Prenatal nicotine exposure up-regulates catecholaminergic traits in peripheral arterial chemoreceptors of newborn rat pups

Abstract

Infants born to smoking mothers have depressed hypoxic arousal responses, reduced respiratory drive, and blunted ventilatory responses to hypoxia. These abnormalities in respiratory control are believed to be features of infants at risk for Sudden Infant Death Syndrome (SIDS). The peripheral arterial chemoreceptors in the carotid body are extensively involved in modulating respiratory responses to hypoxia, and arousal responses during sleep. Similar to findings in infants exposed prenatally to tobacco smoke, prenatal exposure to nicotine, a major component of tobacco smoke, alters acute ventilatory responses to short exposures to hypoxia and hyperoxia (Dejours test), manipulations that are used as a test of peripheral arterial chemoreceptor in function in newborn rats. Nicotine, through binding to cholinergic receptors, causes depolarization and catecholamine and opioid release from cells and neurons. Chemosensory type 1 cells in the carotid body and a subset of chemoreceptor sensory neurons in the petrosal ganglion are rich in catecholamines and contain nicotinic receptors. Physiology and pharmacology data also suggest that the carotid body contains met-enkephalins. Release of dopamine and norepineph-rine from chemosensory type 1 cells with subsequent binding to inhibitory dopaminergic and adrenergic receptors on carotid sinus nerve fibers results in diminished neuronal output from the carotid body leading to depressed hypoxic ventilatory responses. Similarly, the release of met-enkephalins from type 1 cells and binding to delta-opioid receptors on the carotid sinus nerve decreases hypoxic chemosensitivity. We used in situ hybridization histochemistry to determine the effect of prenatal nicotine exposure on the change in the levels of mRNAs for the enzymes regulating dopamine and norepinephrine synthesis, tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DβH), respectively and preproenkephalin (PPE) mRNA in the rat carotid body and petrosal ganglion during postnatal development. We also determined the change in the level of D2-dopamine receptor mRNA expression in these tissues induced by prenatal exposure to nicotine. In the carotid body, prenatal nicotine exposure increased THmRNA expression in animals at 0 and 3 postnatal days (both, P < 0.05 vs control) without affecting THmRNA levels at 6 and 15 days. However, at 15 postnatal days, DβH mRNA levels were increased in the carotid body of animals prenatally exposed to nicotine. D2-dopamine receptor mRNA expression in the carotid body increased with postnatal age and was unaffected by nicotine exposure. In the petrosal ganglion, prenatal nicotine exposure increased the number of ganglion cells expressing THmRNA in animals at 3 days (P < 0.01 vs control). DβH mRNA expression was not induced nor was PPE mRNA expression up-regulated in the petrosal ganglion in treated animals. PPE was not expressed in the carotid body in control or prenatally treated animals. In conclusion, prenatal nicotine exposure up-regulates mRNAs for synthesizing enzymes for two inhibitory neuromodulators, dopamine and norepinephrine, in peripheral arterial chemoreceptors that might contribute to abnormalities in cardiorespiratory control in animals prenatally exposed to nicotine. A possible role for brain-derived neurotrophic factor (BDNF) in nicotine induced up-regulation of catecholaminergic traits in peripheral arterial chemoreceptors will be discussed.