The development of nicotinic receptors in the human medulla oblongata: Inter-relationship with the serotonergic system

Abstract

Maternal cigarette smoking during pregnancy adversely affects fetal development and increases the risk for the sudden infant death syndrome (SIDS). In SIDS we have reported abnormalities in the medullary serotonergic (5-HT) system, which is vital for homeostatic control. In this study we analyzed the inter-relationship between nicotinic receptors (nAChRs), to which nicotine in cigarette smoke bind, and the medullary 5-HT system in the human fetus and infant as a step towards determining the mechanisms whereby smoking increases SIDS risk in infants with 5-HT defects. Immunohistochemistry for the α4 nAChR subunit and 5-HT neurons was applied in fetal and infant medullae (15-92 postconceptional weeks, n=9). The distribution of different nAChRs was determined from 39-82 postconceptional weeks (n=5) using tissue autoradiography for 3 Hnicotine, 3 H-epibatidine, 3 H-cytisine, and 125 I-bungarotoxin; the findings were compared to laboratory 5-HT 1A and 5-HT transporter binding data, and 5-HT neuronal density. Alpha4 immunoreactivity was ubiquitously expressed in medullary nuclei related to homeostatic functions from 15 weeks on, including rhombic lip germinal cells. At all ages, α4 co-localized with 5-HT neurons, indicating a potential site of interaction whereby exogenous nicotine may adversely affect 5-HT neuronal development and function. Binding for heteromeric nAChRs was highest in the inferior olive, and for homomeric nAChRs, in the vagal complex. In the paragigantocellularis lateralis, 5-HT 1A receptor binding simultaneously increased as α7 binding decreased across infancy. This study indicates parallel dynamic and complex changes in the medullary nicotinic and 5-HT systems throughout early life, i.e., the period of risk for SIDS.

Nicotine and Tobacco as Substances of Abuse in Children and Adolescents

“…67 Nicotinic acetylcholine receptors are strongly associated with serotonergic (5-HT receptors) in the brainstem during fetal development, and abnormalities of serotonergic neurotransmission in the brainstem have been consistent with neuropathologic findings in cases of sudden unexpected and unexplained death in infancy. 74,75 In first-trimester human fetuses, abnormal nicotinic receptor subunit levels have also been detected in the brainstem regions associated with sudden infant death syndrome. 76 Dysfunction of these brainstem regions, which can be associated with sudden infant death syndrome, is strongly associated with maternal cigarette use during pregnancy, and the alterations that are seen with gene expression in these cholinergic receptor subunits may be a contributing factor to the brainstem abnormalities seen in these infants.…”

Central cholinergic regulation of respiration: nicotinic receptors

“…Impairments in central cholinergic system are implicated in pathophysiology of some prevalent neurological disorders involving respiratory control such as SIDS and sleep apnea [13,[22][23][24][25][26] . Studies of central cholinergic regulation of respiration date to the early 1930s.…”

Prenatal nicotine exposure increases hyperventilation in α4-knock-out mice during mild asphyxia

“…Indeed, ␣4-containing nAChRs reside in both the carotid bodies (Meza et al, 2012;Shirahata et al, 1998) and chemoreceptive brainstem respiratory nuclei (Duncan et al, 2008;Shao et al, 2008;Shao and Feldman, 2002) alike. This has been shown in both the cat and mouse carotid body (Cohen et al, 2002;Shirahata et al, 1998) and in the brainstem of rats and human infants (Duncan et al, 2008;Shao et al, 2008;Shao and Feldman, 2002).…”

“…Indeed, ␣4-containing nAChRs reside in both the carotid bodies (Meza et al, 2012;Shirahata et al, 1998) and chemoreceptive brainstem respiratory nuclei (Duncan et al, 2008;Shao et al, 2008;Shao and Feldman, 2002) alike. This has been shown in both the cat and mouse carotid body (Cohen et al, 2002;Shirahata et al, 1998) and in the brainstem of rats and human infants (Duncan et al, 2008;Shao et al, 2008;Shao and Feldman, 2002). Further, the ␣4 receptor modulates excitatory control in the carotid body through the release of adenosine (Conde and Monteiro, 2006) and in the brainstem, inhibitory control through dopaminergic and GABAergic release (Klink et al, 2001;Marubio et al, 2003;Ross et al, 2000).…”

“…More importantly, this subtype is found in both the chemoreceptive brainstem nuclei (Duncan et al, 2008;Shao et al, 2008;Shao and Feldman, 2002) and the carotid bodies (Bairam et al, 2007;Cohen et al, 2002;Meza et al, 2012;Shirahata et al, 1998) and has the highest sensitivity to nicotine (Flores et al, 1992;Sharples and Wonnacott, 2001). Studies performed on neonatal ␣4-knockin mice, expressing a hypersensitive version of the ␣4 subunit, have reported an excitatory role for ␣4-containing nAChRs on the activity of respiratory neurons in vitro (Shao et al, 2008;Shao and Feldman, 2002).…”