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https://www.readbyqxmd.com/read/28814463/neurobiological-correlates-of-state-dependent-context-fear
#1
Mariah A A Meyer, Kevin A Corcoran, Helen J Chen, Sonia Gallego, Guanguan Li, Veda V Tiruveedhula, James M Cook, Jelena Radulovic
Retrieval of fear memories can be state-dependent, meaning that they are best retrieved if the brain states at encoding and retrieval are similar. Such states can be induced by activating extrasynaptic γ-aminobutyric acid type A receptors (GABAAR) with the broad α-subunit activator gaboxadol. However, the circuit mechanisms and specific subunits underlying gaboxadol's effects are not well understood. Here we show that gaboxadol induces profound changes of local and network oscillatory activity, indicative of discoordinated hippocampal-cortical activity, that were accompanied by robust and long-lasting state-dependent conditioned fear...
September 2017: Learning & Memory
https://www.readbyqxmd.com/read/28782830/altered-behavioral-responses-to-gamma-aminobutyric-acid-pharmacological-agents-in-a-mouse-model-of-huntington-s-disease
#2
Yi-Ting Hsu, Ya-Gin Chang, Ching-Pang Chang, Jian-Jing Siew, Hui-Mei Chen, Chon-Haw Tsai, Yijuang Chern
BACKGROUND: Disruptions in gamma-aminobutyric (GABA) acid signaling are believed to be involved in Huntington's disease pathogenesis, but the regulation of GABAergic signaling remains elusive. Here we evaluated GABAergic signaling by examining the function of GABAergic drugs in Huntington's disease and the expression of GABAergic molecules using mouse models and human brain tissues from Huntington's disease. METHODS: We treated wild-type and R6/2 mice (a transgenic Huntington's disease mouse model) acutely with vehicle, diazepam, or gaboxadol (drugs that selectively target synaptic or extrasynaptic GABAA receptors) and monitored their locomotor activity...
August 7, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28160299/sedative-and-motor-incoordination-effects-of-ethanol-in-mice-lacking-cd14-tlr2-tlr4-or-myd88
#3
Yuri A Blednov, Mendy Black, Jillian M Benavidez, Adriana Da Costa, Jody Mayfield, R Adron Harris
BACKGROUND: In our companion article, we examined the role of MyD88-dependent signaling in ethanol (EtOH) consumption in mice lacking key components of this inflammatory pathway and observed differential effects on drinking. Here, we studied the role of these same signaling components in the acute sedative, intoxicating, and physiological effects of EtOH. Toll-like receptor 4 (TLR4) has been reported to strongly reduce the duration of EtOH-induced sedation, although most studies do not support its direct involvement in EtOH consumption...
March 2017: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/26901591/effects-of-gaboxadol-on-the-expression-of-cocaine-sensitization-in-rats
#4
Nora Siegal Silverman, Susanna Popp, Vincent Vialou, Konstantin Astafurov, Eric J Nestler, Diana Dow-Edwards
Behavioral sensitization to psychostimulants is associated with changes in dopamine (DA), glutamate, and GABA within the mesocorticolimbic and nigrostriatal DA systems. Because GABAA receptors are highly expressed within these systems, we examined the role of these receptors containing a δ subunit in cocaine behavioral sensitization. Experiment 1 examined the effects of Gaboxadol (GBX, also known as THIP [4,5,6,7-tetrahydro-isoxazolo[5,4-c]pyridin-3-ol]), a selective δ-GABAA receptor agonist, on the locomotor responses to acute cocaine...
April 2016: Experimental and Clinical Psychopharmacology
https://www.readbyqxmd.com/read/26900079/comparing-the-discriminative-stimulus-effects-of-modulators-of-gabaa-receptors-containing-%C3%AE-4-%C3%AE-subunits-with-those-of-gaboxadol-in-rats
#5
Claudio Zanettini, Jeffrey D Pressly, Miguel H Ibarra, Kelsey R Smith, Lisa R Gerak
RATIONALE: Gaboxadol is a selective agonist at γ-aminobutyric acidA (GABAA) receptors that contain α4-δ subunits, and it produces anxiolytic and sedative effects. Although adverse effects preclude its clinical use, its mechanism of action suggests that those receptors might provide novel therapeutic targets, particularly for modulators of those GABAA receptor subtypes, by retaining therapeutic effects of gaboxadol and not adverse effects. OBJECTIVES: The current study compared discriminative stimulus effects of gaboxadol with those of modulators acting at GABAA receptors containing α4-δ subunits...
