Sympathoinhibition from ventrolateral periaqueductal gray mediated by 5-HT<sub>1A</sub> receptors in the RVLM

Bago, Maja; Dean, Caron

doi:10.1152/ajpregu.2001.280.4.r976

Cited by 54 publications

(48 citation statements)

References 39 publications

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“…Although a significant proportion of serotonergic innervation in the RVLM arises from medullary sources, the majority of serotonergic projections in the midbrain/pons to the RVLM arise almost exclusively from serotonergic neurons in the DRVL/VLPAG region (Bago et al, 2002), consistent with the finding that lesioning the DR leads to a 35% reduction in concentrations of 5-HT within the RVLM (Underwood et al, 1999). Serotonin appears to act in the RVLM to suppress sympathetic activity, since microinjections of 5-HT or 5-HT 1A receptor agonists into the RVLM inhibit pre-existing hypertension (Bago et al, 1999;Bago and Dean, 2001). Overall these findings suggest that serotonergic projections arising from the DRVL/VLPAG region may play a fundamental role in the mechanisms underlying the effects of serotonergic drugs on fear-or panic-associated physiological and behavioral responses.…”

Section: Discussionmentioning

confidence: 82%

“…In support of this hypothesis, microstimulation of the DLPAG elicits sympathoexcitatory and "fight or flight" responses (Beckett et al, 1992;Beckett and Marsden, 1997;Jacob et al, 2002), whereas chemical stimulation of the VLPAG, which contains serotonergic neurons, leads to an inhibition of sympathoexcitation and freezing behavior (Bago and Dean, 2001;Odeh et al, 2003). Although it has been hypothesized that the VLPAG directly holds the DLPAG in check, the underlying mechanisms are largely unknown (Graeff et al, 1996;Graeff et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

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Disruption of GABAergic tone in the dorsomedial hypothalamus attenuates responses in a subset of serotonergic neurons in the dorsal raphe nucleus following lactate-induced panic

et al. 2008

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Panic patients are vulnerable to induction of panic attacks by subthreshold interoceptive stimuli such as intravenous (i.v.) sodium lactate infusions. Facilitation of serotonergic signaling with selective serotonin re-uptake inhibitors (SSRIs) can suppress anxiety and panic-like responses, but the mechanisms involved are not clearly defined. We investigated the effects of i.v. 0.5M sodium lactate or saline, in control and panic-prone rats on c-Fos expression in serotonergic neurons within subdivisions of the midbrain/pontine raphe nuclei. Rats were chronically infused with either the GABA synthesis inhibitor l-allylglycine (l-AG) into the dorsomedial hypothalamus (DMH) to make them panic-prone, or the enantiomer d-allylglycine (d-AG) in controls. Lactate increased c-Fos expression in serotonergic neurons located in the ventrolateral part of the dorsal raphe nucleus (DRVL) and ventrolateral periaqueductal gray (VLPAG) of control, but not panicprone, rats. The distribution of lactate-sensitive serotonergic neurons in d-AG-treated rats is virtually identical to previously defined pre-sympathomotor serotonergic neurons with multisynaptic projections to peripheral organs mediating "fight-or-flight"-related autonomic and motor responses. We hypothesize that serotonergic neurons within the DRVL/VLPAG region represent a "sympathomotor control system" that normally limits autonomic/behavioral responses to innocuous interoceptive and exteroceptive stimuli, and that dysfunction of this serotonergic system contributes to an anxiety-like state and increases vulnerability to panic in animals and humans.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Disruption of GABAergic tone in the dorsomedial hypothalamus attenuates responses in a subset of serotonergic neurons in the dorsal raphe nucleus following lactate-induced panic

et al. 2008

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“…Numerous studies have demonstrated that activation of the vlPAG neurons during EA regulates sympathoexcitatory reflex responses by modulating the sympathetic outflow (3,30,50). In this respect, using immunohistochemical and electrophysiological approaches, we previously showed that stimulation of somatic afferents during EA activates neurons in the vlPAG (18,19) mainly through activation of neurons in the ARC in the hypothalamus that provide excitatory projections to the vlPAG.…”

