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Bicuculline caused a concentration dependent increase in ACh release during wakefulness and REM sleep. *, concentrations of bicuculline that significantly (P 0.01) increased ACh release over control (p) levels. Each concentration of bicuculline was tested in 3 animals. The number of dialysis samples (n) that contributed to each mean follows the concentration of bicuculline. A: wakefulness: 0 mM (33); 0.1 mM (17); 0.3 mM (18); 1 mM (20); 3 mM (4). B: NREM sleep: 0 mM (26); 0.1 mM (4); 0.3 mM (3). C: REM sleep: 0 mM (19); 0.1 mM (3); 0.3 mM (3); 1 mM (3); 3 mM (8). These data were obtained from 13 dialysis sites in 4 animals.
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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,...
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... effects of four bicuculline concentrations on ACh re- lease during sleep and wakefulness are summarized by Fig. 6. ANOVA revealed a significant concentration main effect of bicuculline on ACh release during wakefulness ( Fig. 6A; F 7.5; df 4, 16.3; P 0.001) and during REM sleep ( Fig. 6C; FIG. 4. Muscimol blocked the bicuculline-induced increase in ACh release. A: ACh release in the pontine reticular formation was quantified during dialysis with ...
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... effects of four bicuculline concentrations on ACh re- lease during sleep and wakefulness are summarized by Fig. 6. ANOVA revealed a significant concentration main effect of bicuculline on ACh release during wakefulness ( Fig. 6A; F 7.5; df 4, 16.3; P 0.001) and during REM sleep ( Fig. 6C; FIG. 4. Muscimol blocked the bicuculline-induced increase in ACh release. A: ACh release in the pontine reticular formation was quantified during dialysis with Ringer solution (control; n 30 dialysis samples), during dialysis administration of bicuculline (0.3 mM; n 15), and ...
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... effects of four bicuculline concentrations on ACh re- lease during sleep and wakefulness are summarized by Fig. 6. ANOVA revealed a significant concentration main effect of bicuculline on ACh release during wakefulness ( Fig. 6A; F 7.5; df 4, 16.3; P 0.001) and during REM sleep ( Fig. 6C; FIG. 4. Muscimol blocked the bicuculline-induced increase in ACh release. A: ACh release in the pontine reticular formation was quantified during dialysis with Ringer solution (control; n 30 dialysis samples), during dialysis administration of bicuculline (0.3 mM; n 15), and during co-administration of bicuculline (0.3 mM) and muscimol (0.1 ...
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... bicuculline muscimol, and musci- mol) was tested in 3 anesthetized animals. These data were obtained from 6 dialysis sites in 3 animals. F 9.7; df 4, 5.8; P 0.01). Dunnett's T3 post hoc multiple comparisons test showed that perfusion of the dialysis probe with 1 mM bicuculline significantly (P 0.01) in- creased ACh release during wakefulness (Fig. 6A). Although 3 mM bicuculline increased ACh release during wakefulness by 261% over control levels, this increase was not statistically significant because of the small sample size (n 4) and large variability (coefficient of variation 39%). The amount of time spent in NREM sleep was reduced by lower concentra- tions of bicuculline (0.1 ...
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... sample size (n 4) and large variability (coefficient of variation 39%). The amount of time spent in NREM sleep was reduced by lower concentra- tions of bicuculline (0.1 and 0.3 mM), and NREM sleep was completely suppressed by higher bicuculline concentrations (1 and 3 mM). Thus ANOVA was not applied to the ACh measures obtained during NREM sleep (Fig. 6B) due to the small sample size. During REM sleep (Fig. 6C), Dunnett's T3 indicated that dialysis with 1 and 3 mM bicuculline signifi- cantly (P 0.01) increased ACh ...
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... variation 39%). The amount of time spent in NREM sleep was reduced by lower concentra- tions of bicuculline (0.1 and 0.3 mM), and NREM sleep was completely suppressed by higher bicuculline concentrations (1 and 3 mM). Thus ANOVA was not applied to the ACh measures obtained during NREM sleep (Fig. 6B) due to the small sample size. During REM sleep (Fig. 6C), Dunnett's T3 indicated that dialysis with 1 and 3 mM bicuculline signifi- cantly (P 0.01) increased ACh ...
