Central and Peripheral GABA<sub><b>A</b></sub>Receptor Regulation of the Heart Rate Depends on the Conscious State of the Animal

Bentzen, Bo Hjorth; Grunnet, Morten

doi:10.1155/2011/578273

Cited by 21 publications

(18 citation statements)

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“…However, differences in metabolite rates could affect the radioactive concentration in blood and therefore is a potential bias on the V T * calculations. The heart ventricle image-derived input function serves for calculation of distribution volume for tracers without substantial binding in the myocardium and without important metabolism during the scan [48, 49]. Finally, we calculated V T * on a group basis rather than for individual mice, thus affording a better comparison of PET scans and the ex vivo experimental results.…”

Section: Discussionmentioning

confidence: 99%

“…We cannot rule out that some effects of anesthesia on [ 18 F]flumazenil uptake and binding arose from changes in cardiac output, since central and peripheral GABA A receptors do regulate heart rate [48], although cerebral blood flow is the more salient issue, since it can influence delivery of lipophilic tracers to the brain. We argue that the V T * index is a less biased measurement than %ID/g in this regard, as it is a steady-state index.…”

Section: Discussionmentioning

confidence: 99%

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Effects of common anesthetic agents on [18F]flumazenil binding to the GABAA receptor

et al. 2016

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BackgroundThe availability of GABAA receptor binding sites in the brain can be assessed by positron emission tomography (PET) using the radioligand, [18F]flumazenil. However, the brain uptake and binding of this PET radioligand are influenced by anesthetic drugs, which are typically needed in preclinical imaging studies and clinical imaging studies involving patient populations that do not tolerate relatively longer scan times. The objective of this study was to examine the effects of anesthesia on the binding of [18F]flumazenil to GABAA receptors in mice.MethodsBrain and whole blood radioactivity concentrations were measured ex vivo by scintillation counting or in vivo by PET in four groups of mice following administration of [18F]flumazenil: awake mice and mice anesthetized with isoflurane, dexmedetomidine, or ketamine/dexmedetomidine. Dynamic PET recordings were obtained for 60 min in mice anesthetized by either isoflurane or ketamine/dexmedetomidine. Static PET recordings were obtained at 25 or 55 min after [18F]flumazenil injection in awake or dexmedetomidine-treated mice acutely anesthetized with isoflurane. The apparent distribution volume (VT*) was calculated for the hippocampus and frontal cortex from either the full dynamic PET scans using an image-derived input function or from a series of ex vivo experiments using whole blood as the input function.ResultsPET images showed persistence of high [18F]flumazenil uptake (up to 20 % ID/g) in the brains of mice scanned under isoflurane or ketamine/dexmedetomidine anesthesia, whereas uptake was almost indiscernible in late samples or static scans from awake or dexmedetomidine-treated animals. The steady-state VT* was twofold higher in hippocampus of isoflurane-treated mice and dexmedetomidine-treated mice than in awake mice.ConclusionsAnesthesia has pronounced effects on the binding and blood-brain distribution of [18F]flumazenil. Consequently, considerable caution must be exercised in the interpretation of preclinical and clinical PET studies of GABAA receptors involving the use of anesthesia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of common anesthetic agents on [18F]flumazenil binding to the GABAA receptor

et al. 2016

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“…Several studies have discovered that GABA A R are expressed in the heart and intestinal tissues. Some researchers suggest that GABA A R plays a certain function in the cardiovascular and intestinal endocrine systems (Bentzen and Grunnet, ; Vigliano et al., ). These findings were consistent with prior GABA A R expression profiles.…”

Section: Discussionmentioning

confidence: 99%

Effect of avermectin (AVM) on the expression of γ -aminobutyric acid A receptor (GABA_A R) in Carassius gibelio (Bloch, 1782)

