Acute nicotine withdrawal blunts the hypoxic ventilatory response in young adult female rats.

Nicotine withdrawal after chronic exposure causes dysregulation of neural circuits, producing a variety of adverse signs and symptoms that are largely mediated through changes to nicotinic acetylcholine receptors (nAChRs). nAChRs are expressed throughout neural circuits mediating the hypoxic ventilatory response (HVR), however whether nicotine withdrawal impacts this critical chemoreflex is unknown. We tested the hypothesis that nicotine withdrawal blunts the HVR in rats. We exposed 6-week-old male and female Sprague-Dawley rats to chronic nicotine through their drinking water (0.2 g/L nicotine in 1% saccharin). Prior to experiments, half of the nicotine exposed rats were switched to saccharin water alone to produce a nicotine withdrawal group. Rats in the control group drank saccharin water alone. We used plethysmography to test the early- and late- phase ventilatory response to a 5-minute episode of 10% oxygen in all rats, corresponding to 6, 24, and 48 hours of withdrawal in the withdrawal group. In both male and female rats, serum cotinine was significantly reduced by 6 hours of nicotine withdrawal. In males, the HVR was not different between treatment groups. However, in females, while the HVR was the same in control rats and rats who continued nicotine exposure, both the early- and late-phase HVR were significantly blunted in animals in nicotine withdrawal. Nicotine withdrawal, although uncomfortable, is not considered dangerous. However, these results indicate that a blunted HVR is a previously unidentified consequence of nicotine withdrawal, which may help to explain the link between nicotine withdrawal and worse clinical outcomes in hospitalized patients.