Hypoxia and nicotine effects on Pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor 1 (PAC1) in the developing piglet brainstem

Pituitary adenylate cyclase activating polypeptide (PACAP) and its cognate receptor 1 (PAC1), have been implicated in the pathophysiology of the Sudden Infant Death Syndrome (SIDS). Two main risk factors for SIDS are prone sleeping and cigarette smoke exposure. Using piglet models of these risk factors, intermittent hypercapnic hypoxia (IHH-mimicking rebreathing in prone position) and nicotine (main reinforcing element of cigarettes), this study aimed to determine their effects on PACAP and PAC1 protein expression in the medulla. IHH was delivered for 1 (n = 7), 2 (n = 6), 3 (n = 6) and 4 (n = 7) days prior to euthanasia at 13-14 days of age, while nicotine (n = 7) was continuous for the first 14 days of life. An additional group of combined nicotine and 1 day IHH (1DIHH) was studied to determine the combined effects of the risk factors. Changes in expression were seen after the acute 1DIHH exposure (none after repeated daily exposures) and included a decrease in PACAP in the dorsal motor nucleus of vagus (DMNV; p = 0.024), nucleus of the solitary tract (NTS; p = 0.024) and the gracile nucleus (GRAC; p = 0.001), and a decrease in PAC1 in the NTS (p = 0.01). No PACAP change was noted in the nicotine-exposed piglets, however, a decrease in PAC1 was found in the DMNV (p = 0.02). IHH exposure in piglets with pre-exposure to nicotine led to a significant decrease in PACAP in the Grac (p = 0.04) but had no effect on PAC1. These findings show for the first time, the vulnerability of PACAP in the brainstem during early development to an acute hypercapnic hypoxic exposure and that those effects are greater than from nicotine exposure.