May 2016: Psychopharmacology
https://www.readbyqxmd.com/read/26843648/sex-differences-in-gabaa-signaling-in-the-periaqueductal-gray-induced-by-persistent-inflammation
#6
Karen J Tonsfeldt, Katherine L Suchland, Kathleen A Beeson, Janet D Lowe, Ming-Hua Li, Susan L Ingram
UNLABELLED: The ventrolateral periaqueductal gray (vlPAG) is a key structure in the descending pain modulatory circuit. Activation of the circuit occurs via disinhibition of GABAergic inputs onto vlPAG output neurons. In these studies, we tested the hypothesis that GABAergic inhibition is increased during persistent inflammation, dampening activation of the descending circuit from the vlPAG. Our results indicate that persistent inflammation induced by Complete Freund's adjuvant (CFA) modulates GABA signaling differently in male and female rats...
February 3, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/26832169/the-interaction-of-central-nitrergic-and-gabaergic-systems-on-food-intake-in-neonatal-layer-type-chicks
#7
Kasra Mokhtarpouriani, Morteza Zendehdel, Hossein Jonaidi, Vahab Babapour, Parviz Shayan
Most physiological behaviors such as food intake are controlled by the hypothalamus and its nuclei. It has been demonstrated that injection of the paraventricular nucleus of the hypothalamus with nitric oxide (NO) donors elicited changes in the concentration of some amino acids, including GABA. Also, central nitrergic and GABAergic systems are known to provide inputs to the paraventricular nucleus and are involved in food intake control. Therefore, the present study examines the probable interaction of central nitrergic and GABAergic systems on food intake in neonatal layer-type chicks...
May 2016: Amino Acids
https://www.readbyqxmd.com/read/26631583/interaction-of-gaba-mimetics-with-the-taurine-transporter-taut-slc6a6-in-hyperosmotic-treated-caco-2-llc-pk1-and-rat-renal-skpt-cells
#8
Rune Nørgaard Rasmussen, Candela Lagunas, Jakob Plum, René Holm, Carsten Uhd Nielsen
The aim of the present study was to investigate if basic GABA-mimetics interact with the taurine transporter (TauT, Slc6a6), and to find a suitable cell based model that is robust towards extracellular changes in osmolality during uptake studies. Taurine uptake was measured in human Caco-2 cells, porcine LLC-PK1 cells, and rat SKPT cells using radiolabelled taurine. Hyperosmotic conditions were obtained by incubation with raffinose (final osmolality of 500mOsm) for 24h prior to the uptake experiments. Expression of the taurine transporter, TauT, was investigated at the mRNA level by real-time PCR...
January 20, 2016: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/26592470/flumazenil-decreases-surface-expression-of-%C3%AE-4%C3%AE-2%C3%AE-gabaa-receptors-by-increasing-the-rate-of-receptor-internalization
#9
Aarti Kuver, Sheryl S Smith
Increases in expression of α4βδ GABAA receptors (GABARs), triggered by fluctuations in the neurosteroid THP (3α-OH-5α[β]-pregnan-20-one), are associated with changes in mood and cognition. We tested whether α4βδ trafficking and surface expression would be altered by in vitro exposure to flumazenil, a benzodiazepine ligand which reduces α4βδ expression in vivo. We first determined that flumazenil (100 nM-100 μM, IC50=∼1 μM) acted as a negative modulator, reducing GABA (10 μM)-gated current in the presence of 100 nM THP (to increase receptor efficacy), assessed with whole cell patch clamp recordings of recombinant α4β2δ expressed in HEK-293 cells...
January 2016: Brain Research Bulletin
https://www.readbyqxmd.com/read/26457884/utility-of-pbpk-absorption-modeling-to-guide-modified-release-formulation-development-of-gaboxadol-a-highly-soluble-compound-with-region-dependent-absorption
#10
Filippos Kesisoglou, Anand Balakrishnan, Kimberly Manser
Given the complexity of controlled release (CR) formulations, selecting the right preclinical tools is important to enable decision making on the in vivo performance of these formulations during development. In recent years, with the advancements of absorption/physiologically based pharmacokinetic (PBPK) modeling, such computational approaches play an increasing role in guiding formulation development. Development of PBPK models for CR formulations requires additional information compared with immediate release (IR) products...
