing in Non‐anesthetized Freely Behaving Rats
Author(s) -
Rana Sabhya,
Sunshine Michael D.,
Fuller David D.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.09742
Subject(s) - tidal volume , diaphragm (acoustics) , ampa receptor , medicine , respiratory rate , respiratory center , anesthesia , control of respiration , respiratory minute volume , ventilation (architecture) , respiratory system , chemistry , receptor , heart rate , glutamate receptor , mechanical engineering , physics , acoustics , loudspeaker , blood pressure , engineering
Glutamatergic neurotransmission is partly mediated by ionotropic AMPA receptors, and these receptors play an important role in the neural control of breathing. Ampakines are positive allosteric modulators of AMPA receptors. These drugs can stimulate breathing during hypo‐ventilated states, such as following an opioid overdose. Our laboratory has recently shown that acute exposure to an ampakine, CX717 (15 mg/kg), can acutely stimulate neural drive to the diaphragm in anesthetized but otherwise healthy rats. The goal of the current work is to evaluate the impact of ampakine on diaphragm muscle activation in freely moving non‐anesthetized rats. Ventilation and metabolic rate (V CO2 ) were measured using whole body plethysmography and diaphragm EMG was assessed using intramuscular electrodes. Spinally intact rats (n=2) were given a single intravenous bolus of CX717 at four months after implantation of diaphragm EMG electrodes. Delivering CX717 at 15 mg/kg had no detectable impact on V CO2 , inspiratory tidal volume or diaphragm EMG burst amplitude. In addition, at 30 minutes following IV ampakine, both animals showed a robust increase in diaphragm EMG activity, tidal volume, and the ratio of ventilation V CO2 (V E /V CO2 ) during an acute hypoxic challenge (5 min, 10.5% inspired O2). Qualitatively, we observed a possible sedative effect as shown of lack of movement and exploratory behavior following ampakine exposure. Our preliminary conclusion is that ampakine CX717 at a dose of 15 mg/kg has little impact on breathing in the otherwise healthy rat. Ongoing studies are evaluating impact of the vehicle (2‐hydroxypropyl‐beta‐cyclodextrin) versus ampakine using a cross‐over study design in spinally intact rats and in rats with spinal cord injury. Support or Funding Information 5 R01 HL139708 02 (DDF)F31 HL145831‐01 (MDS)