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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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Brandon M Fritz, Stephen L Boehm
Extrasynaptic GABAA receptors, often identified as those containing both α4 and δ subunits, demonstrate super-sensitivity to GABA and are involved in tonic inhibitory processes regulating activity within mesolimbocortical circuitry. Rodent studies testing the effects of the δ-subunit selective agonist Gaboxadol (THIP) on alcohol consumption have produced mixed results. The goal of this study was to determine the role of extrasynaptic GABAA receptors located in the infralimbic cortex (ILC) in the alcohol consumption of male C57BL/6J (B6) mice...
October 15, 2014: Behavioural Brain Research
Lucian Medrihan, Enrico Ferrea, Barbara Greco, Pietro Baldelli, Fabio Benfenati
Idiopathic epilepsies have frequently been linked to mutations in voltage-gated channels (channelopathies); recently, mutations in several genes encoding presynaptic proteins have been shown to cause epilepsy in humans and mice, indicating that epilepsy can also be considered a synaptopathy. However, the functional mechanisms by which presynaptic dysfunctions lead to hyperexcitability and seizures are not well understood. We show that deletion of synapsin II (Syn II), a presynaptic protein contributing to epilepsy predisposition in humans, leads to a loss of tonic inhibition in mouse hippocampal slices due to a dramatic decrease in presynaptic asynchronous GABA release...
October 2015: Cerebral Cortex
Joris C Verster, Aurora J A E van de Loo, Margaret L Moline, Thomas Roth
STUDY OBJECTIVES: Sleep maintenance problems are common, hence treatments enabling patients to fall asleep more rapidly after middle-of-the-night (MOTN) awakenings, without impairing next morning alertness, are needed. This literature review compares the effects of MOTN administration of various hypnotics on morning driving ability, a potentially dangerous daily activity under conditions of impairment. METHODS: A literature search was conducted identifying on-the-road driving studies examining the effects of MOTN administration of hypnotics on morning driving performance...
2014: Current Drug Safety
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