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GABAB Receptor Agonist (gabab + receptor_agonist)
Terms modified by GABAB Receptor Agonist Selected AbstractsInflux of calcium through L-type calcium channels in early postnatal regulation of chloride transporters in the rat hippocampusDEVELOPMENTAL NEUROBIOLOGY, Issue 13 2009Jennifer G. Bray Abstract During the early postnatal period, GABAB receptor activation facilitates L-type calcium current in rat hippocampus. One developmental process that L-type current may regulate is the change in expression of the K+Cl, co-transporter (KCC2) and N+K+2Cl, co-transporter (NKCC1), which are involved in the maturation of the GABAergic system. The present study investigated the connection between L-type current, GABAB receptors, and expression of chloride transporters during development. The facilitation of L-type current by GABAB receptors is more prominent in the second week of development, with the highest percentage of cells exhibiting facilitation in cultures isolated from 7 day old rats (37.5%). The protein levels of KCC2 and NKCC1 were investigated to determine the developmental timecourse of expression as well as expression following treatment with an L-type channel antagonist and a GABAB receptor agonist. The time course of both chloride transporters in culture mimics that seen in hippocampal tissue isolated from various ages. KCC2 levels increased drastically in the first two postnatal weeks while NKCC1 remained relatively stable, suggesting that the ratio of the chloride transporters is important in mediating the developmental change in chloride reversal potential. Treatment of cultures with the L-type antagonist nimodipine did not affect protein levels of NKCC1, but significantly decreased the upregulation of KCC2 during the first postnatal week. In addition, calcium current facilitation occurs slightly before the large increase in KCC2 expression. These results suggest that the expression of KCC2 is regulated by calcium influx through L-type channels in the early postnatal period in hippocampal neurons. © 2009 Wiley Periodicals, Inc. Develop Neurobiol 2009 [source] Effect of lesogaberan, a novel GABAB -receptor agonist, on transient lower oesophageal sphincter relaxations in male subjectsALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 11 2010G. E. BOECKXSTAENS Aliment Pharmacol Ther,31, 1208,1217 Summary Background, Transient lower oesophageal sphincter relaxations (TLESRs) are a major mechanism behind gastro-oesophageal reflux disease (GERD). Aim, To assess the effect of lesogaberan (AZD3355) , a novel peripherally active GABAB receptor agonist , on TLESRs. Methods, Twenty-four healthy men were enrolled in this single-blind, placebo-controlled, randomized, single-centre, three-period crossover phase 1 study. Subjects were randomized to receive single oral doses of lesogaberan (0.8 mg/kg), baclofen (40 mg) and placebo, separated by washout periods of ,7 days. Subjects finished a meal 1 h after the dose. Oesophageal manometry and pH-metry measurements were taken during the 3 h after the meal. Results, Twenty-one subjects completed the study. Compared with placebo, lesogaberan 0.8 mg/kg significantly reduced the number of TLESRs by 36% [geometric mean ratio (GMR): 0.64; 95% confidence interval (CI): 0.51,0.82] and significantly reduced the number of acid reflux episodes (mean reduction: 1.6; 95% CI: 0.34,2.9). Lesogaberan also significantly increased lower oesophageal sphincter (LES) pressure by 39% compared with placebo (GMR: 1.39; 95% CI: 1.18,1.64). Comparable results were observed with baclofen. Similar numbers of adverse events were reported by subjects taking lesogaberan and placebo. Conclusion, Compared with placebo, lesogaberan significantly reduced TLESRs and acid reflux episodes and increased LES pressure. [source] The GABAB receptor agonist AZD9343 inhibits transient lower oesophageal sphincter relaxations and acid reflux in healthy volunteers: a phase I studyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 9 2009H. BEAUMONT Summary Background, Transient lower oesophageal sphincter relaxations (TLESRs) represent an interesting target for the treatment of gastro-oesophageal reflux. Baclofen reduces TLESRs and reflux episodes, but is not optimal for clinical application because of its central side effects. Therefore, new agents are required. Aim, To study the effect of AZD9343, a new selective GABAB receptor agonist, in healthy volunteers. Methods, A total of 27 subjects participated in a placebo-controlled, randomized, two-centre phase I study. Subjects underwent oesophageal manometry and pH-metry