Section: Discussionmentioning

confidence: 89%

Electroacupuncture modulates vlPAG release of GABA through presynaptic cannabinoid CB₁ receptors

Fu¹,

Longhurst²

2009

Journal of Applied Physiology

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Fu L-W, Longhurst JC. Electroacupuncture modulates vlPAG release of GABA through presynaptic cannabinoid CB1 receptors. J Appl Physiol 106: 1800 -1809, 2009. First published April 9, 2009 doi:10.1152/japplphysiol.91648.2008.-Previous studies have demonstrated that electroacupuncture (EA) attenuates sympathoexcitatory reflex responses by activating a long-loop pathway involving the hypothalamic arcuate nucleus (ARC), midbrain ventrolateral periaqueductal gray (vlPAG), and rostral ventrolateral medulla (rVLM). Neurons in the ARC provide excitatory input to the vlPAG, whereas the vlPAG inhibits neuronal activity in the rVLM. ␥-Aminobutyric acid (GABA) and glutamate (Glu) have been identified in the vlPAG. Endocannabinoids (ECs), acting as atypical neurotransmitters, inhibit the release of both neurotransmitters in the hypothalamus and midbrain through a presynaptic cannabinoid type 1 (CB1) receptor mechanism. The EC system has been observed in the dorsal but not in the vlPAG. Since it is uncertain whether ECs influence GABA and Glu in the vlPAG, the present study tested the hypothesis that EA modulates the release of these neurotransmitters in the vlPAG through a presynaptic CB1 receptor mechanism. We measured the release of GABA and Glu simultaneously by using HPLC to assess samples collected with microdialysis probes inserted unilaterally into the vlPAG of intact anesthetized rats. Twenty-eight min of EA (2 Hz, 2-4 mA, 0.5 ms) at the P5-6 acupoints reduced the release of GABA by 39% during EA and by 44% 15 min after EA. Thirty-five minutes after EA, GABA concentrations returned to pre-EA levels. In contrast, sham EA did not change the vlPAG GABA concentration. Blockade of CB1 receptors with AM251, a selective CB1 receptor antagonist, reversed the EA-modulated changes in GABA concentration, whereas microinjection of vehicle into the vlPAG did not alter EA-modulated GABA changes. In addition, we observed no changes in the vlPAG Glu concentrations during EA, although the baseline concentration of Glu was much higher than that of GABA (3,541 Ϯ 373 vs. 33.8 Ϯ 8.7 nM, Glu vs. GABA). These results suggest that EA modulates the sympathoexcitatory reflex responses by decreasing the release of GABA, but not Glu, in the vlPAG, most likely through a presynaptic CB1 receptor mechanism. somatic afferents; sympathoexcitatory reflex; cannabinoid type 1 receptor; microdialysis ELECTROACUPUNCTURE (EA), a potent alternative to manual acupuncture, has been suggested to be effective in treating certain cardiovascular diseases including hypertension, arrhythmias, and angina pectoris (5, 6, 41). Clinically, EA at the NeiguanJianshi (P5-6) acupoints has been used to treat cardiovascular diseases in Eastern and, more recently, Western countries (5, 21, 41). We and others have demonstrated that EA at P5-6 acupoints overlying the median nerve on the wrist modulate blood pressure elevation evoked by gastric distension (GD) in rats (27) or by gallbladder stimulation in cats (50) through a long-loop neural pathway, extending from the arcuate...