Citations
... These findings perfectly explain the phenomenon of CNS disinhibition after exposure to moderate doses of IR (Letzkus et al., 2015;Kokhan et al., 2016) that may pos-sibly result in improving the performance in spatial tasks. In this context, it is also important to note that the decrease in GABA neurotransmission leads to enhancement in the cholinergic neurotransmission (Vazquez and Baghdoyan, 2004). This fact also meets our previous data (Kokhan et al., 2017). ...
Ionizing radiation (IR) is one of the major biological limiting factors of human deep-space missions. Despite the dominant paradigm about the negative effects of IR on the CNS, the anxiolytic, antidepressant, anti-aggressive, and pro-cognitive effects have recently been discovered. The mechanisms of these phenomena remain undisclosed. Here, we study the effects of combined IR exposure (γ-rays and ¹²C nuclei) on the psycho-emotional state, cognitive abilities, and the metabolism of glutamate and GABA in Wistar rats, with an emphasis on the age factor. Irradiation resulted in the anxiogenic effect, reversing during maturation, and the sustained increase in spatial learning performance. A persistent decrease in the content of GABA was observed, which confirmed the hypothesis of disinhibition of the CNS under irradiation with moderate doses, proposed earlier. Glutamate/GABA imbalance was accompanied by an increase in the metabolism of these neurotransmitters: an increase in expression level of GLT-1, GAD65, GABAT and GAT1. Besides, a decrease in the expression level of NR1 subunit of the NMDA receptor was noted. Notably, the maturation of rats led not only to the rebalancing of the glutamate/GABA ratio by reducing the glutamate content, but also to leveling the differences in the expression levels of the analyzing biomolecules. Thus, the combined action of IR at moderate doses resulted in long-term changes in psycho-emotional status and, surprisingly, an increase in the efficiency of spatial learning performance. We suggest that IR (within the range of composition and doses used) can be relatively safe for the functions of the CNS.
... Cholinergic receptors also play a significant role in sleep-dependent changes. The cholinergic neurotransmission in the brainstem is an important integral component of rapid eyeball movement sleep generation (87,88). Change in cholinergic receptor activity is associated with potentiation of TCR and trigeminally evoked respiratory suppression (89) as well as with altered sleep-awake cycles in infants both of which are also seen in victims of SIDS. ...
Sudden infant death syndrome (SIDS) is an unexplained death in infants, which usually occurs during sleep. The cause of SIDS remains unknown and multifactorial. In this regard, the diving reflex (DR), a peripheral subtype of trigeminocardiac reflex (TCR), is also hypothesized as one of the possible mechanisms for this condition. The TCR is a well-established neurogenic reflex that manifests as bradycardia, hypotension, apnea, and gastric hypermotility. The TCR shares many similarities with the DR, which is a significant physiological adaptation to withstand hypoxia during apnea in many animal species including humans in clinical manifestation and mechanism of action. The DR is characterized by breath holding (apnea), bradycardia, and vasoconstriction, leading to increase in blood pressure. Several studies have described congenital anomalies of autonomic nervous system in the pathogenesis of SIDS such as hypoplasia, delayed neuronal maturation, or decreased neuronal density of arcuate nucleus, hypoplasia, and neuronal immaturity of the hypoglossal nucleus. The abnormalities of autonomic nervous system in SIDS may explain the role of TCR in this syndrome involving sympathetic and parasympathetic nervous system. We reviewed the available literature to identify the role of TCR in the etiopathogenesis of SIDS and the pathways and cellular mechanism involved in it. This synthesis will help to update our knowledge and improve our understanding about this mysterious, yet common condition and will open the door for further research in this field.
... First, opioid use can induce the reduction of adenosine in sleep-regulating brain regions (the pontine reticular formation and substantia innominata region of the basal forebrain) 35 , and adenosine has long been known as a promoter of sleep 36 . Furthermore, prior studies have also shown that by agitating μ -opioid receptors, opioids can decrease GABAergic transmission in the oral part of the pontine reticular nucleus, which regulates sleep and wakefulness, thereby disrupting sleep 37,38 . ...
