Cardiac Vagal Neurons Research Articles

Orexinergic modulation of GABAergic neurotransmission to cardiac vagal neurons in the brain stem nucleus ambiguus changes during development

Cardiac vagal neurons (CVNs) in the nucleus ambiguus (NA) are the major determinant of parasympathetic activity to the heart. Spontaneous GABAergic neurotransmission to CVNs is modulated by hypothalamic neuropeptide orexin-A in postnatal days 2–5 (P5) rats; however, during early postnatal development, orexin expression changes, and the role of orexin-A in modulating CVN activity at other stages of development is unknown. In this study, we compared changes in GABAergic inhibitory postsynaptic currents (IPSCs) in CVNs evoked by orexin-A in P5, P16–20 (P20), and P27–30 (P30) rats using an in vitro brain stem slice preparation. Bath-applied orexin-A enhanced GABAergic IPSCs in all CVNs tested in P5 and P30 animals and in the majority of neurons tested in P20 pups. Focal application of orexin-A ejected from a pipette positioned within 30 μm of the patched CVN did not alter GABAergic signaling in P5 pups. In contrast, in both P20 and P30 rats, focal application of orexin-A inhibited GABAergic IPSCs, and this inhibition persisted in the presence of tetrodotoxin. These results indicate orexin-A facilitates GABAergic IPSCs likely by activating preceding GABAergic neurons that project to CVNs. Orexin-A also likely acts at GABAergic presynaptic terminals surrounding CVNs within the NA to inhibit GABA release. The latter mechanism is absent in P5 pups but occurs in P20 and P30 rats. In conclusion, this study elucidates an important maturation of the parasympathetic cardiac control system. Alterations in these developmental mechanisms may play a role in pathogenesis of disorders related to a specific stage of development maturation.

Anaesthetics differentially modulate the trigeminocardiac reflex excitatory synaptic pathway in the brainstem

The trigeminocardiac reflex (TCR) occurs upon excitation of the trigeminal nerve with a resulting bradycardia and hypotension. While several anaesthetics and analgesics have been reported to alter the incidence and strength of the TCR the mechanisms for this modulation are unclear. This study examines the mechanisms of action of ketamine, isoflurane and fentanyl on the synaptic TCR responses in both neurones in the spinal trigeminal interpolaris (Sp5I) nucleus and cardiac vagal neurones (CVNs) in the Nucleus Ambiguus (NA). Stimulation of trigeminal afferent fibres evoked an excitatory postsynaptic current (EPSC) in trigeminal neurones with a latency of 1.8 ± 0.1 ms, jitter of 625 μs, and peak amplitude of 239 ± 45 pA. Synaptic responses further downstream in the reflex pathway in the CVNs occurred with a latency of 12.1 ± 1.1 ms, jitter of 0.8-2 ms and amplitude of 57.8 ± 7.5 pA. The average conduction velocity to the Sp5I neurones was 0.94 ± 0.18 mm ms(-1) indicating a mixture of A-δ and C fibres. Stimulation-evoked EPSCs in both Sp5I and CVNs were completely blocked by AMPA/kainate and NMDA glutamatergic receptor antagonists. Ketamine (10 μm) inhibited the peak amplitude and duration in Sp5I as well as more distal synapses in the CVNs. Isoflurane (300 μm) significantly inhibited, while fentanyl (1 μm) significantly enhanced, EPSC amplitude and area in CVNs but had no effect on the responses in Sp5l neurones. These findings indicate glutamatergic excitatory synaptic pathways are critical in the TCR, and ketamine, isoflurane and fentanyl differentially alter the synaptic pathways via modulation of both AMPA/kainate and NMDA receptors at different synapses in the TCR.

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

Synaptic inputs to cardiac vagal neurons (CVNs) regulate parasympathetic activity to the heart. Previous work has shown insults such as hypoxia and hypercapnia (H/H) alter CVN activity by activating post-synaptic serotonergic, purinergic, and glutamatergic receptors in CVNs. This study examines the role of serotonergic 5HT1A receptors in modulating these excitatory neurotransmissions to CVNs during control conditions, H/H and recovery from H/H. Excitatory post-synaptic currents (EPSCs) were recorded from identified CVNs in vitro before, during and post H/H. The 5HT1A receptor antagonist WAY 100635 had no effect on EPSCs in CVNs before, and during H/H. However, during recovery from H/H inspiratory-related excitatory serotonergic and purinergic pathways were recruited to excite CVNs. However, when these serotonergic and purinergic pathways are blocked, the 5HT1A receptor antagonist WAY 100635 restores an excitatory glutamatergic neurotransmission to CVNs. This study indicates endogenous activation of serotonergic 5HT1A receptors diminishes glutamatergic neurotransmission to CVNs following H/H, likely via a presynaptic site of action.

