Developmental Nicotine Exposure Alters Neurotransmission and Excitability in Hypoglossal Motoneurons

Hypoglossal motoneurons (XII MNs) control muscles of the mammalian tongue and are rhythmically active during breathing. Acetylcholine (ACh) modulates XII MN activity by promoting the release of glutamate from neurons that express nicotinic ACh receptors (nAChRs). Chronic nicotine exposure alters nAChRs on neurons throughout the brain, including brain stem respiratory neurons. Here we test the hypothesis that developmental nicotine exposure (DNE) reduces excitatory synaptic input to XII MNs. Voltage-clamp experiments in rhythmically active medullary slices showed that the frequency of excitatory postsynaptic currents (EPSCs) onto XII MNs from DNE animals is reduced by 61% (DNE = 1.7 ± 0.4 events/s; control = 4.4 ± 0.6 events/s; P < 0.002). We also examine the intrinsic excitability of XII MNs to test whether cells from DNE animals have altered membrane properties. Current-clamp experiments showed XII MNs from DNE animals had higher intrinsic excitability, as evaluated by measuring their response to injected current. DNE cells had high-input resistances (DNE = 131.9 ± 13.7 MΩ, control = 78.6 ± 9.7 MΩ, P < 0.008), began firing at lower current levels (DNE = 144 ± 22 pA, control = 351 ± 45 pA, P < 0.003), and exhibited higher frequency–current gain values (DNE = 0.087 ± 0.012 Hz/pA, control = 0.050 ± 0.004 Hz/pA, P < 0.02). Taken together, our data show previously unreported effects of DNE on XII MN function and may also help to explain the association between DNE and the incidence of central and obstructive apneas

Expression of vasoactive intestinal peptide and related receptors in overcirculation-induced pulmonary hypertension in piglets.

The pathobiology of pulmonary arterial hypertension (PAH) is not understood completely. Recent observations in patients with PAH and in knockout models have raised the idea that a defect in vasoactive intestinal peptide (VIP) may be involved in PAH physiopathology. Therefore, we investigated the expressions of VIP, the related pituitary adenylate cyclase-activating polypeptide (PACAP), and their receptors (VPAC1, VPAC2, and PAC1) in piglets with overcirculation-induced pulmonary hypertension as an early-stage PAH model. Seventeen piglets were randomized to an anastomosis between the innominate and the main pulmonary artery, or to a sham operation. After 3 mo, a hemodynamic evaluation was performed and the lung tissue was sampled for biologic and histologic studies. The shunting increased pulmonary vascular resistance (PVR) by 100% and arteriolar medial thickness by 85%. VIP and VPAC1 gene expressions were decreased and increased, respectively. VPAC1 gene expression was positively correlated to PVR. VPAC2 and PAC1 immunoreactivity was seen in pulmonary arterial smooth muscle. VIP and PACAP immunostaining was observed in nerve fibers surrounding the pulmonary arterial smooth muscle. In conclusion, overcirculation-induced pulmonary hypertension is accompanied by a down-regulation of VIP signaling, without change in PACAP expression. These results are consistent with the notion that abnormal VIP signaling takes part in PAH pathogenesis.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe