Gabaa antagonist

RATIONALE: Both prefrontal cortex (PFC) GABAA and NMDA transmission regulate attentional processes, yet how they may differentially regulate signal detection or other aspects of attention is unclear. OBJECTIVES: We examined PFC GABAA and NMDA receptor regulation of attention using a sustained attention task (SAT) permitting identification of distinct forms of impairments. As this task requires implementation of conditional rules, we also investigated how reducing PFC GABA transmission affected performance of visual and auditory conditional discriminations...

The aim of the present study was to observe whether dopamine receptor (DR) was involved in the effects of sodium salicylate (SS) on the expressions of N-methyl-D-aspartic acid (NMDA) and γ-aminobutyric acid (GABA) receptors in rat cochlear spiral ganglion neurons (SGNs). Forty-eight hours after primary culture of rat SGNs, immunofluorescence technique was applied to detect expressions of DR1 and DR2, the two subtypes of dopamine receptors. Western blot was performed to assess NMDA receptor NR1 subunit and GABAA receptor subunit α2 (GABRα2) protein expressions in the SGNs after the treatments of SS alone or in combination with DR antagonists...

BACKGROUND: Chronic stress induces an impaired GABAA (γ-aminobutyric acid type A) receptor-mediated inhibition in the hypothalamic paraventricular nucleus (PVN). It is not clear whether GABAB receptor function is altered in chronic stress. We hypothesize that chronic stress alters GABAB receptor function in PVN corticotrophin-releasing hormone (CRH) neurons to control hypothalamus-pituitary-adrenal (HPA) axis activity. EXPERIMENTAL APPROACH: Whole cell patch-clamp recording was performed on PVN-CRH neurons expressing eGFP driven by CRH promoter in brain slices from unstressed rats and rats that had been subjected to chronic unpredictable mild stress (CUMS)...

Experimental exposure to ocean and freshwater acidification affects the behaviour of multiple aquatic organisms in laboratory tests. One proposed cause involves an imbalance in plasma chloride and bicarbonate ion concentrations as a result of acid-base regulation, causing the reversal of ionic fluxes through GABAA receptors, which leads to altered neuronal function. This model is exclusively based on differential effects of the GABAA receptor antagonist gabazine on control animals and those exposed to elevated CO2 However, direct measurements of actual chloride and bicarbonate concentrations in neurons and their extracellular fluids and of GABAA receptor properties in aquatic organisms are largely lacking...

In Huntington's disease (HD), dysfunctional affective processes emerge as key symptoms of disturbances. In human HD and transgenic rat models of the disease, the amygdala was previously shown to have a reduced volume and to carry a high load of mutant huntingtin (mHTT) aggregates. In search of the pathophysiology of affective dysregulation in HD, we hypothesized a specific role of the central amygdala (CeA), known to be particularly involved in emotional regulation. Using transgenic BACHD rats carrying full-length human mHTT, we compared behavioral consequences of pharmacological modulation of CeA function by infusing GABAA receptor (GABAAR) antagonist picrotoxin into ∼4...

The bed nucleus of the stria terminalis (BST) consists of multiple anatomically distinct nuclei. The lateral division, which receives dense noradrenergic innervation, has been implicated in cardiovascular regulation and modulation of responses to stress. This study is performed to identify the cardiovascular and single-unit responses of the lateral BST to norepinephrine (NE), involved adrenoceptors, and possible interaction with GABAergic system of the BST in urethane-anesthetized rats. NE, adrenoreceptor antagonists, and GABAA antagonist were microinjected into the lateral division of BST, while arterial pressure (AP), heart rate (HR), and single-unit responses were simultaneously recorded...

OBJECTIVE: Mutations of the KCNQ2 gene, which encodes the Kv 7.2 subunit of voltage-gated M-type potassium channels, have been associated with epilepsy in the neonatal period. This developmental stage is unique in that the neurotransmitter gamma aminobutyric acid (GABA), which is inhibitory in adults, triggers excitatory action due to a reversed chloride gradient. METHODS: To examine whether KCNQ2-related neuronal hyperexcitability involves neonatally excitatory GABA, we examined 1-week-old knockin mice expressing the Kv 7...

Swietenia humilis Zucc. (Meliaceae) seeds are used in Mexico for the treatment of type 2 diabetes mellitus. Mexicanolides are the main hypoglycemic and antihyperglycemic compounds of the species. This study was conducted to investigate the antihyperalgesic effect of an aqueous extract of the seeds of Swietenia humilis (SHAE) and of mexicanolide 2-hydroxy-destigloyl-6-deoxyswietenine acetate (1), using the formalin test in mice. The antihyperalgesic actions of SHAE and mexicanolide 1, as well as its possible transductional activity, were assessed in nicotinamide-streptozotocin (NA-STZ) hyperglycemic mice...

PURPOSE: The zona incerta (ZI) is below the ventral tier of the thalamus and has a strong influence selectively in higher-order thalamic relays. Although neuropathic pain has been suggested to result from reduced gamma-aminobutyric acid (GABA) and GABAergic signaling in the ZI, the mechanisms remain unclear. Here, the role of GABA and GABAergic signaling was investigated in the ZI in neuropathic pain using sciatic nerve chronic constriction injury (CCI) rats. MATERIALS AND METHODS: Single-unit neuronal activity was recorded, and microdialysis was performed in the ZI of CCI rats and sham-treated rats in vivo...