α1-adrenergic receptors facilitate inhibitory neurotransmission to cardiac vagal neurons in the nucleus ambiguus

The cholinergic cardiac vagal neurons (CVNs), located in the nucleus ambiguus, are the origin of cardioinhibitory parasympathetic activity. Catecholaminergic neurons in nearby regions of the brainstem, including the C1 and C2 cell groups, are thought to play a key role in both arousing from sleep and maintaining wakefulness. Because norepinephrine (NE) could play an important role in influencing the activity of CVNs, particularly in response to sleeping/waking and arousal states, the present study investigated the contribution of α(1)-adrenergic receptor activation to augment inhibitory and/or blunt excitatory neurotransmission to CVNs. To test the effects of α(1)-adrenergic receptor activation, CVNs were labeled in rats by retrograde tracing and synaptic events were recorded by whole cell voltage clamp techniques in vitro. Prazosin, an inverse agonist of α(1)-adrenergic receptor, significantly decreased the frequency of both GABAergic and glycinergic neurotransmission to CVNs. Activation of α(1)-adrenergic receptors by the α(1)-adrenergic receptor agonists NE or phenylephrine (PE) both significantly increased GABAergic and glycinergic inhibitory event frequency. This effect was prevented by the sodium channel blocker tetrodotoxin (TTX). Activation of α(1)-adrenergic receptors did not alter glutamatergic neurotransmission to CVNs. This study indicates that α(1)-adrenergic receptor activation in the brainstem can facilitate inhibitory GABAergic and glycinergic neurotransmission so as to reduce CVN activity; this synaptic modulation may play a role in the tachycardia seen during NE-dependent behavioral arousal.

β1 adrenergic receptors decrease glutamatergic neurotransmission to cardiac vagal neurons

β adrenergic receptors (βAR) are a frequent target for drugs used to treat cardiac arrhythmias, hypertension, as well as other heart conditions. One of the most commonly used drugs for treatment, β antagonists, act by blocking catecholamine binding sites in the heart, autonomic system as well as the kidneys. Despite the highly beneficial effect of β blockers in lowering heart rate and blood pressure, very little is known about the role of βAR in modulating parasympathetic activity that controls heart rate. In this study we examined, using patch clamp electrophysiology in-vitro, the effect of βAR on cardiac vagal neurons (CVNs), which are the neurons that dominate parasympathetic control of heart rate and originate in the brainstem nucleus ambiguus. Application of the β1 receptor subtype specific agonist dobutamine significantly decreased the frequency of excitatory postsynaptic currents (EPSCs) in CVNs. To determine the role of β2 receptors in altering glutamatergic EPSCs, albuterol, a β2 receptor agonist was applied. Albuterol did not evoke any significant change in excitatory glutamatergic neurotransmission to CVNs. These results suggest CVNs are inhibited by β1 but not β2 receptor activation, and that the beneficial effect of β receptor blockers in treating arrhythmias and tachycardia may include a disinhibition and increase in cardioprotective parasympathetic activity to the heart.

Photostimulation of spinal trigeminal neuron pathways to parasympathetic cardiac vagal neurons

Activation of the trigeminocardiac reflex by airborne irritants or water, stimulates nasotrigeminal sensory fibers eliciting a pronounced bradycardia and increase in parasympathetic cardiac activity. Exaggeration of this response can be fatal, and has been implicated in cardiorespiratory diseases such as sudden infant death syndrome (SIDS). Parasympathetic cardiac vagal neurons (CVNs) in the nucleus ambiguus (NA) play an integral role in mediating this reflex. Stimulation of trigeminal sensory afferents elicits a polysynaptic excitatory glutamatergic neurotransmission to CVNs. We use a UV photo uncaging system to identify the neurons in the spinal trigeminal nucleus (sp5) that project to CVNs by sequential photostimulation of different neuron clusters as well as individual neurons that elicit excitatory glutamatergic neurotransmission to CVNs. Herpes simplex virus 1 expressing GFP was injected into the nasal mucosa of neonatal rats, and, using 2 photon confocal microscopy, areas of the brainstem expressing GFP+ trigeminal sensory afferent fibers within sp5 were identified. Preliminary results indicate scattered neurons in the sp5 that receive sensory afferent synaptic terminals project to and excite CVNs. Further work is necessary to determine if these neurons are located diffusely or in discrete clusters within the sp5.