Zhang

Ruan

et al. 2015

J. Appl. Ichthyol.

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This study describes the effect of avermectin (AVM) on the expression of c-aminobutyric acid A receptor (GABA A R) in Carassius gibelio. To assess the specific expression of GABA A R in the brain, gonads, liver, kidneys, heart, muscles, and skin of C. gibelio, the expression of GABA A R a1 subunit (GABA A Ra1) was measured by Western blotting. To study the effects of AVM on the expression of GABA A R, the median lethal concentration (LC 50 ) at 24, 48, and 96 h of AVM was determined and the expression of GABA A R in the brain, liver, and kidneys of the corresponding C. gibelio evaluated by Western blotting and immunohistochemistry. The results show that GABA A R was expressed in the brain, gonads, liver, kidneys, heart, intestines, muscles, and skin, while primarily distributed in the central nervous system and moderately distributed in peripheral tissues. The expression of GABA A R in the brain, liver, and kidney tissues of C. gibelio was increased with the treatment of AVM at 24 h LC 50 , but attenuated by the treatment of AVM at 48 h LC 50 and 96 h LC 50 . This suggests a threshold effect of AVM.

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“…Furthermore, several amino acid residues on α and γ subunits have been identified that are crucial for benzodiazepine activity and form benzodiazepine binding pocket [86,[103][104][105]. It is considered that antagonists bind in a pocket partly overlapping with the agonist site, although they can extend further into the solvent accessible cavity [106].…”

Section: Effects Of Drugs Acting At Benzodiazepine Binding Sites At Gmentioning

confidence: 99%

GABA Receptors: Pharmacological Potential and Pitfalls

Jembrek¹,

Vlainić

2015

CPD

106

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Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, plays a key role in the regulation of neuronal transmission throughout the brain, affecting numerous physiological and psychological processes. Changes in GABA levels provoke disbalance between excitatory and inhibitory signals, and are involved in the development of numerous neuropsychiatric disorders. GABA exerts its effects via ionotropic (GABAA) and metabotropic (GABAB) receptors. Both types of receptors are targeted by many clinically important drugs that affect GABAergic function and are widely used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, aggressive behaviour, and other pathophysiological conditions and diseases. Of particular importance are drugs that modulate GABAA receptor complex, such as benzodiazepines, barbiturates, neuroactive steroids, intravenous and inhalational anesthetics, and ethanol. Molecular interactions and subsequent pharmacological effects induced by drugs acting at GABAA receptors are extremely complex due to structural heterogeneity of GABAA receptors and existence of numerous allosterically interconnected binding sites and various chemically distinct ligands that are able to bound to them. There is a growing interest in the development and application of subtype-selective drugs that will achieve specific therapeutic benefits without undesirable side effects. The aim of this review is to briefly summarize the key pharmacological properties of GABA receptors, and to present selected novel findings with the potential to open new perspectives in the development of more effective therapeutic strategies.

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Central and Peripheral GABA_AReceptor Regulation of the Heart Rate Depends on the Conscious State of the Animal

Cited by 21 publications

References 64 publications

Effects of common anesthetic agents on [18F]flumazenil binding to the GABAA receptor

Effects of common anesthetic agents on [18F]flumazenil binding to the GABAA receptor

Effect of avermectin (AVM) on the expression of γ -aminobutyric acid A receptor (GABA_A R) in Carassius gibelio (Bloch, 1782)

GABA Receptors: Pharmacological Potential and Pitfalls

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Central and Peripheral GABAAReceptor Regulation of the Heart Rate Depends on the Conscious State of the Animal

Cited by 21 publications

References 64 publications

Effects of common anesthetic agents on [18F]flumazenil binding to the GABAA receptor

Effects of common anesthetic agents on [18F]flumazenil binding to the GABAA receptor

Effect of avermectin (AVM) on the expression of γ -aminobutyric acid A receptor (GABAA R) in Carassius gibelio (Bloch, 1782)

GABA Receptors: Pharmacological Potential and Pitfalls

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Central and Peripheral GABA_AReceptor Regulation of the Heart Rate Depends on the Conscious State of the Animal

Effect of avermectin (AVM) on the expression of γ -aminobutyric acid A receptor (GABA_A R) in Carassius gibelio (Bloch, 1782)