1,721,052 research outputs found
The neurobiology of GABA receptors
No full textGamma-aminobutyric acid (GABA) was first identified in 1950 (Roberts
1950; Awapara 1950) in brain extracts of various animal species and was
subsequently found to be the principal inhibitory neurotransmitter in the central
nervous system (CNS). GABA is synthesized as a result of decarboxylation of
glutamic acid and is released by neurons into the synaptic cleft in order to
transmit inhibitory signals to other nerve cells. Given the wide distribution of
GABA throughout the brain (more than 30% of all central synapses in mammals
are GABAergic), it is not surprising that GABA-mediated neurotransmission
plays an important role not only in the control of various brain functions but
also, as reviewed in this chapter, in the pathophysiology of several mental and
neurological conditions including anxiety, sleep disorders, epilepsy, and
Huntington’s chorea.
Recent insights into the structure, function, and pharmacology of GABA
receptors have contributed substantially to the identification of key neurobiological
and neurochemical mechanisms that underlie the regulation of
neuronal excitability and of emotional and behavioral states. They have also
facilitated the development as well as characterization of the mechanisms of
action of therapeutic agents used in the treatment of GABA-related pathologies
Social isolation stress and neuroactive steroids
No full textSocial isolation of rats immediately after weaning is associated to a reduction in the cerebrocortical and plasma concentrations of progesterone and its metabolites 3,5-TH PROG and 3,5-THDOC. Although we found that the basal plasma concentration of adrenocorticotropic hormone in isolated rats was slightly decreased compared with that in group-housed animals no other significant changes were found in the steroidogenic machinery (peripheral benzodiazepine receptors, steroidogenic regulatory protein (StAR)). However, the functional response of the hypothalamic-pituitary-adrenal axis HPA axis to an acute stressful stimulus (foot shock), or to an acute injection of ethanol or isoniazid is markedly increased in isolated rats. Behavioral studies have also indicated that the ability of ethanol to inhibit isoniazid-induced convulsions is greater in isolated rats than in group-housed animals and this effect of isolation is prevented by treatment with the 5α-reductase inhibitor finasteride. Social isolation modified the effects of ethanol on the amounts of StAR mRNA and protein in the brain suggesting an alteration in the mechanism of cholesterol transport in mithocondria. Moreover, the amounts of the α4 and δ subunits of the GABAA receptor in the hippocampus were increased in isolated rats, and these effects were accompanied by an increase in GABAA receptor–mediated tonic inhibitory currents in granule cells of the dentate gyrus. Ethanol also increased the amplitude of GABAA receptor–mediated miniature inhibitory postsynaptic currents ( mIPSC) recorded from CA1 pyramidal neurons with a greater potency in hippocampal slices prepared from socially isolated rats than in those from group-housed, an effect inhibited by finasteride
Stress, ethanol, and neuroactive steroids
No full textNeurosteroids play a crucial role in stress, alcohol dependence and withdrawal, and other physiological and pharmacological actions by potentiating or inhibiting neurotransmitter action. This review article focuses on data showing that the interaction among stress, ethanol, and neuroactive steroids may result in plastic molecular and functional changes of GABAergic inhibitory neurotransmission. The molecular mechanisms by which stress-ethanol-neuroactive steroids interactions can produce plastic changes in GABAA receptors have been studied using different experimental models in vivo and in vitro in order to provide useful evidence and new insights into the mechanisms through which acute and chronic ethanol and stress exposure modulate the activity of GABAergic synapses. We show detailed data on a) the effect of acute and chronic stress on peripheral and brain neurosteroid levels and GABAA receptor gene expression and function; b) ethanol-stimulated brain steroidogenesis; c) plasticity of GABAA receptor after acute and chronic ethanol exposure. The implications of these new mechanistic insights to our understanding of the effects of ethanol during stress are also discussed. The understanding of these neurochemical and molecular mechanisms may shed new light on the physiopathology of diseases, such as anxiety, in which GABAergic transmission plays a pivotal role. These data may also lead to the need for new anxiolytic, hypnotic and anticonvulsant selective drugs devoid of side effects. © 2007 Elsevier Inc. All rights reserved
Plasticity and function of extrasynaptic GABA(A) receptors during pregnancy and after delivery
No full textNeuroactive steroids such as 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP) are reduced metabolites of progesterone and are thought to play an important physiological role in local modulation of neuronal excitability by "fine-tuning" the action of γ-aminobutyric acid (GABA) at GABAA receptors. Fluctuations in the concentrations of neuroactive steroids in the brain are also thought to contribute to GABAA receptor plasticity. We here review results from our laboratory related to the regulation of GABAA receptor function and plasticity by changes in the levels of neuroactive steroids during pregnancy and after delivery in rats. Pregnancy is characterized by marked and progressive increases in the plasma and brain concentrations of neuroactive steroids, which are implicated in the changes in mood, anxiety, and other psychiatric states associated with this condition. We have shown that the increases in the brain levels of neuroactive steroids during pregnancy are causally related to changes in the expression of specific GABAA receptor subunits and the function of extrasynaptic GABAA receptors in the hippocampus
Inclusion complexation of propofol with 2-hydroxypropyl-beta-cyclodextrin. Physicochemcial, nuclear magnetic resonance spectroscopic studies, and anesthetic properties in rat
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Changes in neuroactive steroid content during social isolation stress modulate GABA(A) receptor plasticity and function
No full textRats deprived of social contact with other rats at a young age experience a form of prolonged stress that leads to long-lasting alteration in their behavior profile. This chronic stress paradigm is thus thought to be anxiogenic for these normally gregarious animals and their abnormal reactivity to environmental stimuli, when reared under this condition, is thought to be a product of prolonged stress. Neurochemical, molecular, and electrophysiological evidences demonstrate that social isolation is associated with alteration in the structure and function of GABA(A) receptors and suggest that endogenous content of the progesterone metabolite 3 alpha,5 alpha-TH PROG may be an important determinant in regulating brain excitability and sensitivity to stimuli and point out its possible role in psychiatric and neurological disorder. (c) 2007 Elsevier B.V. All rights reserved
DIFFERENTIAL SUBUNIT DEPENDENCE OF THE ACTIONS OF THE GENERAL ANESTHETICS ALPHAXALONE AND ETOMIDATE AT GAMMA-AMINOBUTYRIC ACID TYPE A RECEPTORS EXPRESSED IN XENOPUS LAEVIS OOCYTES
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