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      Central and Peripheral GABA A Receptor Regulation of the Heart Rate Depends on the Conscious State of the Animal

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      Advances in Pharmacological Sciences

      Hindawi Publishing Corporation

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          Abstract

          Intuitively one might expect that activation of GABAergic inhibitory neurons results in bradycardia. In conscious animals the opposite effect is however observed. GABAergic neurons in nucleus ambiguus hold the ability to control the activity of the parasympathetic vagus nerve that innervates the heart. Upon GABA activation the vagus nerve will be inhibited leaving less parasympathetic impact on the heart. The picture is however blurred in the presence of anaesthesia where both the concentration and type of anaesthetics can result in different effects on the cardiovascular system. This paper reviews cardiovascular outcomes of GABA activation and includes own experiments on anaesthetized animals and isolated hearts. In conclusion, the impact of changes in GABAergic input is very difficult to predict in these settings, emphasizing the need for experiments performed in conscious animals when aiming at determining the cardiovascular effects of compounds acting on GABAergic neurons.

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          Most cited references 75

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          Cortical inhibitory neurons and schizophrenia.

          Impairments in certain cognitive functions, such as working memory, are core features of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB neurotrophin receptor leads to reduced GABA (gamma-aminobutyric acid) synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a diminished capacity for the gamma-frequency synchronized neuronal activity that is required for working memory function. These findings reveal specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.
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            Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.

            Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.
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              International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.

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                Author and article information

                Journal
                Adv Pharmacol Sci
                APS
                Advances in Pharmacological Sciences
                Hindawi Publishing Corporation
                1687-6334
                1687-6342
                2011
                17 November 2011
                : 2011
                Affiliations
                NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark
                Author notes

                Academic Editor: Keith Wafford

                Article
                10.1155/2011/578273
                3226329
                22162673
                Copyright © 2011 B. H. Bentzen and M. Grunnet.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Review Article

                Pharmacology & Pharmaceutical medicine

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