GABAA Receptors Inhibit Acetylcholine Release in Cat Pontine Reticular Formation: Implications for REM Sleep Regulation

2004 ◽  
Vol 92 (4) ◽  
pp. 2198-2206 ◽  
Author(s):  
Jacqueline Vazquez ◽  
Helen A. Baghdoyan
Keyword(s):  
Reticular Formation ◽  
Rem Sleep ◽  
In Vivo Microdialysis ◽  
Pontine Reticular Formation ◽  
Gamma Aminobutyric Acid ◽  
Ach Release ◽  
Sleep Regulation ◽  
Maximal Increase ◽  
Series Of Experiments

This study used in vivo microdialysis in cat ( n = 12) to test the hypothesis that gamma aminobutyric acid A (GABAA) receptors in the pontine reticular formation (PRF) inhibit acetylcholine (ACh) release. Animals were anesthetized with halothane to hold arousal state constant. Six concentrations of the GABAA receptor antagonist bicuculline (0.03, 0.1, 0.3, 1, 3, and 10 mM) were delivered to a dialysis probe in the PRF, and endogenously released ACh was collected simultaneously. Bicuculline caused a concentration dependent increase in ACh release (maximal increase = 345%; EC50 = 1.3 mM; r2 = 0.997). Co-administration of the GABAA receptor agonist muscimol prevented the bicuculline-induced increase in ACh release. In a second series of experiments, the effects of bicuculline (0.1, 0.3, 1, and 3 mM) on ACh release were examined without the use of general anesthesia. States of wakefulness, rapid-eye-movement (REM) sleep, and non-REM sleep were identified polygraphically before and during dialysis delivery of bicuculline. Higher concentrations of bicuculline (1 and 3 mM) significantly increased ACh release during wakefulness (36%), completely suppressed non-REM sleep, and increased ACh release during REM sleep (143%). The finding that ACh release in the PRF is modulated by GABAA receptors is consistent with the interpretation that inhibition of GABAergic transmission in the PRF contributes to the generation of REM sleep, in part, by increasing pontine ACh release.

Pedunculopontine stimulation alters respiration and increases ACh release in the pontine reticular formation

1993 ◽  
Vol 264 (3) ◽  
pp. R544-R554 ◽  
Author(s):  
R. Lydic ◽  
H. A. Baghdoyan
Keyword(s):  
Respiratory Rate ◽  
Respiratory Depression ◽  
Reticular Formation ◽  
Time Course ◽  
Cholinergic Neurons ◽  
In Vivo Microdialysis ◽  
Pedunculopontine Tegmental Nucleus ◽  
Pontine Reticular Formation ◽  
Ach Release

The present study examined the hypothesis that cholinergic neurons in the pedunculopontine tegmental nucleus (PPT) can cause the release of acetylcholine (ACh) in the pontine reticular formation and contribute to respiratory depression. In vivo microdialysis of the gigantocellular tegmental field (FTG) was performed in 10 adult male cats while respiration was being measured. In four intact, unanesthetized cats these measurements were obtained during states of quiet wakefulness and during the rapid eye movement (REM) sleeplike state caused by FTG microinjections of carbachol. The results demonstrate a simultaneous time course of enhanced ACh release in the FTG and respiratory rate depression. In six barbiturate-anesthetized cats similar measurements were obtained while PPT regions containing NADPH-positive neurons were electrically stimulated. PPT stimulation caused increased ACh release in the FTG and caused respiratory rate depression. Together, these findings are consistent with the hypothesis of a causal relationship between ACh release in the FTG and respiratory depression.

Basal forebrain acetylcholine release during REM sleep is significantly greater than during waking

2001 ◽  
Vol 280 (2) ◽  
pp. R598-R601 ◽  
Author(s):  
Jacqueline Vazquez ◽  
Helen A. Baghdoyan
Keyword(s):  
Cognitive Deficits ◽  
Rem Sleep ◽  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Nrem Sleep ◽  
In Vivo Microdialysis ◽  
Ach Release ◽  
Behavioral Arousal ◽  
Function Of Sleep