February 2016: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/26365141/advances-in-the-understanding-of-the-gabaergic-neurobiology-of-fmr1-expanded-alleles-leading-to-targeted-treatments-for-fragile-x-spectrum-disorder
#11
REVIEW
Reymundo Lozano, Veronica Martinez-Cerdeno, Randi J Hagerman
Fragile X spectrum disorder (FXSD) includes: fragile X syndrome (FXS), fragile X-associated tremor ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI), as well as other medical, psychiatric and neurobehavioral problems associated with the premutation and gray zone alleles. FXS is the most common monogenetic cause of autism (ASD) and intellectual disability (ID). The understanding of the neurobiology of FXS has led to many targeted treatment trials in FXS. The first wave of phase II clinical trials in FXS were designed to target the mGluR5 pathway; however the results did not show significant efficacy and the trials were terminated...
2015: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/26109660/enhanced-gabaa-mediated-tonic-inhibition-in-auditory-thalamus-of-rats-with-behavioral-evidence-of-tinnitus
#12
Evgeny A Sametsky, Jeremy G Turner, Deb Larsen, Lynne Ling, Donald M Caspary
Accumulating evidence suggests a role for inhibitory neurotransmitter dysfunction in the pathology of tinnitus. Opposing hypotheses proposed either a pathologic decrease or increase of GABAergic inhibition in medial geniculate body (MGB). In thalamus, GABA mediates fast synaptic inhibition via synaptic GABAA receptors (GABAARs) and persistent tonic inhibition via high-affinity extrasynaptic GABAARs. Given that extrasynaptic GABAARs control the firing mode of thalamocortical neurons, we examined tonic GABAAR currents in MGB neurons in vitro, using the following three groups of adult rats: unexposed control (Ctrl); sound exposed with behavioral evidence of tinnitus (Tin); and sound exposed with no behavioral evidence of tinnitus (Non-T)...
June 24, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/26073942/sleep-facilitates-memory-by-blocking-dopamine-neuron-mediated-forgetting
#13
Jacob A Berry, Isaac Cervantes-Sandoval, Molee Chakraborty, Ronald L Davis
Early studies from psychology suggest that sleep facilitates memory retention by stopping ongoing retroactive interference caused by mental activity or external sensory stimuli. Neuroscience research with animal models, on the other hand, suggests that sleep facilitates retention by enhancing memory consolidation. Recently, in Drosophila, the ongoing activity of specific dopamine neurons was shown to regulate the forgetting of olfactory memories. Here, we show this ongoing dopaminergic activity is modulated with behavioral state, increasing robustly with locomotor activity and decreasing with rest...
June 18, 2015: Cell
https://www.readbyqxmd.com/read/25766937/paradoxical-widespread-c-fos-expression-induced-by-a-gaba-agonist-in-the-forebrain-of-transgenic-mice-with-ectopic-expression-of-the-gaba-a-%C3%AE-6-subunit
#14
K S Hellsten, A-M Linden, E R Korpi
A GABA-site agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) at 3 mg/kg induces strong anxiolytic response in a transgenic Thy1α6 mouse line ectopically expressing the GABA(A) receptor α6 subunit gene under the Thy-1.2 promoter. Now, we compared brain activation patterns between Thy1α6 and wild-type mice to identify brain structures potentially mediating this anxiolytic response. Acutely efficient anxiolytics such as benzodiazepines typically depress most brain regions while activating specifically neurons within the central extended amygdala...
May 7, 2015: Neuroscience
https://www.readbyqxmd.com/read/25368340/n-methyl-d-aspartate-receptor-channel-blocker-like-discriminative-stimulus-effects-of-nitrous-oxide-gas
#15
Kellianne J Richardson, Keith L Shelton
Nitrous oxide (N2O) gas is a widely used anesthetic adjunct in dentistry and medicine that is also commonly abused. Studies have shown that N2O alters the function of the N-methyl-d-aspartate (NMDA), GABAA, opioid, and serotonin receptors among others. However, the receptors systems underlying the abuse-related central nervous system effects of N2O are unclear. The present study explores the receptor systems responsible for producing the discriminative stimulus effects of N2O. B6SJLF1/J male mice trained to discriminate 10 minutes of exposure to 60% N2O + 40% oxygen versus 100% oxygen served as subjects...
