Nicotine withdrawal alters the ventilatory response to mixed hypoxia/hypercapnia in female rats

Nicotine withdrawal after chronic exposure alters nicotinic acetylcholine receptor (nAChR) signaling leading to dysregulation of neural circuits. This process underlies the many adverse signs and symptoms of nicotine withdrawal, the most well-known of which include anxiety, restlessness, irritability, and depressed mood. Due to widespread expression of nAChRs throughout the central nervous system, it is becoming appreciated that any neural circuit that depends in whole or in part on nAChR signaling can be impacted by nicotine withdrawal. nAChRs are expressed throughout the brainstem neural networks that control breathing, potentially contributing to increased ventilation during chemoreflex stimulation. Indeed, previous work from our lab shows that nicotine withdrawal blunts the ventilatory response to peripheral chemoreceptor stimulation with hypoxia in anesthetized female, but not male, rats. Here, we report the results of experiments designed to test the hypothesis that short-term (6 hours) nicotine withdrawal blunts the ventilatory response to combined stimulation of peripheral and central chemoreceptors. Young adult female Sprague-Dawley rats were randomly assigned to one of three 4-week exposure groups: Control rats (n=8) drank tap water; nicotine exposed rats (n=8) drank nicotine water (0.2 mg/L tap water), nicotine withdrawal rats (n=8) drank nicotine water but were switched to tap water 6 hours prior to study. To test the ventilatory response to hypoxia/hypercapnia (HH) challenge, urethane anesthetized and tracheotomized freely breathing rats were exposed to room air, followed by 20 minutes of HH (10% O 2 / 7% CO 2 ). Tidal volume (TV) and breathing frequency (f) were measured using a pneumotach on the outflow port of a t-tube inserted into the trachea and used to calculate the pulmonary ventilation rate (VE). CO 2 production (VCO 2 ) was calculated from measurements of mixed expired gas. TV (normalized to body weight), f, and VE/VCO 2 were averaged across the last 5 minutes of the 20-minute challenge and compared between groups using a 2-way ANOVA. Our results show that nicotine withdrawal significantly blunted the tidal volume response to HH compared to nicotine exposed animals (P=0.0494) and significantly blunted the frequency response compared to control animals (P=0.0196). Total ventilation during HH was not different between control and nicotine exposed animals (P=0.9796) but was blunted in nicotine withdrawal animals compared to both other groups (p=0.0433). These results suggest that short-term nicotine withdrawal blunts O2 and/or CO 2 sensing. K99HL164973 (Wollman), RFGA2023-008-29 (Wollman) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.