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“…Microstimulation of the dlPAG in rodents and humans produces marked sympathoexcitatory responses, such as tachycardia and hypertension, thus facilitating rapid autonomic and behavioral "fight-or-flight" responses. Microstimulation of the DRL/vlPAG, by contrast, results in sympathetic inhibition (Beckett and Marsden, 1997; Underwood et al, 1999;Bago and Dean, 2001;Johnson et al, 2004). The emerging hypothesis is that neurons in the DRL/vlPAG are activated and help inhibit sympathetic excitation as a part of normative response to innocuous stressors (Crawford et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Distinct Neurochemical and Functional Properties of GAD67-Containing 5-HT Neurons in the Rat Dorsal Raphe Nucleus

Shikanai

Yoshida²,

Konno

et al. 2012

J. Neurosci.

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The serotonergic (5-HTergic) system arising from the dorsal raphe nucleus (DRN) is implicated in various physiological and behavioral processes, including stress responses. The DRN is comprised of several subnuclei, serving specific functions with distinct afferent and efferent connections. Furthermore, subsets of 5-HTergic neurons are known to coexpress other transmitters, including GABA, glutamate, or neuropeptides, thereby generating further heterogeneity. However, despite the growing evidence for functional variations among DRN subnuclei, relatively little is known about how they map onto neurochemical diversity of 5-HTergic neurons. In the present study, we characterized functional properties of GAD67-expressing 5-HTergic neurons (5-HT/GAD67 neurons) in the rat DRN, and compared with those of neurons expressing 5-HTergic molecules (5-HT neurons) or GAD67 alone. While 5-HT/GAD67 neurons were absent in the dorsomedial (DRD) or ventromedial (DRV) parts of the DRN, they were selectively distributed in the lateral wing of the DRN (DRL), constituting 12% of the total DRL neurons. They expressed plasmalemmal GABA transporter 1, but lacked vesicular inhibitory amino acid transporter. By using whole-cell patch-clamp recording, we found that 5-HT/GAD67 neurons had lower input resistance and firing frequency than 5-HT neurons. As revealed by c-Fos immunohistochemistry, neurons in the DRL, particularly 5-HT/GAD67 neurons, showed higher responsiveness to exposure to an open field arena than those in the DRD and DRV. By contrast, exposure to contextual fear conditioning stress showed no such regional differences. These findings indicate that 5-HT/GAD67 neurons constitute a unique neuronal population with distinctive neurochemical and electrophysiological properties and high responsiveness to innocuous stressor.

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Sympathoinhibition from ventrolateral periaqueductal gray mediated by 5-HT_1A receptors in the RVLM

Cited by 54 publications

References 39 publications

Disruption of GABAergic tone in the dorsomedial hypothalamus attenuates responses in a subset of serotonergic neurons in the dorsal raphe nucleus following lactate-induced panic

Disruption of GABAergic tone in the dorsomedial hypothalamus attenuates responses in a subset of serotonergic neurons in the dorsal raphe nucleus following lactate-induced panic

Electroacupuncture modulates vlPAG release of GABA through presynaptic cannabinoid CB₁ receptors

Distinct Neurochemical and Functional Properties of GAD67-Containing 5-HT Neurons in the Rat Dorsal Raphe Nucleus

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Sympathoinhibition from ventrolateral periaqueductal gray mediated by 5-HT1A receptors in the RVLM

Cited by 54 publications

References 39 publications

Disruption of GABAergic tone in the dorsomedial hypothalamus attenuates responses in a subset of serotonergic neurons in the dorsal raphe nucleus following lactate-induced panic

Disruption of GABAergic tone in the dorsomedial hypothalamus attenuates responses in a subset of serotonergic neurons in the dorsal raphe nucleus following lactate-induced panic

Electroacupuncture modulates vlPAG release of GABA through presynaptic cannabinoid CB1 receptors

Distinct Neurochemical and Functional Properties of GAD67-Containing 5-HT Neurons in the Rat Dorsal Raphe Nucleus

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Sympathoinhibition from ventrolateral periaqueductal gray mediated by 5-HT_1A receptors in the RVLM

Electroacupuncture modulates vlPAG release of GABA through presynaptic cannabinoid CB₁ receptors