Alpha-7 nicotinic acetylcholine receptor (α7-nAChR) agonists can prevent glutamate-induced excitotoxicity in cultured retinal ganglion cells (RGCs). However, the neuroprotective effects and the mechanism of action of PNU-282987, an α7-nAChR agonist, in a chronic in vivo rat glaucoma model are poorly understood. We found that elevated intraocular pressure (IOP) downregulated retinal α7-nAChR expression. Electroretinography revealed that the amplitude of the photopic negative response (PhNR) decreased in parallel with the loss of RGCs caused by elevated IOP...

Gamma-aminobutyric acid type A (GABAA) receptors are major inhibitory neurotransmitter receptors in the central nervous system and a target for numerous clinically important drugs used to treat anxiety, insomnia, and epilepsy. A series of allosteric GABAA receptor agonists was identified previously with the aid of HPLC-based activity profiling, whereby activity was tracked with an electrophysiological assay in Xenopus laevis oocytes. To accelerate the discovery process, an approach has been established for HPLC-based profiling using a larval zebrafish (Danio rerio) seizure model induced by pentylenetetrazol (PTZ), a pro-convulsant GABAA receptor antagonist...

Alcohol addiction is a worldwide problem. It has mainly two components: dependence and withdrawal. Characteristic properties of most anti-addictive compounds include anti-anxiety, anticonvulsant, antidepressant, and nootropic actions. Shankhpushpi (Convolvulus pluricaulis. Convolvulaceae), known ethnopharmacologically as brain tonic, possess all the properties mentioned above. Here, we screen shankhpushpi for possible anti-addictive potential. Effect of shankhpushpi churna was measured on ethanol withdrawal anxiety using elevated plus maze...

Early maladaptive internalization of synaptic GABAA receptors (GABAAR) and externalization of NMDA receptors (NMDAR) may explain the time-dependent loss of potency of standard anti-epileptic drugs (AED) in refractory status epilepticus (SE). We hypothesized that correcting the effects of changes in GABAAR and NMDAR would terminate SE, even when treatment is delayed 40 minutes. SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAAR agonist midazolam, the NMDAR antagonist ketamine and the AED valproate were injected 40 min after SE onset in combination or as monotherapy...

INTRODUCTION: Beside its autonomic functions, the nucleus paragigantocellularis lateralis (LPGi) is involved in the descending pain modulation. 17β-Estradiol is a neuroactive steroid found in several brain areas such as LPGi. Intra-LPGi microinjection of 17β-estradiol can elicit the analgesic responses. 17β-Estradiol modulates nociception by binding to estrogenic receptors as well as allosteric interaction with other membrane-bound receptors like GABAA receptors. This study aimed to examine the role of GABAA receptors in the pain modulating effect of intra-LPGi injection of 17β-estradiol...

Chronic insomnia is defined as a persistent difficulty with sleep initiation maintenance or non-restorative sleep. The therapeutic standard of care for this condition is treatment with gamma-aminobutyric acid (GABA)A receptor modulators, which promote sleep but are associated with a panoply of side effects, including cognitive and memory impairment. Dual orexin receptor antagonists (DORAs) have recently emerged as an alternative therapeutic approach that acts via a distinct and more selective wake-attenuating mechanism with the potential to be associated with milder side effects...

Positive allosteric modulators of GABAA receptors transduce a host of beneficial effects including anxiolytic actions. We have recently shown that bioavailability and anxiolytic-like activity can be improved by eliminating the ester functionality in imidazo[1,5-a][1,4]diazepines. In the present series of experiments, we further substantiate the value of heterocyle replacement of the ester for potential treatment of anxiety. None of three esters was active in a Vogel conflict test in rats that detects anxiolytic drugs like diazepam...

Rostral ventrolateral medulla (RVLM) plays an essential role in blood pressure homeostasis. This study was aimed to investigate the mechanism of neuronal activity and synaptic transmission in the RVLM. Medulla oblongata slices were carefully obtained from brainstem of rats. With continues perfusion of artificial cerebrospinal fluid (ACSF), the spontaneous firing of slices and amplitudes were assayed by conventional whole cell patch-clamp recording after addition of gamma-aminobutyric acid (GABA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl d-aspartate (NMDA)...

Gamma-aminobutyric acid (GABA) depolarizes dorsal root ganglia (DRG) primary afferent neurons through activation of Cl(-) permeable GABAA receptors but the physiologic role of GABAA receptors in the peripheral terminals of DRG neurons remains unclear. In this study, we investigated the role of peripheral GABAA receptors in nociception using a mouse model of acute inflammation. In vivo, peripheral administration of the selective GABAA receptor agonist muscimol evoked spontaneous licking behavior, as well as spinal wide dynamic range (WDR) neuron firing, after pre-conditioning with formalin but had no effect in saline-treated mice...

Fluorometric imaging plate reader membrane potential dye (FMP-Red-Dye) is a proprietary tool for basic discovery and high-throughput drug screening for G-protein-coupled receptors and ion channels. We optimized and validated this potentiometric probe to assay functional modulators of heterologous expressed GABAA receptor (GABAAR) isoforms (synaptic α1β3γ2, extrasynaptic α4β3δ, and β3 homopentomers). High-resolution mass spectrometry identified FMP-Red-Dye as 5,5'-(1-propen-1-yl-3-ylidene)bis[1,3-dimethyl-2-thio-barbituric acid]...

Scutellariae Radix (SR) and its bioactive flavones elicit a variety of effects in the brain. However, the brain uptake of individual SR flavones and its relationship to the elicited effects after SR administration remain unknown. Moreover, previous studies seldom measured pharmacokinetic and pharmacodynamic outcomes simultaneously. In the current study, the brain uptake of six major SR flavones and the anxiolytic behavior following oral administration of a SR extract at two clinically relevant doses (600 and 1200 mg/kg twice daily) were simultaneously investigated in mice (n = 18 per group)...