Ventilatory responses to acute and chronic hypoxia in mice: effects of dopamine D₂receptors

Abstract

We used genetically engineered D(2) receptor-deficient [D(2)-(-/-)] and wild-type [D(2)-(+/+)] mice to test the hypothesis that dopamine D(2) receptors modulate the ventilatory response to acute hypoxia [hypoxic ventilatory response (HVR)] and hypercapnia [hypercapnic ventilatory response (HCVR)] and time-dependent changes in ventilation during chronic hypoxia. HVR was independent of gender in D(2)-(+/+) mice and significantly greater in D(2)-(-/-) than in D(2)-(+/+) female mice. HCVR was significantly greater in female D(2)-(+/+) mice than in male D(2)-(+/+) and was greater in D(2)-(-/-) male mice than in D(2)-(+/+) male mice. Exposure to hypoxia for 2-8 days was studied in male mice only. D(2)-(+/+) mice showed time-dependent increases in "baseline" ventilation (inspired PO(2) = 214 Torr) and hypoxic stimulated ventilation (inspired PO(2) = 70 Torr) after 8 days of acclimatization to hypoxia, but D(2)-(-/-) mice did not. Hence, dopamine D(2) receptors modulate the acute HVR and HCVR in mice in a gender-specific manner and contribute to time-dependent changes in ventilation and the acute HVR during acclimatization to hypoxia.

Respiratory Adaptations to Lung Morphological Defects in Adult Mice Lacking Hoxa5 Gene Function

“…These data indicate that the acute frequency response is a transient overshoot that may reflect an increased sensitivity of Hoxa5 -/-mice to hypoxia. The absence of a tidal volume increase during hypoxia in wild-type mice is consistent with previous reports (30,39,40). The significant tidal volume increase observed in Hoxa5 -/-mice does not reflect an inability to further increase breathing frequency since mutant mice exposed to hypercapnia breathe at a much faster rate.…”

“…In mammals, 39 Hox genes are arrayed in four clusters (HoxA to D), each located on a different chromosome. Based on sequence similarity and relative position within the complex, the Hox genes have been subdivided into paralogous groups 1-13.…”

Breathing at high altitude

“…These findings indicate that central dopamine is an important excitatory neuromodulator of HVA, but does not contribute to the early stage of HVA. The implication of dopamine to HVA is also supported by data showing that knock-out mice lacking the D2R gene display abnormal HVA, i.e., no timedependent increases in baseline ventilation or hypoxic ventilatory response during chronic hypoxia [66].…”

β2 nicotinic acetylcholine receptor subunit modulates protective responses to stress: A receptor basis for sleep-disordered breathing after nicotine exposure

“…Activation of inhibitory circuits by nicotine is an important mechanism depressing respiratory drive, possibly contributing to SIDS (5). Absence of the ␤2 nAChR subunit, by disengaging critical signaling cascades normally triggered by nicotine, could be neuroprotective (17,26).…”