GABAergic control of the activity of the central nucleus of the amygdala in low- and high-anxiety rats

Skórzewska, Anna; Lehner, Małgorzata; Wisłowska-Stanek, Aleksandra; Turzyńska, Danuta; Sobolewska, Alicja; Krząścik, Paweł; Płaźnik, Adam

doi:10.1016/j.neuropharm.2015.08.039

Cited by 14 publications

(14 citation statements)

References 61 publications

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“…The amygdala significantly contributes to the regulation of fear and anxiety. Hyperexcitability of its neuronal activity is closely related to anxiety and evidence is strong that the GABAergic system is crucial for its regulation (Marowsky et al, 2004;Nuss, 2015;Prager et al, 2016;Skorzewska et al, 2015). Besides the amygdala, striatum, hippocampus, hypothalamus and basal forebrain and septum had high fractions of 2-subunit containing diazepam-sensitive GABA A receptors in our PET study.…”

Section: Distribution Of 1 2 and 5-containing Diazepam-sensitive supporting

confidence: 48%

GABAA receptor subtypes in the mouse brain: Regional mapping and diazepam receptor occupancy by in vivo [18F]flumazenil PET

et al. 2017

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Classical benzodiazepines, which are widely used as sedatives, anxiolytics and anticonvulsants, exert their therapeutic effects through interactions with heteropentameric GABA receptors composed of two α, two β and one γ2 subunit. Their high affinity binding site is located at the interface between the γ2 and the adjacent α subunit. The α-subunit gene family consists of six members and receptors can be homomeric or mixed with respect to the α-subunits. Previous work has suggested that benzodiazepine binding site ligands with selectivity for individual GABA receptor subtypes, as defined by the benzodiazepine-binding α subunit, may have fewer side effects and may even be effective in diseases, such as schizophrenia, autism or chronic pain, that do not respond well to classical benzodiazepines. The distributions of the individual α subunits across the CNS have been extensively characterized. However, as GABA receptors may contain two different α subunits, the distribution of the subunits does not necessarily reflect the distribution of receptor subtypes with respect to benzodiazepine pharmacology. In the present study, we have used in vivo [F]flumazenil PET and in vitro [H]flumazenil autoradiography in combination with GABA receptor point-mutated mice to characterize the distribution of the two most prevalent GABA receptor subtypes (α1 and α2) throughout the mouse brain. The results were in agreement with published in vitro data. High levels of α2-containing receptors were found in brain regions of the neuronal network of anxiety. The α1/α2 subunit combinations were predictable from the individual subunit levels. In additional experiments, we explored in vivo [F]flumazenil PET to determine the degree of receptor occupancy at GABA receptor subtypes following oral administration of diazepam. The dose to occupy 50% of sensitive receptors, independent of the receptor subtype(s), was 1-2mg/kg, in agreement with published data from ex vivo studies with wild type mice. In conclusion, we have resolved the quantitative distribution of α1- and α2-containing homomeric and mixed GABA receptors in vivo at the millimeter scale and demonstrate that the regional drug receptor occupancy in vivo at these GABA receptor subtypes can be determined by [F]flumazenil PET. Such information should be valuable for drug development programs aiming for subtype-selective benzodiazepine site ligands for new therapeutic indications.

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Section: Distribution Of 1 2 and 5-containing Diazepam-sensitive supporting

confidence: 48%

GABAA receptor subtypes in the mouse brain: Regional mapping and diazepam receptor occupancy by in vivo [18F]flumazenil PET

et al. 2017

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“…A research provides further support that high-anxiety rats sustaining repeated corticosterone treatment showed more anxiety-like behavior accompanying with a decrease in GABAA α2 subunit density in the CeA. Acute midazolam administration can significantly reverse the behavior impairment and increase GABAA α2 subunit density (Skórzewska et al, 2015 ). Different experimental conditions and procedure might explain the paradoxical results.…”

Section: Stress-induced Gaba Levels and Gaba Receptor Alterationmentioning

confidence: 91%

“…Notably, GABA is one of the most important inhibitory neurotransmitters in the central nervous system (CNS) (Shiah and Yatham, 1998 ). Under resting state, the amygdala sustains a high GABAergic inhibitory control which contributes to the organism's resistance to various physiological and environmental stressors (Skórzewska et al, 2015 ). The hyperactivity and hyperresponsiveness of amygdala induced by stress is always accompanied by the removal of inhibitory control.…”

Section: Introductionmentioning

confidence: 99%

Stress-Induced Functional Alterations in Amygdala: Implications for Neuropsychiatric Diseases

Zhang

Yin

et al. 2018

Front. Neurosci.

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The amygdala plays a major role in the processing of physiologic and behavioral responses to stress and is characterized by gamma-aminobutyric acid (GABA)-mediated high inhibitory tone under resting state. Human and animal studies showed that stress lead to a hyperactivity of amygdala, which was accompanied by the removal of inhibitory control. However, the contribution of hyperactivity of amygdala to stress-induced neuropsychiatric diseases, such as anxiety and mood disorders, is still dubious. In this review, we will summarize stress-induced various structural and functional alterations in amygdala, including the GABA receptors expression, GABAergic transmission and synaptic plasticity. It may provide new insight on the neuropathologic and neurophysiological mechanisms of neuropsychiatric diseases.

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“…Rats subjected to repeated corticosterone administration showed an increase in anxiety-like behavior, examined using the open field test. The behavioral effects caused by corticosterone injections may because of increased expression of c-Fos in the LA and CeA nuclei of the amygdala and decreased GABA A α-2 subunit density in the CeA of these rats ( Skórzewska et al, 2015 ). These findings are consistent with those of another study ( Lussier et al, 2013 ).…”

Section: Influence Of the Gabaergic System In Amygdala Responses To Smentioning

confidence: 99%

Stress in Regulation of GABA Amygdala System and Relevance to Neuropsychiatric Diseases

et al. 2018

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The amygdala is an almond-shaped nucleus located deep and medially within the temporal lobe and is thought to play a crucial role in the regulation of emotional processes. GABAergic neurotransmission inhibits the amygdala and prevents us from generating inappropriate emotional and behavioral responses. Stress may cause the reduction of the GABAergic interneuronal network and the development of neuropsychological diseases. In this review, we summarize the recent evidence investigating the possible mechanisms underlying GABAergic control of the amygdala and its interaction with acute and chronic stress. Taken together, this study may contribute to future progress in finding new approaches to reverse the attenuation of GABAergic neurotransmission induced by stress in the amygdala.

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GABAergic control of the activity of the central nucleus of the amygdala in low- and high-anxiety rats

Cited by 14 publications

References 61 publications

GABAA receptor subtypes in the mouse brain: Regional mapping and diazepam receptor occupancy by in vivo [18F]flumazenil PET

GABAA receptor subtypes in the mouse brain: Regional mapping and diazepam receptor occupancy by in vivo [18F]flumazenil PET

Stress-Induced Functional Alterations in Amygdala: Implications for Neuropsychiatric Diseases

Stress in Regulation of GABA Amygdala System and Relevance to Neuropsychiatric Diseases

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