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.

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.

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.

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.

scholarly journals Disrupted choline clearance and sustained acetylcholine release in vivo by a common choline transporter coding variant associated with poor attentional control in humans

2021 ◽  
Author(s):  
Eryn Donovan ◽  
Cassandra Avila ◽  
Vinay Parikh ◽  
Cristina Fenollar-Ferrer ◽  
Randy D. Blakely ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Conformational Changes ◽  
Cognitive Disorders ◽  
Cholinergic Neurons ◽  
Dominant Negative ◽  
Ach Release ◽  
Negative Effects ◽  
Choline Transport ◽  
Choline Transporter

Transport of choline via the neuronal high-affinity choline transporter (CHT; SLC5A7) is essential for cholinergic terminals to synthesize and release acetylcholine (ACh). In humans, we previously demonstrated an association between a common CHT coding substitution (rs1013940; Ile89Val) and reduced attentional capacity as well as attenuated frontal cortex activation. Here, we used a CRISPR/Cas9 approach to generate mice expressing the I89V substitution and assessed, using in vivo cortical choline biosensing, CHT-mediated choline transport, and ACh release. CHT-mediated clearance of choline in mice expressing one or two Val89 alleles was reduced by over 7-fold relative to wild type (WT) mice, suggesting dominant-negative effects. Choline clearance in CHT Val89 mice was further reduced by neuronal inactivation. Deficits in ACh release, 5 and 10 min after repeated depolarization at a low, behaviorally relevant frequency, support an attenuated reloading capacity of cholinergic neurons in mutant mice. The density of CHTs in total synaptosomal lysates and neuronal plasma-membrane-enriched fractions was not impacted by the Val89 variant, indicating a selective impact on CHT function. Consistent with this hypothesis, structural modeling revealed that Val89 may attenuate choline transport by changing the ability of choline to induce conformational changes of CHT that support normal transport rates. Our findings suggest that diminished, sustained cholinergic signaling capacity in the frontal cortex underlies perturbed attentional performance in individuals expressing CHT Val89. Our work supports the utility of the CHT Val89 mouse model as a valuable model to study heritable risk for cognitive disorders arising from cholinergic dysfunction.

Excitation of the Brain Stem Pedunculopontine Tegmentum Cholinergic Cells Induces Wakefulness and REM Sleep

1997 ◽  
Vol 77 (6) ◽  
pp. 2975-2988 ◽  
Author(s):  
Subimal Datta ◽  
Donald F. Siwek
Keyword(s):  
Brain Stem ◽  
Slow Wave ◽  
Rem Sleep ◽  
Slow Wave Sleep ◽  
Cholinergic Neurons ◽  
Dependent Manner ◽  
Cell Compartment ◽  
Recording Time ◽  
Cholinergic Cell ◽  
The Brain

Datta, Subimal and Donald F. Siwek. Excitation of the brain stem pedunculopontine tegmentum cholinergic cells induces wakefulness and REM sleep. J. Neurophysiol. 77: 2975–2988, 1997. Considerable evidence suggests that brain stem pedunculopontine tegmentum (PPT) cholinergic cells are critically involved in the normal regulation of wakefulness and rapid eye movement (REM) sleep. However, much of this evidence comes from indirect studies. Thus, although involvement of PPT cholinergic neurons has been suggested by numerous investigations, the excitation of PPT cholinergic neurons causal to the behavioral state of wakefulness and REM sleep has never been directly demonstrated. In the present study we examined the effects of three different levels of activation of PPT cholinergic cells in wakefulness and sleep behavior. The effects of glutamate on the activity of PPT cholinergic cells were studied by microinjection of one of the three different doses of l-glutamate (0.3, 1.0, and 3.0 μg) or saline (vehicle control) into the PPT cholinergic cell compartment while quantifying the effects on wakefulness and sleep in free moving chronically instrumented cats. All microinjections were made during wakefulness and were followed by 4 h of recording. Polygraphic records were scored for wakefulness, slow-wave sleep states 1 and 2, slow-wave sleep with pontogeniculooccipital waves, and REM sleep. Dependent variables quantified after each microinjection included the percentage of recording time spent in each state, the latency to onset of REM sleep, the number of episodes per hour for REM sleep, and the duration of each REM sleep episode. A total of 48 microinjections was made into 12 PPT sites in six cats. Microinjection of 0.3- and 1.0-μg doses of l-glutamate into the cholinergic cell compartment of the PPT increased the total amount of REM sleep in a dose-dependent manner. Both doses of l-glutamate increased REM sleep at the expense of slow-wave sleep but not wakefulness. Microinjection of 3.0 μg l-glutamate kept animals awake for 2–3 h by eliminating slow-wave and REM sleep. The results show that the microinjection of the excitatory amino acid l-glutamate into the PPT cholinergic cell compartments can increase wakefulness and/or REM sleep depending on the l-glutamate dosage. These findings unambiguously confirm the hypothesis that the excitation of the PPT cholinergic cells is causal to the generation of wakefulness and REM sleep.

scholarly journals Different cholinergic cell groups in the basal forebrain regulate social interaction and social recognition memory

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kana Okada ◽  
Kayo Nishizawa ◽  
Tomoko Kobayashi ◽  
Shogo Sakata ◽  
Kouichi Hashimoto ◽  
...  
Keyword(s):  
Social Interaction ◽  
Recognition Memory ◽  
Basal Forebrain ◽  
Social Behaviour ◽  
Cholinergic Neurons ◽  
Social Recognition ◽  
Social Ability ◽  
Cell Groups ◽  
Cholinergic Cell ◽  
Social Recognition Memory

AbstractSocial behaviour is a complex construct that is reported to include several components of social approach, interaction and recognition memory. Alzheimer’s disease (AD) is mainly characterized by progressive dementia and is accompanied by cognitive impairments, including a decline in social ability. The cholinergic system is a potential constituent for the neural mechanisms underlying social behaviour, and impaired social ability in AD may have a cholinergic basis. However, the involvement of cholinergic function in social behaviour has not yet been fully understood. Here, we performed a selective elimination of cholinergic cell groups in the basal forebrain in mice to examine the role of cholinergic function in social interaction and social recognition memory by using the three-chamber test. Elimination of cholinergic neurons in the medial septum (MS) and vertical diagonal band of Broca (vDB) caused impairment in social interaction, whereas ablating cholinergic neurons in the nucleus basalis magnocellularis (NBM) impaired social recognition memory. These impairments were restored by treatment with cholinesterase inhibitors, leading to cholinergic system activation. Our findings indicate distinct roles of MS/vDB and NBM cholinergic neurons in social interaction and social recognition memory, suggesting that cholinergic dysfunction may explain social ability deficits associated with AD symptoms.

Somatostatin modulates cholinergic neurotransmission in canine antral muscle

1988 ◽  
Vol 254 (2) ◽  
pp. G201-G209 ◽  
Author(s):  
C. B. Koelbel ◽  
G. van Deventer ◽  
S. Khawaja ◽  
M. Mogard ◽  
J. H. Walsh ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Substance P ◽  
Prostaglandin E2 ◽  
Positive Inotropic Effect ◽  
Mechanical Response ◽  
Inhibitory Effect ◽  
Inotropic Effect ◽  
Inotropic Response ◽  
Cholinergic Neurotransmission

Somatostatin has been shown to inhibit antral motility in vivo. To examine the effect of somatostatin on cholinergic neurotransmission in the canine antrum, we studied the mechanical response of and the release of [3H]acetylcholine from canine longitudinal antral muscle in response to substance P, gastrin 17, and electrical stimulation. In unstimulated tissues, somatostatin had a positive inotropic effect on spontaneous phasic contractions. In tissues stimulated with substance P and gastrin 17, but not with electrical stimulation, somatostatin inhibited the phasic inotropic response dose dependently. This inhibitory effect was abolished by indomethacin. Somatostatin stimulated the release of prostaglandin E2 radioimmunoreactivity, and prostaglandin E2 inhibited the release of [3H]acetylcholine induced by substance P and electrical stimulation. Somatostatin increased the release of [3H]acetylcholine from unstimulated tissues by a tetrodotoxin-sensitive mechanism but inhibited the release induced by substance P and electrical stimulation. These results suggest that somatostatin has a dual modulatory effect on cholinergic neurotransmission in canine longitudinal antral muscle. This effect is excitatory in unstimulated tissues and inhibitory in stimulated tissues. The inhibitory effect is partially mediated by prostaglandins.

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