Cholinergic neurons of the basal forebrain supply the neocortex with ACh and play a major role in regulating behavioral arousal and cortical electroencephalographic activation. Cortical ACh release is greatest during waking and rapid eye movement (REM) sleep and reduced during non-REM (NREM) sleep. Loss of basal forebrain cholinergic neurons contributes to sleep disruption and to the cognitive deficits of many neurological disorders. ACh release within the basal forebrain previously has not been quantified during sleep. This study used in vivo microdialysis to test the hypothesis that basal forebrain ACh release varies as a function of sleep and waking. Cats were trained to sleep in a head-stable position, and dialysis samples were collected during polygraphically defined states of waking, NREM sleep, and REM sleep. Results from 22 experiments in four animals demonstrated that means ± SE ACh release (pmol/10 min) was greatest during REM sleep (0.77 ± 0.07), intermediate during waking (0.58 ± 0.03), and lowest during NREM sleep (0.34 ± 0.01). The finding that, during REM sleep, basal forebrain ACh release is significantly elevated over waking levels suggests a differential role for basal forebrain ACh during REM sleep and waking.

Location and quantification of muscarinic receptor subtypes in rat pons: implications for REM sleep generation

1997 ◽  
Vol 273 (3) ◽  
pp. R896-R904 ◽  
Author(s):  
H. A. Baghdoyan
Keyword(s):  
Muscarinic Receptor ◽  
Reticular Formation ◽  
Muscarinic Receptors ◽  
Rem Sleep ◽  
Binding Sites ◽  
Reticular Nucleus ◽  
Homogeneous Distribution ◽  
Receptor Subtypes ◽  
Pontine Reticular Formation ◽  
Muscarinic Receptor Subtypes

Microinjecting cholinomimetics into the pontine reticular formation produces a state that resembles natural rapid eye movement (REM) sleep. Evocation of this REM sleeplike states is anatomically site dependent within the pons and is mediated by muscarinic receptors. The cellular and molecular mechanisms underlying cholinergic REM sleep generation and muscarinic receptor subtype involvement remain to be specified. This study tested the hypothesis that muscarinic receptor subtypes are differentially distributed within the oral and caudal divisions of rat pontine reticular nucleus. In vitro receptor autoradiography was used to localize and quantify M1, M2, and M3 binding sites in the pontine reticular formation and in pontine brain stem regions known to regulate REM sleep. M1-M3 binding sites were present in some REM sleep-related nuclei, such as dorsal raphe and locus ceruleus. The pontine reticular formation was found to have a homogeneous distribution of M2 binding sites across its rostral to caudal extent, indicating that anatomic specificity of cholinergic REM sleep induction cannot be accounted for by a differential density of muscarinic receptors.

scholarly journals 0074 Inhibitory Neurons in the Dorsomedial Medulla Promote REM Sleep

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A30-A30
Author(s):  
J Stucynski ◽  
A Schott ◽  
J Baik ◽  
J Hong ◽  
F Weber ◽  
...  
Keyword(s):  
Rem Sleep ◽  
Nrem Sleep ◽  
Inhibitory Neurons ◽  
Brain State ◽  
Sleep Regulation ◽  
Optogenetic Stimulation ◽  
Electrophysiological Recordings ◽  
Stimulation Of

Abstract Introduction The neural circuits controlling rapid eye movement (REM) sleep, and in particular the role of the medulla in regulating this brain state, remains an active area of study. Previous electrophysiological recordings in the dorsomedial medulla (DM) and electrical stimulation experiments suggested an important role of this area in the control of REM sleep. However the identity of the involved neurons and their precise role in REM sleep regulation are still unclear. Methods The properties of DM GAD2 neurons in mice were investigated through stereotaxic injection of CRE-dependent viruses in conjunction with implantation of electrodes for electroencephalogram (EEG) and electromyogram (EMG) recordings and optic fibers. Experiments included in vivo calcium imaging (fiber photometry) across sleep and wake states, optogenetic stimulation of cell bodies, chemogenetic excitation and suppression (DREADDs), and connectivity mapping using viral tracing and optogenetics. Results Imaging the calcium activity of DM GAD2 neurons in vivo indicates that these neurons are most active during REM sleep. Optogenetic stimulation of DM GAD2 neurons reliably triggered transitions into REM sleep from NREM sleep. Consistent with this, chemogenetic activation of DM GAD2 neurons increased the amount of REM sleep while inhibition suppressed its occurrence and enhanced NREM sleep. Anatomical tracing revealed that DM GAD2 neurons project to several areas involved in sleep / wake regulation including the wake-promoting locus coeruleus (LC) and the REM sleep-suppressing ventrolateral periaquaductal gray (vlPAG). Optogenetic activation of axonal projections from DM to LC, and DM to vlPAG was sufficient to induce REM sleep. Conclusion These experiments demonstrate that DM inhibitory neurons expressing GAD2 powerfully promote initiation of REM sleep in mice. These findings further characterize the dorsomedial medulla as a critical structure involved in REM sleep regulation and inform future investigations of the REM sleep circuitry. Support R01 HL149133

