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

Dergacheva, Olga; Philbin, Kerry E.; Bateman, Ryan; Mendelowitz, David

doi:10.1016/j.neuroscience.2010.11.067

Cited by 27 publications

(22 citation statements)

References 42 publications

(63 reference statements)

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“…Since acute H/H strongly impacts central parasympathetic cardiac activity and the neurotransmission to CVNs 19, 20 , the responses in CVNs upon photoactivation of PVN fibers were studied before, during, and post-acute H/H (see Fig. 5).…”

Section: Resultsmentioning

confidence: 99%

“…However, these adaptive responses could be altered by chronic exposures to repetitive episodes of H/H. Previous work has shown dramatic changes in both excitatory and inhibitory neurotransmission to CVNs elicited by acute hypoxia or acute H/H 19, 20, 37 . For example, respiratory-related glutamatergic neurotransmission to CVNs is recruited post hypoxia increasing EPSC frequency during re-oxygenation 38 .…”

Section: Discussionmentioning

confidence: 99%

“…However, the alterations that occur with CIHH in this neurotransmission are unknown. In addition, the results from recent studies have demonstrated that the excitatory neurotransmission to CVNs are very sensitive to acute H/H exposures 19, 20 . Accordingly, in this study we tested the hypothesis that CIHH impairs activation of CVNs and diminishes the excitatory glutamatergic pathway from the PVN to CVNs under both normoxic conditions and during acute H/H challenges.…”

Section: Introductionmentioning

confidence: 99%

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Chronic Intermittent Hypoxia and Hypercapnia Inhibit the Hypothalamic Paraventricular Nucleus Neurotransmission to Parasympathetic Cardiac Neurons in the Brain Stem

et al. 2014

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Obstructive sleep apnea is associated with chronic intermittent hypoxia/hypercapnia (CIHH) episodes during sleep that heighten sympathetic and diminish parasympathetic activity to the heart. While one population of neurons in the paraventricular nucleus of the hypothalamus strongly influence sympathetic tone and have increased activity following CIHH, little is known about the role of this pathway to parasympathetic neurons, and how this network is altered in CIHH. We hypothesized that CIHH inhibits the excitatory pathway from the paraventricular nucleus of the hypothalamus to parasympathetic cardiac vagal neurons in the brainstem. To test this hypothesis channelrhodopsin was selectively expressed, using viral vectors, in neurons in the paraventricular nucleus of the hypothalamus and channelrhodopsin expressing fibers were photoactivated to evoke postsynaptic currents in cardiac vagal neurons in brainstem slices. Excitatory postsynaptic currents were diminished in animals exposed to CIHH. The paired-pulse and prolonged facilitation of the postsynaptic current amplitudes and frequencies evoked by paired and bursts of photoactivation of channelrhodopsin fibers, respectively, occurred in unexposed rats but were blunted in CIHH animals. In response to an acute challenge of hypoxia/hypercapnia the amplitude of postsynaptic events was unchanged during, but increased post hypoxia/hypercapnia in unexposed animals. In contrast, postsynaptic currents were inhibited during hypoxia/hypercapnia in rats exposed to CIHH. In conclusion, the excitatory pathway to cardiac vagal neurons is diminished in response to both acute and chronic exposures to hypoxia/hypercapnia. This could elicit a reduced cardioprotective parasympathetic activity and an enhanced risk of adverse cardiovascular events in episodes of apnea and chronic obstructive sleep apnea.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chronic Intermittent Hypoxia and Hypercapnia Inhibit the Hypothalamic Paraventricular Nucleus Neurotransmission to Parasympathetic Cardiac Neurons in the Brain Stem

et al. 2014

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“…Doses for SB-334867 and the HCRT-1 peptide were based on a limited number of pilot studies and previously published data (17; 18; 20; 31–33) and had no discernible behavioral side effects. DMSO vehicle is shown to be acceptable for intra-cerebral injections and does not appear to result in neural tissue damage (34).…”