January 2015: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/25342197/effect-of-nucleus-accumbens-shell-infusions-of-ganaxolone-or-gaboxadol-on-ethanol-consumption-in-mice
#16
Marcia J Ramaker, Moriah N Strong-Kaufman, Matthew M Ford, Tamara J Phillips, Deborah A Finn
RATIONALE: Allopregnanolone (ALLO) is an endogenous neuroactive steroid thought to alter the reinforcement value of alcohol (ethanol) due to its actions as a positive modulator of the GABAA receptor (GABAAR). Extrasynaptic GABAARs may be a particularly sensitive target of ethanol and neuroactive steroids. Previous work showed that systemic injections of an ALLO analog, ganaxolone (GAN), or an extrasynaptic GABAAR agonist (gaboxadol; THIP) decreased ethanol intake in male mice with limited access to ethanol...
April 2015: Psychopharmacology
https://www.readbyqxmd.com/read/25258535/modulation-of-the-gabaergic-pathway-for-the-treatment-of-fragile-x-syndrome
#17
REVIEW
Reymundo Lozano, Emma B Hare, Randi J Hagerman
Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway...
2014: Neuropsychiatric Disease and Treatment
https://www.readbyqxmd.com/read/25197807/electroencephalographic-power-spectral-density-profile-of-the-orexin-receptor-antagonist-suvorexant-in-patients-with-primary-insomnia-and-healthy-subjects
#18
RANDOMIZED CONTROLLED TRIAL
Junshui Ma, Vladimir Svetnik, Ellen Snyder, Christopher Lines, Thomas Roth, W Joseph Herring
STUDY OBJECTIVES: Suvorexant, an orexin receptor antagonist, improves sleep in healthy subjects (HS) and patients with insomnia. We compared the electroencephalographic (EEG) power spectral density (PSD) profile of suvorexant with placebo using data from a phase 2 trial in patients with insomnia. We also compared suvorexant's PSD profile with the profiles of other insomnia treatments using data from 3 HS studies. DESIGN: Phase 2 trial--randomized, double-blind, two-period (4 w per period) crossover...
October 2014: Sleep
https://www.readbyqxmd.com/read/25195191/differences-between-magnetoencephalographic-meg-spectral-profiles-of-drugs-acting-on-gaba-at-synaptic-and-extrasynaptic-sites-a-study-in-healthy-volunteers
#19
RANDOMIZED CONTROLLED TRIAL
David Nutt, Sue Wilson, Anne Lingford-Hughes, Jim Myers, Andreas Papadopoulos, Suresh Muthukumaraswamy
A range of medications target different aspects of the GABA system; understanding their effects is important to inform further drug development. Effects on the waking EEG comparing these mechanisms have not been reported; in this study we compare the effects on resting MEG spectra of the benzodiazepine receptor agonist zolpidem, the delta sub-unit selective agonist gaboxadol (also known as THIP) and the GABA reuptake inhibitor tiagabine. These were two randomised, single-blind, placebo-controlled, crossover studies in healthy volunteers, one using zolpidem 10 mg, gaboxadol 15 mg and placebo, and the other tiagabine 15 mg and placebo...
January 2015: Neuropharmacology
https://www.readbyqxmd.com/read/25172951/ionotropic-gaba-and-glycine-receptor-subunit-composition-in-human-pluripotent-stem-cell-derived-excitatory-cortical-neurones
#20
Owain T James, Matthew R Livesey, Jing Qiu, Owen Dando, Bilada Bilican, Ghazal Haghi, Rinku Rajan, Karen Burr, Giles E Hardingham, Siddharthan Chandran, Peter C Kind, David J A Wyllie
We have assessed, using whole-cell patch-clamp recording and RNA-sequencing (RNA-seq), the properties and composition of GABAA receptors (GABAARs) and strychnine-sensitive glycine receptors (GlyRs) expressed by excitatory cortical neurons derived from human embryonic stem cells (hECNs). The agonists GABA and muscimol gave EC50 values of 278 μm and 182 μm, respectively, and the presence of a GABAAR population displaying low agonist potencies is supported by strong RNA-seq signals for α2 and α3 subunits. GABAAR-mediated currents, evoked by EC50 concentrations of GABA, were blocked by bicuculline and picrotoxin with IC50 values of 2...
October 1, 2014: Journal of Physiology
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