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-wk-old male and female Sprague-Dawley rats to chronic nicotine through their drinking water (0.2 g/L nicotine in 1% saccharin). Before 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-min episode of 10% oxygen in all rats, corresponding to 6, 24, and 48 h of withdrawal in the withdrawal group. In both male and female rats, serum cotinine was significantly reduced by 6 h of nicotine withdrawal. In males, the HVR was not different between treatment groups. However, in females, although 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.NEW & NOTEWORTHY Nicotine is the highly addictive component of tobacco, and nicotine withdrawal is often observed in hospitalized smokers and is associated with poor clinical outcomes. Here, we show that a blunted HVR is a previously unidentified, and sex-specific consequence of nicotine withdrawal, suggesting that female patients in nicotine withdrawal may experience relatively more severe oxygen desaturation for a given hypoxic episode, which could lead to end-organ damage or failure, especially in the brain and heart.