The purpose of this study was to investigate the prevalences of and association between nonmedical prescription opioid use (NMPOU) and sleep quality among Chinese high school students. A cross-sectional study was conducted in Chongqing high school students in 2012, and questionnaires from 18,686 students were completed and eligible for this study. Demographic and NMPOU information was collected using a self-administered questionnaire. The Chinese Pittsburgh Sleep Quality index (CPSQI) was used to assess the occurrence of poor sleep. Among the total sample, 18.0% were classified as poor sleepers (27.4% of the subjects with past-month NMPOU), and the prevalences of lifetime, past-year and past-month NMPOU were 14.6, 4.6 and 2.8% across the entire sample, respectively. The most commonly used medicine was licorice tablets with morphine (9.1, 2.5 and 1.5% for lifetime, past-year and past-month, respectively), followed by cough syrup with codeine, Percocet, diphenoxylate and tramadol. After adjustment for potential confounders, the association between past-month NMPOU and poor sleep remained significant (AOR = 1.47, 95% CI 1.17 to 1.85). Programs aimed at decreasing NMPOU should also pay attention to sleep quality among adolescents.
... The results of our study show that GABA agonists at the C-PBL region did not inhibit REM sleep. It has been demonstrated in vivo microdialysis in cat, that GABA A receptors in the pontine reticular formation (PRF) inhibit ACh release (Vazquez and Baghdoyan, 2004). The finding that ACh release in the PRF is modulated by GABA A 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 (Vazquez and Baghdoyan, 2004). ...
... It has been demonstrated in vivo microdialysis in cat, that GABA A receptors in the pontine reticular formation (PRF) inhibit ACh release (Vazquez and Baghdoyan, 2004). The finding that ACh release in the PRF is modulated by GABA A 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 (Vazquez and Baghdoyan, 2004). In a similar manner, GABA could be exerting an inhibitory influence at C-PBL which, in turn, could be diminishing ACh release thus lessening SP and PGO overall activity. ...
... The MS is also the source of widespread cholinergic projections that target both principal cells and interneurons in these areas via the dorsal fornix. Previous studies have shown that muscimol, which is a GABA A -agonist, can inactivate cholinergic cells (Casamenti et al., 1986: nucleus basalis; Vazquez and Baghdoyan, 2004: pontine reticular formation) as well. In addition, there is diminished cholinergic staining in MEC following MS lesions (Mitchell et al., 1982). ...
Oscillations in the coordinated firing of brain neurons have been proposed to play important roles in perception, cognition, attention, learning, navigation, and sensory-motor control. The network theta rhythm has been associated with properties of spatial navigation, as has the firing of entorhinal grid cells and hippocampal place cells. Two recent studies reduced the theta rhythm by inactivating the medial septum (MS) and demonstrated a correlated reduction in the characteristic hexagonal spatial firing patterns of grid cells. These results, along with properties of intrinsic membrane potential oscillations (MPOs) in slice preparations of medial entorhinal cortex (MEC), have been interpreted to support oscillatory interference models of grid cell firing. The current article shows that an alternative self-organizing map (SOM) model of grid cells can explain these data about intrinsic and network oscillations without invoking oscillatory interference. In particular, the adverse effects of MS inactivation on grid cells can be understood in terms of how the concomitant reduction in cholinergic inputs may increase the conductances of leak potassium (K(+)) and slow and medium after-hyperpolarization (sAHP and mAHP) channels. This alternative model can also explain data that are problematic for oscillatory interference models, including how knockout of the HCN1 gene in mice, which flattens the dorsoventral gradient in MPO frequency and resonance frequency, does not affect the development of the grid cell dorsoventral gradient of spatial scales, and how hexagonal grid firing fields in bats can occur even in the absence of theta band modulation. These results demonstrate how models of grid cell self-organization can provide new insights into the relationship between brain learning and oscillatory dynamics.