Section: Methodsmentioning

confidence: 99%

Hypocretin Neurotransmission Within the Central Amygdala Mediates Escalated Cocaine Self-administration and Stress-Induced Reinstatement in Rats

Schmeichel

Herman

Roberto

et al. 2017

Biological Psychiatry

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Background Cocaine addiction is characterized by patterns of compulsive drug-taking, including preoccupation with obtaining cocaine and loss of control over drug intake. The lateral hypothalamic hypocretin/orexin (HCRT) system has been implicated in drug-taking and the reinstatement of drug-seeking. Evidence suggests HCRT may drive drug-seeking through activation of specific brain regions implicated in stress system dysfunction, including the central amygdala (CeA). The role of HCRT in the persistence of compulsive-like cocaine-taking has yet to be fully elucidated. Methods Systemic and intra-CeA microinfusions of the HCRT-receptor 1 antagonist, SB-334867, were administered to rats allowed either short (1 h; ShA) or long (6 h; LgA) access to cocaine self-administration. Animals were tested for fixed and progressive ratio responding for cocaine and stress-induced reinstatement of drug-seeking. Additionally, using electrophysiological techniques on in vitro slices, we investigated GABAergic neurotransmission in the medial CeA and the sensitivity of GABAergic synapses to modulation of the HCRT system in ShA or LgA rats Results We found systemic administration of SB-334867 (0, 7.5, 15, 30 mg/kg) dose-dependently decreased cocaine intake specifically in LgA, but not in ShA, rats. Microinjections of SB-334867 (20 nmol) bilaterally into the CeA significantly reduced cocaine intake in LgA rats. We also observed a significant attenuation of yohimbine-induced reinstatement of cocaine-seeking following intra-CeA SB-334867 (10 nmol) administration. Finally, electrophysiological data indicated enhanced GABAergic neurotransmission within the medial CeA in LgA rats, which was blocked with SB-334867 (10μM). Conclusions These findings suggest that HCRT neurotransmission within the CeA is implicated in compulsive-like cocaine-seeking.

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“…Recent studies demonstrate that other state-related brain nuclei and neuropeptides modulate CVNs through changes in all three input types, GABA, glycine and glutamate. For example, the REM regulatory center, the lateral paragigantocellular nucleus, mediates inhibitory neurotransmission to CVNs through GABAergic neurotransmission, while the wake promoting neuropeptide, orexin, alters both inhibitory and excitatory inputs (Dergacheva et al, 2005, Dergacheva et al, 2010, Dergacheva et al, 2011). Previous work from our laboratory also demonstrated that α 2 -adrenergic receptor activation decreased the frequency of GABAergic events to CVNs (Philbin et al, 2009).…”

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confidence: 99%

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

et al. 2011

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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. Since 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 α1-adrenergic receptor activation to augment inhibitory and/or blunt excitatory neurotransmission to CVNs. To test the effects of α1-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 α1-adrenergic receptor, significantly decreased the frequency of both GABAergic and glycinergic neurotransmission to CVNs. Activation of α1-adrenergic receptors by the α1-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 α1-adrenergic receptors did not alter glutamatergic neurotransmission to CVNs. This study indicates that α1-adrenergic receptor activation in the brainstem can facilitate inhibitory GABAergic and glycinergic neurotransmission to reduce CVN activity; this synaptic modulation may play a role in the tachycardia seen during NE-dependent behavioral arousal.

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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

Cited by 27 publications

References 42 publications

Chronic Intermittent Hypoxia and Hypercapnia Inhibit the Hypothalamic Paraventricular Nucleus Neurotransmission to Parasympathetic Cardiac Neurons in the Brain Stem

Chronic Intermittent Hypoxia and Hypercapnia Inhibit the Hypothalamic Paraventricular Nucleus Neurotransmission to Parasympathetic Cardiac Neurons in the Brain Stem

Hypocretin Neurotransmission Within the Central Amygdala Mediates Escalated Cocaine Self-administration and Stress-Induced Reinstatement in Rats

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

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