The Role of 5-HT3 and Other Excitatory Receptors in Central Cardiorespiratory Responses to Hypoxia: Implications for Sudden Infant Death Syndrome

Abstract

Although brainstem serotonergic (5-HT) systems are involved in the protective responses to hypoxia, abnormalities of 5-HT function are strongly implicated in SIDS, and the neurochemical mechanisms by which 5-HT receptors influence brainstem cardiorespiratory responses to hypoxia remains unclear. This study focuses on the role of excitatory neurotransmission, including 5-HT3 signaling, to cardiac vagal neurons (CVNs) that dominate the control of heart rate. Excitatory synaptic inputs to CVNs, located in the nucleus ambiguus (NA), were recorded simultaneously with respiratory activity in in vitro brainstem slices. During control conditions excitatory inputs to CVNs were blocked by application of NMDA and AMPA/kainate glutamatergic receptor antagonists, whereas the 5-HT3 and purinergic receptor antagonists ondansetron and pyridoxalphosphate-6-azophenyl-2Ј,4Ј-disulfonic acid (PPADS), respectively, had no effect. However, during hypoxia ondansetron inhibited excitatory neurotransmission to CVNs. In recovery from hypoxia, spontaneous and respiratory-related excitatory events were blocked by glutamatergic and purinergic receptor blockers, respectively, whereas ondancetron had no effect. These results demonstrate that hypoxia recruits a 5-HT pathway to CVNs that activates 5-HT3 receptors on CVNs to maintain parasympathetic cardiac activity during hypoxia. Exaggeration of this 5-HT neurotransmission could increase the incidence of bradycardia and risk of sudden infant death during hypoxia. (Pediatr Res 65: 625-630, 2009) E pisodes of apnea and bradycardia are common in infants who succumb to SIDS (1,2). Although a specific cause in a majority of SIDS death is unknown, developmental abnormalities of serotonin (5-HT) function in the ventral medulla have recently been closely correlated with SIDS (3). These abnormalities involve multiple elements of 5-HT function including increased number of 5-HT neurons, reduction of 5-HT1A receptor binding, and relative reduction of 5-HT transporter function (4). In agreement with these findings, the study of cerebrospinal fluids of SIDS victims showed a significant increase of the metabolites of 5-HT (5,6). Medullary 5-HT abnormalities and enhanced 5-HT activity may result in exaggeration of responses to hypoxia including deleterious bradyarrhythmias.Respiratory responses to hypoxia include initial an increase, followed by a decrease, in the respiratory frequency in most mammals (7,8). Similarly, hypoxia evokes an initial increase in heart rate followed by a parasympathetically mediated bradycardia and ultimately, cessation of cardiac contractions (9 -11). This biphasic response to hypoxia is likely partly because of the biphasic increase followed by decrease in inhibitory GABAergic and glycinergic inputs to cardiac vagal neurons (CVNs) located within the nucleus ambiguus (NA) (12). However, the role of excitatory neurotransmission to CVNs in cardiorespiratory responses to hypoxia remains unclear.Hypoxia evokes neurotransmitter release in the brainstem including 5-HT (13), ATP...

Activation of D2-like dopamine receptors inhibits GABA and glycinergic neurotransmission to pre-motor cardiac vagal neurons in the nucleus ambiguus

“…Hence it was important to test whether dopamine induced effects on inhibitory neurotransmission to CVNs were mediated due to the activation of 5-HT and noradrenergic receptors. The concentrations of 5-HT antagonists and adrenergic receptor antagonists used in this study are consistent with the previous studies (Dergacheva et al, 2007, Dergacheva et al, 2009, Gorini et al, 2009, Philbin et al, 2010, Boychuk et al, 2011) and the data in this study indicates that the effects of dopamine in this study were mediated independent from adrenergic or serotonergic receptor activation and involved D 2 –like, but not D 1 –like, receptor activation.…”

5HT1A receptors inhibit glutamate inputs to cardiac vagal neurons post-hypoxia/hypercapnia

“…Although other neurotransmitter containing pathways and receptors have been identified within the nucleus ambiguous, and particularly on CVNs, their physiological role remains unclear. For example, multiple serotonergic terminals and receptor subtypes have been characterized in the nucleus ambiguus region (Izzo et al, 1993; Dergacheva et al, 2007; Audero et al, 2008; Dergacheva et al, 2008; Dergacheva et al, 2009a; Dergacheva et al, 2009b; Duncan et al, 2009; Hodges et al, 2009; Kinney, 2009; Pavone et al, 2009). In particular, 5HT1A receptors are expressed within the nucleus ambiguus and ventrolateral medulla respectively (Chitravanshi and Calaresu, 1992; Thor et al, 1992; Futuro-Neto et al, 1993; Dando et al, 1998; Paterson et al, 2006a; Paterson et al, 2006b).…”

5-HT2 receptors modulate excitatory neurotransmission to cardiac vagal neurons within the nucleus ambiguus evoked during and after hypoxia

“…Parasympathetic control of heart remains stable throughout the early postnatal period of the rat (Quigley et al, 1996). In addition, in-vitro studies carried out on medullary slices obtained from 2-6 day old rat pups suggest hypoxia can elicit robust changes in activity of parasympathetic CVNs (Neff et al, 2004; Dergacheva et al, 2009). In summary, it is likely the parasympathetic cardioinhibitory system is involved in mediation of hypoxia-elicited bradycardia in animals of different ages, including neonates, although other factors such as adenosine-mediated effects during hypoxia can not be excluded.…”

“…In addition, hypoxia recruits excitatory 5-HT3 mediated signaling to CVNs (Dergacheva et al, 2009). Measurement of neurotransmitter release within the VRG, an area located close to CVNs, in response to hypoxia indicates the concentration of 5-HT in the extracellular fluids increases significantly during hypoxia and declines slowly in the posthypoxia period (Richter et al, 1999).…”

“…The cellular mechanisms for this phenomenon include transient inhibition and subsequently disinhibition of cardiac vagal neurons (CVNs) within the nucleus ambiguus (NA) during hypoxia by a biphasic increase, followed by a decrease, in the frequency of spontaneous and inspiratory-related GABAergic and glycinergic neurotransmission to CVNs (Neff et al, 2004). In addition to the changes in inhibitory neurotransmission to CVNs, hypoxia also recruits 5-HT3 receptor-mediated excitatory neurotransmission to CVNs (Dergacheva et al, 2009). …”