... We hypothesized a mechanism by which antagonizing GABA disinhibits acetylcholine (ACh) release from cholinergic axons in the PnO. Support for this mechanism came from studies of in vivo microdialysis of the GABA A R antagonist, bicuculline, in the PnO of cat and mouse that resulted in significantly increased levels of microdialyzed ACh (Flint et al., 2010;Vazquez and Baghdoyan, 2004). REM sleep increases produced by injecting the GABA A R antagonist, gabazine (GBZ), into rat PnO were blocked by a preceding local injection of the muscarinic antagonist, atropine (Marks et al., 2008). ...
... This is consistent with direct presynaptic control over ACh release by GABA. 2 subunit immunoreactivity has been reported in processes in PnO with moderate density and absent from somata (Pirker et al., 2000). This mechanism is supported further by the finding of local blockade of GABA A Rs in PnO of cat and mouse that resulted in increased levels of ACh (Flint et al., 2010;Vazquez and Baghdoyan, 2004). Cholinergic agonists, GABA A R antagonists and a BZ inverse agonist injected into the PnO of rat induced increases in REM sleep with very similar characteristics and these drug-inductions were blocked by atropine (Bourgin et al., 1995;Marks et al., 2008). ...
It has been reported that non-subtype-selective GABAA receptor antagonists injected into the nucleus pontis oralis (PnO) of rats induced long-lasting increases in REM sleep. Characteristics of these REM sleep increases were identical to those resulting from injection of muscarinic cholinergic agonists. Both actions were blocked by the muscarinic antagonist, atropine. Microdialysis of GABAA receptor antagonists into the PnO resulted in increased acetylcholine levels. These findings were consistent with GABAA receptor antagonists disinhibiting acetylcholine release in the PnO to result in an acetylcholine-mediated REM sleep induction. Direct evidence has been lacking for localization in the PnO of the specific GABAA receptor-subtypes mediating the REM sleep effects. Here, we demonstrated a dose-related, long-lasting increase in REM sleep following injection (60nl) in the PnO of the inverse benzodiazepine agonist, methyl-6,7-dimethoxy-4-ethyl-β-carboline (DMCM, 10(-2)M). REM sleep increases were greater and more consistently produced than with the non-selective antagonist gabazine, and both were blocked by atropine. Fluorescence immunohistochemistry and laser scanning confocal microscopy, colocalized in PnO vesicular acetylcholine transporter, a presynaptic marker of cholinergic boutons, with the γ2 subunit of the GABAA receptor. These data provide support for the direct action of GABA on mechanisms of acetylcholine release in the PnO. The presence of the γ2 subunit at this locus and the REM sleep induction by DMCM are consistent with binding of benzodiazepines by a GABAA receptor-subtype in control of REM sleep.
... GABA controls the activity of the DA-containing cells of the substantia nigra and loss of GABA and its synthesizing enzyme glutamic acid decarboxylase (GAD) have been observed in the basal ganglia of patients dying from Parkinson's disease [58]. GABA is used as a supplement to help prevent the oxidation of L-dopa and also as a method to inhibit acetylcholine [59]. 5-HT and GABA when supplemented in combination along with bone marrow cells reversed significantly (p b 0.001) the decreased SOD activity in 6-OHDA Parkinson's rats to control values. ...
Oxidative stress-induced neuronal cell death has been implicated in Parkinson's disease (PD). Oxidative stress initiated by 6-hydroxydopamine (6-OHDA) causes mitochondrial dysfunction leading to apoptosis and Parkinsonian neurodegeneration. We investigated the neuroprotective potential of serotonin (5-HT), gamma amino butyric acid (GABA) and autologous bone marrow cells (BMC) in combination against oxidative stress-induced cell death. PD was induced in adult male Wistar rats by intranigral infusion of 6-OHDA (8μg/μl). The activities of antioxidant enzymes - superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were analysed. The extent of lipid peroxidation was quantified by measuring the formation of thiobarbituric acid reactive substances (TBARs). Real Time PCR gene expression of SOD, CAT and GPx were performed using specific Taqman probes. 6-OHDA induced decreased activity of SOD, CAT and GPx in corpus striatum was significantly reversed to near control (p<0.001) by treatment with 5-HT, GABA and bone marrow cells. Gene expression studies of SOD, CAT and GPx using Real Time PCR confirmed the above observation. TBAR levels were elevated (p<0.001) in 6-OHDA treated rats indicating lipid peroxidation. 5-HT and GABA along with autologous bone marrow cell supplementation significantly ameliorated 6-OHDA-induced lipid peroxidation (p<0.001). Our results suggest a new therapeutic strategy of neuroprotection against damage by oxidative stress in Parkinson's disease.
