Hypocretin (Orexin) Receptor Subtypes Differentially Enhance Acetylcholine Release and Activate G Protein Subtypes in Rat Pontine Reticular Formation

Bernard, René; Lydic, Ralph; Baghdoyan, Helen A.

doi:10.1124/jpet.105.097071

Cited by 33 publications

(26 citation statements)

References 40 publications

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“…2 Rat PnO contains both hypocretin receptor subtypes, 53 and hcrt-r1 and hcrt-r2 in the PnO each contribute to the hypocretin-induced increase in ACh release within the PnO. 17 Hcrt-r2 is present on GABAergic neurons in rat PnO, 54 suggesting that hcrt-r2 mediates the increase in PnO GABA levels caused by hypocretin-1, 13 as well as the hypocretin-1-induced hyperpolarization of PnO neurons. 10 SB-334867 has a 50-fold higher affinity for hcrt-r1 than for hcrt-r2, 55 and the finding that the hypocretin-1-induced increase in wakefulness was blocked by SB-334867 ( Figure 6A) receptors.…”

Section: Limitations Conclusion and Potential Clinical Significancementioning

confidence: 99%

“…33 This finding means that endogenous hypocretin-1 in rat PnO is antinociceptive. Microdialysis delivery of hypocretin-1 to rat PnO increases ACh release, 17 and ACh in the PnO of cat 34 and mouse 35 is antinociceptive. Future studies can determine whether the antinociceptive effects of hypocretin-1 in rat PnO depend on cholinergic transmission.…”

Section: What Are the Functional Roles Of Hypocretin-1 In The Pno?mentioning

confidence: 99%

“…43 Therefore, GABAmimetics have opposite effects on sleep and wakefulness depending upon their site of action in the brain. 13 Hypocretin-1 increases ACh release in the PnO, 17 and increasing cholinergic transmission in the PnO may contribute to the mechanism by which PnO administration of hypocretin-1 increases wakefulness. Cholinergic transmission in the PnO promotes the EEG activation characteristic of both wakefulness and REM sleep.…”

Section: Limitations Conclusion and Potential Clinical Significancementioning

confidence: 99%

“…15,16 Administering hypocretin-1 into the PnO may increase wakefulness by modulating the release of arousal-promoting neurotransmitters within the PnO. Direct administration of hypocretin-1 to the PnO of isoflurane-anesthetized rat causes a concentration-dependent increase in both acetylcholine (ACh) release 17 and GABA levels 13 within the PnO. Extracellular recording studies of PnO neurons in urethane-anesthetized rat show that iontophoretic application of hypocretin-1 causes a hyperpolarization that is blocked by prior application of bicuculline.…”

Section: The Neuropeptides Hypocretin-1 and Hypo-cretin-2 (Orexin A Amentioning

confidence: 99%

“…Pontine reticular formation administration of bicuculline increases local ACh release, 51 and the increase in REM sleep that occurs by administering GABA A receptor antagonists to the PnO is blocked by the muscarinic cholinergic antagonist atropine. 22 Hypocretin-1 also increases ACh release in the PnO, 17 and PnO administration of cholinomimetics significantly increases REM sleep (reviewed in 52 ). These data support the interpretation that GABAergic transmission in the PnO inhibits REM sleep, in part, by inhibiting ACh release.…”

Section: Limitations Conclusion and Potential Clinical Significancementioning

confidence: 99%

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Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

Brevig

Watson²,

Lydic³

et al. 2010

Sleep

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underlies the pathophysiology of narcolepsy, 4,5 and disruption of hypocretin signaling in mouse, 6 rat, 7,8 and dog 9 leads to narcolepsy-cataplexy. Hypocretinergic neurons project to multiple areas of the brain, including those important for regulating sleep and wakefulness. 1 One such area is the pontine reticular nucleus, oral part (PnO). 1,10 The PnO is the rostral portion of the rodent pontine reticular formation 11 and contributes to the generation of wakefulness and rapid eye movement (REM) sleep. 12 Microinjection of hypocretin-1 into rat PnO causes an increase in wakefulness, 13 and microinjection of hypocretin-1 into cat pontine reticular formation increases the cortically activated states of REM sleep 14 or wakefulness. 15,16 Administering hypocretin-1 into the PnO may increase wakefulness by modulating the release of arousal-promoting neurotransmitters within the PnO. Direct administration of hypocretin-1 to the PnO of isoflurane-anesthetized rat causes a concentration-dependent increase in both acetylcholine (ACh) release 17 and GABA levels 13 within the PnO. Extracellular recording studies of PnO neurons in urethane-anesthetized rat show that iontophoretic application of hypocretin-1 causes a hyperpolarization that is blocked by prior application of bicuculline. 10 This finding indicates that the hypocretin-1-induced inhibition of PnO neurons is mediated by GABA A receptors. Identified GABAergic neurons in brainstem slices of mouse PnO have been shown to be excited by hypocretin-1, 18 and intracellular recording studies in halothane-anesthetized cat show that hypocretin-1 can also cause direct depolarization of PnO neurons and an increase in PnO neuronal firing rate. 14 Numerous studies have demonstrated that GABAergic transmission in the PnO increases wakefulness and inhibits REM sleep. 13,[19][20][21][22][23][24][25] The present study provides the first test of the hypothesis that the wakefulness-promoting effects of delivering hypocretin-1 into the PnO are mediated by GABA A receptors as well as by hypocretin receptors. This hypothesis was evaluated by determining whether (1) microinjection of hypocretin-1 into the PnO causes a concentration-dependent increase in wakefulness, (2) this increase in wakefulness is blocked by coadministration of the hypocretin receptor-1 (hcrt-r1) antagonist SB-334867, and (3) coadministration of the GABA A receptor antagonist bicuculline also blocks the wakefulness response to hypocretin-1. Portions of these data have been presented as abstracts. 26,27 MATERIALS AND METHODS Chemicals and Drug SolutionsHuman hypocretin-1 was purchased from California Peptide Research, Inc. (Napa, CA). Bicuculline methiodide was pur- Study Objectives: Hypocretin-1/orexin A administered directly into the oral part of rat pontine reticular formation (PnO) causes an increase in wakefulness and extracellular g-aminobutyric acid (GABA) levels. The receptors in the PnO that mediate these effects have not been identified. Therefore, this study tested the hypothesis that the increase in wa...