Fentanyl and Morphine, but not Remifentanil, Inhibit Acetylcholine Release in Pontine Regions Modulating Arousal 

1999 ◽  
Vol 90 (4) ◽  
pp. 1070-1077 ◽  
Author(s):  
Steven Mortazavi ◽  
Janel Thompson ◽  
Helen A. Baghdoyan ◽  
Ralph Lydic
Keyword(s):  
Rem Sleep ◽  
Intravenous Infusion ◽  
Cholinergic Neurons ◽  
Body Region ◽  
Ach Release ◽  
Axon Terminals ◽  
Ringer’S Solution ◽  
Cholinergic Neurotransmission ◽  
Cholinergic Cell

Background Opioids inhibit the rapid eye movement (REM) phase of sleep and decrease acetylcholine (ACh) release in medial pontine reticular formation (mPRF) regions contributing to REM sleep generation. It is not known whether opioids decrease ACh release by acting on cholinergic cell bodies or on cholinergic axon terminals. This study used in vivo microdialysis to test the hypothesis that opioids decrease ACh levels at cholinergic neurons in the laterodorsal tegmental nuclei (LDT) and LDT axon terminals in the mPRF. Methods Nine male cats were anesthetized with halothane, and ACh levels within the mPRF or LDT were assayed using microdialysis and high-pressure liquid chromatography (HPLC). ACh levels were analyzed in response to dialysis of the mPRF and LDT with Ringer's solution (control), followed by dialysis with Ringer's solution containing morphine sulfate (MSO4) or naloxone. ACh in the mPRF also was measured during either dialysis delivery or intravenous infusion of remifentanil and during dialysis delivery of fentanyl. Results Compared with dialysis of Ringer's solution, microdialysis with MSO4 decreased ACh by 23% in the mPRF and by 30% in the LDT. This significant decrease in ACh was antagonized by naloxone. MSO4 and fentanyl each caused a dose-dependent decrease in mPRF ACh when delivered by dialysis. Remifentanil delivered by continuous intravenous infusion or by dialysis into the mPRF did not alter mPRF ACh. Conclusions Morphine inhibits ACh at the cholinergic cell body region (LDT) and the terminal field in the mPRF. ACh in the mPRF was not altered by remifentanil and was significantly decreased by fentanyl. Thus, MSO4 and fentanyl disrupt cholinergic neurotransmission in the LDT-mPRF network known to modulate REM sleep and cortical electroencephalographic activation. These data are consistent with the possibility that inhibition of pontine cholinergic neurotransmission contributes to arousal state disruption by opioids.

scholarly journals GABA release in the dorsal raphe nucleus: role in the control of REM sleep

1997 ◽  
Vol 273 (1) ◽  
pp. R451-R455 ◽  
Author(s):  
D. Nitz ◽  
J. Siegel
Keyword(s):  
Rem Sleep ◽  
Dorsal Raphe Nucleus ◽  
Gaba Release ◽  
Dorsal Raphe ◽  
Raphe Nucleus ◽  
Critical Element ◽  
Gamma Aminobutyric Acid ◽  
Sleep State ◽  
Dorsal Raphé

The cessation of firing of serotonergic dorsal raphe neurons is a key controlling event of rapid eye movement (REM) sleep. We tested the hypothesis that this cessation of activity is due to gamma-aminobutyric acid (GABA) release using the in vivo microdialysis technique. We found that REM sleep is accompanied by a selective increase in GABA release, but not by a change in glutamate or glycine release in the dorsal raphe nucleus. Microinjection of the GABA agonist muscimol into the dorsal raphe increased REM sleep, although microperfusion of the GABA antagonist picrotoxin blocked REM sleep. These results implicate GABA release as a critical element in the production of the REM sleep state and in the control of discharge in serotonergic neurons across the sleep/wake cycle.

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