Synaptic and intrinsic activation of respiratory GABAergic neurons in the brainstem

Respiratory sinus arrhythmia is mediated by inspiratory-evoked increases in GABAergic neurotransmission to cardiac vagal neurons (CVNs) that control heart rate. However, the mechanisms responsible for the sources and activation of the inspiratory-related GABAergic neurotransmission to CVNs are unknown. We identified a population of GABAergic neurons in the ventrolateral medulla that are activated during inspiration in a slice preparation that retains rhythmic respiratory activity. This population of inspiratory-activated GABAergic neurons receives inspiratory-related excitatory events that were blocked by the glutamatergic antagonists, NMDA and AMPA/kainate receptor antagonists AP-5 and CNQX, respectively. The nicotinic acetylcholine receptor antagonists, DHbE, 100microM and a-BTX, 100nM had no significant effect. A subset of inspiratory GABAergic neurons continue to fire in the presence of CNQX/AP-5, suggesting they may have the characteristics of a respiratory pacemaker neuron. The pacemaker cells not inhibited by CNQX were insensitive to cadmium. The results from this study demonstrate the existence of a population of GABAergic inspiratory neurons in the ventrolateral medulla that likely project to CVNs, receive increased glutamatergic neurotransmission during inspiration, and a subset of these GABAergic neurons have respiratory pacemaker properties.

Hypoxia reversibly inhibits inspiratory‐related GABAergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus

Hypoxia reversibly inhibits inspiratory‐related GABAergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus

Hypocretin-1 (orexin A) prevents the effects of hypoxia/hypercapnia and enhances the GABAergic pathway from the lateral paragigantocellular nucleus to cardiac vagal neurons in the nucleus ambiguus

Hypocretins (orexins) are hypothalamic neuropeptides that play a crucial role in regulating sleep/wake states and autonomic functions including parasympathetic cardiac activity. We have recently demonstrated stimulation of the lateral paragigantocellular nucleus (LPGi), the nucleus which is thought to play a role in rapid eye movement (REM) sleep control, activates an inhibitory pathway to preganglionic cardiac vagal neurons in the nucleus ambiguus (NA). In this study we test the hypothesis that hypocretin-1 modulates the inhibitory neurotransmission to cardiac vagal neurons evoked by stimulation of the LPGi using whole-cell patch-clamp recordings in an in vitro brain slice preparation from rats. Activation of hypocretin-1 receptors produced a dose-dependent and long-term facilitation of GABAergic postsynaptic currents evoked by electrical stimulation of the LPGi. Hypoxia/hypercapnia diminished LPGi-evoked GABAergic current in cardiac vagal neurons and this inhibition by hypoxia/hypercapnia was prevented by pre-application of hypocretin-1. The action of hypocretin-1 was blocked by the hypocretin-1 receptor antagonist SB-334867. Facilitation of LPGi-evoked GABAergic current in cardiac vagal neurons under both normal condition and during hypoxia/hypercapnia could be the mechanism by which hypocretin-1 affects parasympathetic cardiac function and heart rate during REM sleep. Furthermore, our findings indicate a new potential mechanism that might be involved in the cardiac arrhythmias, bradycardia, and sudden cardiac death that can occur during sleep.