... The lowest BMI concentration that produced a small PS after the second stimulus in a paired pulse paradigm was the most neuroprotective ( Fig 3A and B). Our assumption that a decrease in GABAergic tone increases ACh release agrees with reports that inhibition of GABA A receptors by bicuculline enhances synaptic ACh release (Giorgetti et al. 2000;Moor et al. 1998;Roland and Savage 2009;Vazquez and Baghdoyan 2004). ...
Nicotinic acetylcholine receptor (nAChR)-mediated neuroprotection has been implicated in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases and hypoxic ischemic events as well as other diseases hallmarked by excitotoxic and apoptotic neuronal death. Several modalities of nicotinic neuroprotection have been reported. However, although this process generally involves α4β2 and α7 subtypes, the underlying mechanisms are largely unknown. Interestingly, both activation and inhibition of α7 nAChRs have been reported to be neuroprotective. We have shown that inhibition of α7 nAChRs protects the function of acute hippocampal slices against excitotoxicity in an α4β2-dependent manner. Neuroprotection was assessed as the prevention of the N-methyl-D-aspartate-dependent loss of the area of population spikes (PSs) in the CA1 area of acute hippocampal slices. Our results support a model in which α7 AChRs control the release of γ-aminobutyric acid (GABA). Blocking either α7 or GABA(A) receptors reduces the inhibitory tone on cholinergic terminals, thereby promoting α4β2 activation, which in turn mediates neuroprotection. These results shed light on how α7 nAChR inhibition can be neuroprotective through a mechanism mediated by activation of α4β2 nAChRs. © 2012 Wiley Periodicals, Inc.
... At least two functional groups of brain stem GABAergic neurons seem to be involved in REM control, namely, REM-off GABA neurons preventing activation of REM-on reticular neurons during wakefulness and REM-on GABA neurons inhibiting the activity of aminergic neurons (FIGURE 12B). GABAergic inhibition of cholinergic neurons during wake and/or NREM sleep is also a factor in regulating their state-dependent discharge (1303) and neurotransmitter release (1344). Other groups of GABA neurons outside the brain stem regulate the circadian timing and homeostatic control of REM sleep. ...
This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.
... GABAergic transmission also modulates the release of other neurotransmitters in the PnO that regulate sleep and wakefulness. For example, acetylcholine in the PnO promotes REM sleep (55)(56)(57), and direct administration of bicuculline to PnO in cats increases ACh release and triggers the onset of REM sleep (56). Together, these pharmacological data support the interpretation that enhanced GABAergic transmission promotes wakefulness. ...
We here review experimental findings relevant for the pharmacology of conscious experience, an issue largely neglected in pharmacological research. First, we focus on self-awareness, a pivotal component of conscious experience and its integration within the global neuronal network (GNW), a theoretical concept that unifies convergent approaches on the neural bases of conscious processing. We report recent evidence to show that self-awareness mobilizes a paralimbic circuitry of γ synchrony, and that such synchrony is, in particular, regulated by GABA interneurons under the control of acetylcholine and dopamine. Recent data illustrate that these neurotransmitters establish a causal relationship with the control of self-awareness. The hypothesis is presented that not only is self-awareness chemically regulated, but the reverse may be true. Long-term deficit in self-control of drug intake would result in compulsive substance use, accompanied, in particular, with lesions of the paralimbic circuitry of self-awareness, leading to aggravation of substance abuse, resulting in addiction in a vicious circle. Finally, we propose that the emergent pharmacology of conscious experience may provide new perspectives, not only in substance addiction but also in the many other pathological conditions with deficient self-awareness.