for 3 h postprandially. Before meal ingestion, a single oral dose of placebo, 60 and 320 mg AZD9343 or 40 mg baclofen was given on four separate days. Results, Somnolence was reported after 320 mg AZD9343 and baclofen. Reversible short-lasting paraesthesia was reported after AZD9343. AZD9343 320 mg and baclofen significantly reduced the number of TLESRs with 32% and 40% respectively. Acid reflux was significantly decreased by AZD9343 and baclofen. Like baclofen, AZD9343 increased LES pressure before meal intake. AZD9343 320 mg and baclofen significantly reduced the swallowing rate. Conclusions, Like baclofen, AZD9343 dose-dependently decreases the number of TLESRs and acid reflux episodes, increases LES pressure and reduces swallowing, extending the concept that GABAB agonists are potent reflux inhibitors. However, discovery of analogues with an improved side effect profile is warranted. [source] GABAB receptor modulation of excitatory and inhibitory synaptic transmission onto rat CA3 hippocampal interneuronsTHE JOURNAL OF PHYSIOLOGY, Issue 2 2003Saobo Lei Hippocampal stratum radiatum inhibitory interneurons receive glutamatergic excitatory innervation via the recurrent collateral fibers of CA3 pyramidal neurons and GABAergic inhibition from other interneurons. We examined both presynaptic- and postsynaptic-GABAB receptor-mediated responses at both synapse types. Postsynaptic GABAB receptor-mediated responses were absent in recordings from young (P16-18) but present in recordings from older animals (P30) suggesting developmental regulation. In young animals, the GABAB receptor agonist, baclofen, inhibited the amplitude of evoked EPSCs and IPSCs, an effect blocked by prior application of the selective antagonist CGP55845. Baclofen enhanced the paired-pulse ratio and coefficient of variation of evoked EPSCs and IPSCs, consistent with a presynaptic mechanism of regulation. In addition, baclofen reduced the frequency of miniature IPSCs but not mEPSCs. However, baclofen reduced the frequency of KCl-induced mEPSCs; an effect blocked by Cd2+, implicating presynaptic voltage-gated Ca2+ channels as a target for baclofen modulation. In contrast, although Cd2+ prevented the KCl-induced increase in mIPSC frequency, it failed to block baclofen's reduction of mIPSC frequency. Whereas N- and P/Q-types of Ca2+ channels contributed equally to GABAB receptor-mediated inhibition of EPSCs, more P/Q-type Ca2+ channels were involved in GABAB receptor-mediated inhibition of IPSCs. Finally, baclofen blocked the frequency-dependent depression of EPSCs and IPSCs, but was less effective at blocking frequency-dependent facilitation of EPSCs. Our results demonstrate that presynaptic GABAB receptors are expressed on the terminals of both excitatory and inhibitory synapses onto CA3 interneurons and that their activation modulates essential components of the release process underlying transmission at these two synapse types. [source] GABAB receptor function in the ileum and urinary bladder of wildtype and GABAB1 subunit null miceAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2002G. J. Sanger Summary1 GABAB1 receptor subunit knockout mice were generated and the effects of the GABAB receptor agonist, baclofen, were evaluated within the peripheral nervous system (PNS) of wildtype (+/+), heterozygote (+/,) and knockout (,/,) animals. For this purpose, neuronally-mediated responses were evoked in both the isolated ileum and urinary bladder, using selective electrical field stimulation (EFS). 2 In ileum resected from 4,8-week-old-mice, low frequencies of EFS (0.5 Hz) evoked irregular muscle contractions which were prevented by atropine 1 ,M and reduced by baclofen (33.4 ± 5.6%, 100 ,m). The latter effect was antagonized by the GABAB receptor antagonist CGP54626 0.2 ,m. Baclofen 100 ,m did not affect contractions of similar amplitude induced by carbachol, indicating that the ability of baclofen to inhibit cholinergic function in mouse ileum may be due to an action at prejunctional GABAB receptors. 3 To avoid the development of grand mal seizure by GABAB1 (,/,) mice, a behaviour observed when the mice were greater than 3 weeks old, it was necessary to study the effects of this knockout in 1,3-week-old-animals. However, at this age, EFS at 0.5 Hz did not evoke robust muscle contractions. Consequently we used EFS at 5 Hz, which did evoke cholinergically mediated contractions, found to be of similar amplitude in (+/+) and (+/,) mice, of both 1,3 weeks and 4,8 weeks of age. At this frequency of EFS, baclofen reduced the amplitude of the evoked contractions [n=6 (+/+) and n=5 (+/,), IC50 19.2 ± 4.8 ,m) and this effect was greatly reduced in the presence of CGP54626 0.2 ,m. 4 In urinary bladder from 1,3-week-old-mice, using higher frequencies of EFS to evoke clear, nerve-mediated contractions (10 Hz), baclofen 10,300 ,m concentration-dependently inhibited contractions in (+/+) mice (IC50 9.6 ± 3.8 ,m). This effect was inhibited by CGP54626 (0.2 ,m, 46.2 ± 13.6% inhibition, 300 ,m baclofen n=7) a concentration which, by itself, had no effect on the EFS-evoked contractions. 