GLP-1 receptor stimulation depresses heart rate variability and inhibits neurotransmission to cardiac vagal neurons

glucagon-like peptide 1 (GLP-1) is an incretin hormone released from the gut in response to food intake. Whereas GLP-1 acts in the periphery to inhibit glucagon secretion and stimulate insulin release, it also acts in the central nervous system to mediate autonomic control of feeding, body temperature, and cardiovascular function. Because of its role as an incretin hormone, GLP-1 receptor analogs are used as a treatment for type 2 diabetes. Central or peripheral administration of GLP-1 increases blood pressure and heart rate, possibly by activating brainstem autonomic nuclei and increasing vagus nerve activity. However, the mechanism(s) by which GLP-1 receptor stimulation affects cardiovascular function are unknown. We used the long-lasting GLP-1 receptor agonist Exendin-4 (Ex-4) to test the hypothesis that GLP-1 signalling modulates central parasympathetic control of heart rate. using a telemetry system, we assessed heart rate in mice during central Ex-4 administration. Heart rate was increased by both acute and chronic central Ex-4 administration. Spectral analysis indicated that the high frequency and low frequency powers of heart rate variability were diminished by Ex-4 treatment. Finally, Ex-4 decreased both excitatory glutamatergic and inhibitory glycinergic neurotransmission to preganglionic parasympathetic cardiac vagal neurons. these data suggest that central GLP-1 receptor stimulation diminishes parasympathetic modulation of the heart thereby increasing heart rate.

Endogenous Inhibition of the Trigeminally Evoked Neurotransmission to Cardiac Vagal Neurons by Muscarinic Acetylcholine Receptors

Stimulation of the nasal mucosa by airborne irritants or water evokes a pronounced bradycardia accompanied by peripheral vasoconstriction and apnea. The dive response, which includes the trigeminocardiac reflex, is among the most powerful autonomic responses. These responses slow the heart rate and reduce myocardial oxygen consumption. Although normally cardioprotective, exaggeration of this reflex can be detrimental and has been implicated in cardiorespiratory diseases, including sudden infant death syndrome (SIDS). An essential component of the diving response and trigeminocardiac reflex is activation of the parasympathetic cardiac vagal neurons (CVNs) in the nucleus ambiguus that control heart rate. This study examined the involvement of cholinergic receptors in trigeminally evoked excitatory postsynaptic currents in CVNs in an in vitro preparation from rats. CVNs were identified using a retrograde tracer injected into the fat pads at the base of the heart. Application of the acetylcholinesterase inhibitor neostigmine significantly decreased the amplitude of glutamatergic neurotransmission to CVNs on stimulation of trigeminal fibers. Whereas nicotine did not have any effect on the glutamatergic responses, the muscarinic acetylcholine receptor (mAChR) agonist bethanechol significantly decreased the excitatory neurotransmission. Atropine, an mAChR antagonist, facilitated these responses indicating this trigeminally evoked brain stem pathway in vitro is endogenously inhibited by mAChRs. Tropicamide, an m4 mAChR antagonist, prevented the inhibitory action of the muscarinic agonist bethanechol. These results indicate that the glutamatergic synaptic neurotransmission in the trigeminally evoked pathway to CVNs is endogenously inhibited in vitro by m4 mAChRs.

Clonidine, an α 2-receptor agonist, diminishes GABAergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus

In hypertension, there is an autonomic imbalance in which sympathetic activity dominates over parasympathetic control. Parasympathetic activity to the heart originates from cardiac vagal neurons located in the nucleus ambiguus. Presympathetic neurons that project to sympathetic neurons in the spinal cord are located in the ventral brainstem in close proximity to cardiac vagal neurons, and many of these presympathetic neurons are catecholaminergic. In addition to their projection to the spinal cord, many of these presympathetic neurons have axon collaterals that arborize into neighboring cardiorespiratory locations and likely release norepinephrine onto nearby neurons. Activation of α 2-adrenergic receptors in the central nervous system evokes a diverse range of physiological effects, including reducing blood pressure. This study tests whether clonidine, an α 2-adrenergic receptor agonist, alters excitatory glutamatergic, and/or inhibitory GABAergic or glycinergic synaptic neurotransmission to cardiac vagal neurons in the nucleus ambiguus. Cardiac vagal neurons were identified in an in vitro brainstem slice preparation, and synaptic events were recording using whole cell voltage clamp methodologies. Clonidine significantly inhibited GABAergic neurotransmission but had no effect on glycinergic or glutamatergic pathways to cardiac vagal neurons. This diminished inhibitory GABAergic neurotransmission to cardiac vagal neurons would increase parasympathetic activity to the heart, decreasing heart rate and blood pressure. The results presented here provide a cellular substrate for the clinical use of clonidine as a treatment for hypertension as well as a role in alleviating posttraumatic stress disorder by evoking an increase in parasympathetic cardiac vagal activity, and a decrease in heart rate and blood pressure.

