CNS changes in chronic hypoxia
Respiratory Research volume 2, Article number: 5.3 (2001)
Chronic hypoxia increases the hypoxic ventilatory response (HVR) in awake humans and animals  and we have shown that this involves changes in the "CNS gain of the HVR". The ventilatory or phrenic nerve response to pharmacological stimulation of carotid bodies or electrical stimulation of the carotid sinus nerve is significantly increased in awake and anesthetized rats, respectively, after 2–7 days at PIO2 = 74 Torr . We hypothesize that changes in neurotransmitters and their receptors along the HVR reflex pathway, and specifically in the nucleus tractus solitarius (NTS), increase the CNS gain of the HVR during chronic hypoxia. Previously we found that dramatic time-dependent changes in dopaminergic neurotransmission occur in the NTS during chronic hypoxia but they cannot explain the changes in the HVR . Now we are testing the hypothesis that NMDA receptors in the NTS are necessary for the increased CNS gain of the HVR during chronic hypoxia.
We previously reported no significant changes in mRNA for NMDA-R1 receptors during 7 days of hypoxia  but further experiments are planned to quantify changes in actual receptor protein. In awake unrestrained rats held in normoxic conditions (n = 6), chronic administration of a non-competitive NMDA receptor antagonist to the caudal NTS (25 μL/hr of MK-801 for 7 days via an Alzet miniosmotic pump) did not significantly change the HVR measured with barometric pressure plethysmography after 2 or 7 days of treatment. This is in contrast to the decrease in the HVR observed by other laboratories performing acute microinjections of MK-801 to the NTS . However, acute systemic injections of MK-801 (3 mg/kg ip.) decreased the HVR in our laboratory (n = 8) in agreement with published results . These results suggest time-dependent changes in glutamate neurotransmission with chronic blockade of NMDA receptors and we are testing this by repeating experiments using acute microinjections of MK-801. Experiments with acute or chronic blockade of NMDA receptors after chronic hypoxia will be compared with the former results to determine the independent effects of hypoxia versus NMDA receptor activation on the CNS gain of the HVR.
Future experiments will investigate the role of GABA in determining the CNS gain of the HVR. Chronic hypoxia changes mRNA levels for GABA-R1α  and GABA is reported to modulate the gain of preinspiratory bulbospinal neuron responsiveness to other neural inputs . This change in gain instead of set point is similar to that observed for the HVR during chronic hypoxia.
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Supported by NIH HL17731, NSF Postdoctoral fellowship (NMA) and White Mountain Research Station.