5 The effects of baclofen in both ileum and urinary bladder were absent in the GABAB1 receptor subunit (,/,) mice; however, responses to EFS were unaffected in (,/,) when compared to the (+/+) mice. 6 Our data suggest that, as in the central nervous system (CNS), the GABAB1 receptor subunit is an essential requirement for GABAB receptor function in the enteric and PNS. As such, these data do not provide a structural explanation for the existence of putative subtypes of GABAB receptor, suggested by studies such as those in which different rank-orders of GABAB agonist affinity have been reported in different tissues. [source] GABAB receptor expression and function in olfactory receptor neuron axon growthDEVELOPMENTAL NEUROBIOLOGY, Issue 2 2004Catherine A. Priest Abstract Neurotransmitters have been implicated in regulating growth cone motility and guidance in the developing nervous system. Anatomical and electrophysiological studies show the presence of functional GABAB receptors on adult olfactory receptor neuron (ORN) nerve terminals. Using antisera against the GABAB R1a/b receptor isoforms we show that developing mouse olfactory receptor neurons express GABAB receptors from embryonic day 14 through to adulthood. GABAB receptors are present on axon growth cones from both dissociated ORNs and olfactory epithelial explants. Neurons in the olfactory bulb begin to express glutamic acid decarboxylase (GAD), the synthetic enzyme for GABA, from E16 through to adulthood. When dissociated ORNs were cultured in the presence of the GABAB receptor agonists, baclofen or SKF97541, neurite outgrowth was significantly reduced. Concurrent treatment of the neurons with baclofen and the GABAB receptor antagonist CGP54626 prevented the inhibitory effects of baclofen on ORN neurite outgrowth. These results show that growing ORN axons express GABAB receptors and are sensitive to the effects of GABAB receptor activation. Thus, ORNs in vivo may detect GABA release from juxtaglomerular cells as they enter the glomerular layer and use this as a signal to limit their outgrowth and find synaptic targets in regeneration and development. © 2004 Wiley Periodicals, Inc. J Neurobiol 60:154,165, 2004 [source] Attenuation of the Stimulant Response to Ethanol is Associated with Enhanced Ataxia for a GABAA, but not a GABAB, Receptor AgonistALCOHOLISM, Issue 1 2009Sarah E. Holstein Background:, The ,-aminobutyric acid (GABA) system is implicated in the neurobiological actions of ethanol, and pharmacological agents that increase the activity of this system have been proposed as potential treatments for alcohol use disorders. As ethanol has its own GABA mimetic properties, it is critical to determine the mechanism by which GABAergic drugs may reduce the response to ethanol (i.e., via an inhibition or an accentuation of the neurobiological effects of ethanol). Methods:, In this study, we examined the ability of 3 different types of GABAergic compounds, the GABA reuptake inhibitor NO-711, the GABAA receptor agonist muscimol, and the GABAB receptor agonist baclofen, to attenuate the locomotor stimulant response to ethanol in FAST mice, which were selectively bred for extreme sensitivity to ethanol-induced locomotor stimulation. To determine whether these compounds produced a specific reduction in stimulation, their effects on ethanol-induced motor incoordination were also examined. Results:, NO-711, muscimol, and baclofen were all found to potently attenuate the locomotor stimulant response to ethanol in FAST mice. However, both NO-711 and muscimol markedly increased ethanol-induced ataxia, whereas baclofen did not accentuate this response. Conclusions:, These results suggest that pharmacological agents that increase extracellular concentrations of GABA and GABAA receptor activity may attenuate the stimulant effects of ethanol by accentuating its intoxicating and sedative properties. However, selective activation of the GABAB receptor appears to produce a specific attenuation of ethanol-induced stimulation, suggesting that GABAB receptor agonists may hold greater promise as potential pharmacotherapies for alcohol use disorders. [source] | |||||||||||||