The Lateral Paragigantocellular Nucleus Modulates Parasympathetic Cardiac Neurons: A Mechanism for Rapid Eye Movement Sleep-Dependent Changes in Heart Rate

Rapid eye movement (REM) sleep is generally associated with a withdrawal of parasympathetic activity and heart rate increases; however, episodic vagally mediated heart rate decelerations also occur during REM sleep. This alternating pattern of autonomic activation provides a physiological basis for REM sleep-induced cardiac arrhythmias. Medullary neurons within the lateral paragigantocellular nucleus (LPGi) are thought to be active after REM sleep recovery and play a role in REM sleep control. In proximity to the LPGi are parasympathetic cardiac vagal neurons (CVNs) within the nucleus ambiguus (NA), which are critical for controlling heart rate. This study examined brain stem pathways that may mediate REM sleep-related reductions in parasympathetic cardiac activity. Electrical stimulation of the LPGi evoked inhibitory GABAergic postsynaptic currents in CVNs in an in vitro brain stem slice preparation in rats. Because brain stem cholinergic mechanisms are involved in REM sleep regulation, we also studied the role of nicotinic neurotransmission in modulation of GABAergic pathway from the LGPi to CVNs. Application of nicotine diminished the GABAergic responses evoked by electrical stimulation. This inhibitory effect of nicotine was prevented by the alpha7 nicotinic receptor antagonist alpha-bungarotoxin. Moreover, hypoxia/hypercapnia (H/H) diminished LPGi-evoked GABAergic current in CVNs, and this inhibitory effect was also prevented by alpha-bungarotoxin. In conclusion, stimulation of the LPGi evokes an inhibitory pathway to CVNs, which may constitute a mechanism for the reduced parasympathetic cardiac activity and increase in heart rate during REM sleep. Inhibition of this pathway by nicotinic receptor activation and H/H may play a role in REM sleep-related and apnea-associated bradyarrhythmias.

Respiratory modulation of premotor cardiac vagal neurons in the brainstem.

The respiratory and cardiovascular systems are highly intertwined, both anatomically and physiologically. Respiratory and cardiovascular neurons are often co-localized in the same brainstem regions, and this is particularly evident in the ventral medulla which contains presympathetic neurons in the rostral ventrolateral medulla, premotor parasympathetic cardioinhibitory neurons in the nucleus ambiguus, and the ventral respiratory group, which includes the pre-Botzinger complex. Anatomical studies of respiratory and cardiovascular neurons have demonstrated that many of these neurons have projections and axon collateral processes which extend into their neighboring cardiorespiratory regions providing an anatomical substrate for cardiorespiratory interactions. As other reports in this Special Issue of Respiratory Physiology & Neurobiology focus on interactions between the respiratory network and baroreceptors, neurons in the nucleus tractus solitarius, presympathetic neurons and sympathetic activity, this report will focus on the respiratory modulation of parasympathetic activity and the neurons that generate parasympathetic activity to the heart, cardiac vagal neurons.

Particulate matter exposure decreased spiking response to depolarization and increased potassium current of cardiac vagal neurons in mice

Epidemiologic studies show that exposure to fine particulate matter (PM2.5) increases the total daily cardiovascular mortality. W previously showed that 3 d of PM2.5 exposure (6 hr/d) in the form of iron‐soot reduced heart rate variability in mice. We further showed that PM2.5 exposure reduced neuronal responsiveness to excitation in cardiac vagal neurons in the nucleus ambiguus. Here, we tested the hypothesis that PM2.5 exposure‐induced increases in potassium currents contribute to the decreased neuronal excitability. Using patch‐clamp techniques, we determined the spiking response to depolarization and potassium currents in anatomically identified cardiac vagal neurons, retrogradely labeled with a fluorescent dye applied to the SA node. PM2.5 exposure decreased spiking responses of identified cardiac vagal neurons to depolarization in the presence of glutamatergic and GABAergic receptor antagonists (p < 0.05). PM exposure also increased the peak (by 24%) and stead state (by 17%) potassium currents. The data suggest that PM2.5 exposure‐induced increase in potassium channel conductance maybe one mechanism contributing to the decreased heart rate variability. (Support R01 ES012957)

Expert opinionThe trigemino-cardiac reflex: a view to the future

Expert opinionThe trigemino-cardiac reflex: a view to the future

Hypotensive and bradycardic episodes in the sitting position during shoulder arthroscopy using interscalene block: can those be alerted?