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Section: Limitations Conclusion and Potential Clinical Significancementioning

confidence: 99%

Section: What Are the Functional Roles Of Hypocretin-1 In The Pno?mentioning

confidence: 99%

Section: Limitations Conclusion and Potential Clinical Significancementioning

confidence: 99%

Section: The Neuropeptides Hypocretin-1 and Hypo-cretin-2 (Orexin A Amentioning

confidence: 99%

Section: Limitations Conclusion and Potential Clinical Significancementioning

confidence: 99%

See 3 more Smart Citations

Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

Brevig

Watson²,

Lydic³

et al. 2010

Sleep

Self Cite

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Hypoxia modulates cholinergic but not opioid activation of G proteins in rat hippocampus

et al. 2007

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Intermittent hypoxia, such as that associated with obstructive sleep apnea, can cause neuronal death and neurobehavioral dysfunction. The cellular and molecular mechanisms through which hypoxia alter hippocampal function are incompletely understood. This study used in vitro [(35)S]guanylyl-5'-O-(gamma-thio)-triphosphate ([(35)S]GTP gamma S) autoradiography to test the hypothesis that carbachol and DAMGO activate hippocampal G proteins. In addition, this study tested the hypothesis that in vivo exposure to different oxygen (O(2)) concentrations causes a differential activation of G proteins in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus. G protein activation was quantified as nCi/g tissue in CA1, CA3, and DG from rats housed for 14 days under one of three different oxygen conditions: normoxic (21% O(2)) room air, or hypoxia (10% O(2)) that was intermittent or sustained. Across all regions of the hippocampus, activation of G proteins by the cholinergic agonist carbachol and the mu opioid agonist [D-Ala(2), N-Met-Phe(4), Gly(5)] enkephalin (DAMGO) was ordered by the degree of hypoxia such that sustained hypoxia > intermittent hypoxia > room air. Carbachol increased G protein activation during sustained hypoxia (38%), intermittent hypoxia (29%), and room air (27%). DAMGO also activated G proteins during sustained hypoxia (52%), intermittent hypoxia (48%), and room air (43%). Region-specific comparisons of G protein activation revealed that the DG showed significantly less activation by carbachol following intermittent hypoxia and sustained hypoxia than the CA1. Considered together, the results suggest the potential for hypoxia to alter hippocampal function by blunting the cholinergic activation of G proteins within the DG.

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Modulation of neurotransmitter release in orexin/hypocretin‐2 receptor knockout mice: A microdialysis study

Ortega

Katner

Davis

et al. 2011

J of Neuroscience Research

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Orexinergic neurons are discretely localized within the lateral hypothalamus and have widespread projections to the whole brain. Here, the role of orexin/hypocretin-2 receptors (OX2) in modulating extracellular concentrations of neurotransmitters was evaluated in the hypothalamus and the prefrontal cortex (PFC) of OX2 knockout (KO) mice by using a microdialysis technique. In the hypothalamus, basal concentrations of norephinephrine (NE), acetylcholine (ACh), and histamine (Hist) were significantly higher in KO mice, whereas KCl perfusion (147 mM) resulted in significantly lesser increases in NE, ACh, and Hist release in KO compared with wild-type (WT) mice. No differences in basal concentrations or evoked release of serotonin (5-HT) or dopamine (DA) were found in the hypothalamus between genotypes. In the PFC, no differences in the basal concentrations of the studied neurotransmitters were found between genotypes. After KCl perfusion, significantly higher increases in NE, 5-HT, and DA release were found in KO compared with WT mice. No differences in the evoked release of ACh and Hist in the PFC were found between genotypes. The present results demonstrate that genetic deletion of OX2 receptors differentially modulates extracellular concentrations of distinct neurotransmitters in the somatodendritic region vs. a nerve terminal region of the orexinergic neurons. In the hypothalamus, an inhibitory role of the OX2 receptors in modulating basal concentrations of NE, ACh, and Hist was revealed, which probably accounts for the reduced responsiveness to KCl as well. In the PFC, the evoked release of the monoamines NE, 5-HT, and DA seems to be controlled negatively by OX2 receptors.

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Hypocretin (Orexin) Receptor Subtypes Differentially Enhance Acetylcholine Release and Activate G Protein Subtypes in Rat Pontine Reticular Formation

Cited by 33 publications

References 40 publications

Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

Hypoxia modulates cholinergic but not opioid activation of G proteins in rat hippocampus

Modulation of neurotransmitter release in orexin/hypocretin‐2 receptor knockout mice: A microdialysis study

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