Hypotensive and bradycardic episodes in the sitting position during shoulder arthroscopy using interscalene block: can those be alerted?

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

To examine the role of 5-HT2 receptors in the central cardiorespiratory network, and in particular the respiratory modulation of parasympathetic activity to the heart, we used an in vitro medullary slice that allowed simultaneous examination of rhythmic inspiratory-related activity recorded from hypoglossal rootlet and excitatory inspiratory-related neurotransmission to cardioinhibitory vagal neurons (CVNs) within the nucleus ambiguus (NA). Focal application of ketanserin, a 5-HT2 receptor antagonist, did not significantly alter the frequency of spontaneous excitatory postsynaptic excitatory currents (EPSCs) in CVNs in control conditions. However, ketanserin diminished spontaneous excitatory neurotransmission to CVNs during hypoxia. The inhibitory action of ketanserin was on 5-HT3 mediated EPSCs during hypoxia since these responses were blocked by the 5-HT3 receptor antagonist ondansetron. In addition, a robust inspiratory-related excitatory neurotransmission was recruited during recovery from hypoxia. Focal application of ketanserin during this posthypoxia period evoked a significant augmentation of the frequency of inspiratory-related, but not spontaneous EPSCs in CVNs. This excitatory effect of ketanserin was prevented by application of the purinergic receptor blocker pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS). These results demonstrate 5-HT2 receptors differentially modulate excitatory neurotransmission to CVNs during and after hypoxia. Activation of 5-HT2 receptors acts to maintain excitatory neurotransmission to CVNs during hypoxia, likely via presynaptic facilitation of 5-HT3 receptor-mediated neurotransmission to CVNs. However, activation of 5HT2 receptors diminishes the subsequent inspiratory-related excitatory neurotransmission to CVNs that is recruited during the recovery from hypoxia likely exerting an inhibitory action on inspiratory-related purinergic signaling.

Serotonergic Modulation of the Trigeminocardiac Reflex Neurotransmission to Cardiac Vagal Neurons in the Nucleus Ambiguus

Stimulation of the trigeminal nerve evokes a dramatic decrease in heart rate and blood pressure, and this reflex has generally been termed the trigeminocardiac reflex. A subset of the trigeminocardiac reflex is the diving reflex in which the nasal mucosa is stimulated with water or air-borne chemical irritants. Activation of the diving reflex evokes a pronounced bradycardia, mediated by increased parasympathetic cardiac activity, and is the most powerful autonomic reflex. However, exaggeration of this protective response could be detrimental and has been implicated in Sudden Infant Death Syndrome (SIDS). Despite the importance and strength of the trigeminocardiac reflex, there is little information about the cellular mechanisms and brain stem pathways that constitute this reflex. To address these issues, stimulation of trigeminal afferent fibers and the evoked excitatory postsynaptic currents were recorded in cardiac vagal neurons (CVNs) in an in vitro brain stem slice preparation. This synaptic pathway is robust and activation of the trigeminal pathway often evoked action potentials in CVNs. Application of the serotonin (5-HT) reuptake inhibitor citalopram significantly enhanced these responses. Consistent with the hypothesis this pathway is endogenously modulated by 5-HT receptors the 5-HT1A receptor antagonist, WAY 100635 inhibited, whereas the 5-HT2A/C receptor antagonist, ketanserin facilitated the excitatory neurotransmission to CVNs. The 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin hydrobromide increased, whereas the 5-HT2 receptor agonist, alpha-methylserotonin maleate salt inhibited this reflex pathway. These results indicate stimulation of trigeminal fibers evokes a powerful excitatory and polysynaptic pathway to CVNs, and this pathway is endogenously modulated and differentially enhanced and depressed, by 5-HT1A and 5-HT2 receptors, respectively.

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

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 pyridoxal-phosphate-6-azophenyl-2',4'-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.