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Gaba a inhibitor

Caitlin A Wotton, Elizabeth F Quon, Ashley C Palmer, Lane K Bekar
Both serotonin (5HT) and stress exert changes in cortical inhibitory tone to shape activity of cortical networks. As astrocytes are also known to affect inhibition through established purinergic pathways, we assessed the role of GABA and purinergic pathways in rapid corticosterone (CORT) and 5HT effects on cortical inhibition. We used a paired-pulse paradigm (P1 & P2) in acutely isolated mouse brain slices to evaluate changes in cortical evoked inhibition. Normally, 5HT decreases amplitude of the first pulse P1, while increasing the amplitude of P2 (increase frequency transmission)...
March 15, 2018: Journal of Neuroendocrinology
Alexander J Riordan, Ari W Schaler, Jenny Fried, Tracie A Paine, Janice E Thornton
The cognitive symptoms of schizophrenia are poorly understood and difficult to treat. Estrogens may mitigate these symptoms via unknown mechanisms. To examine these mechanisms, we tested whether increasing estradiol (E) or decreasing luteinizing hormone (LH) could mitigate short-term episodic memory loss in a phencyclidine (PCP) model of schizophrenia. We then assessed whether changes in cortical or hippocampal GABA may underlie these effects. Female rats were ovariectomized and injected subchronically with PCP...
February 27, 2018: Psychoneuroendocrinology
John Peyton Bohnsack, Benjamin A Hughes, Todd K O'Buckley, Kamyra Edokpolor, Joyce Besheer, A Leslie Morrow
Alcohol use disorders are chronic debilitating diseases characterized by severe withdrawal symptoms that contribute to morbidity and relapse. GABAA receptor (GABAA R) adaptations have long been implicated in the chronic effects of alcohol and contribute to many withdrawal symptoms associated with alcohol dependence. In rodents, GABAA R hypofunction results from decreases in Gabra1 expression, although the underlying mechanism controlling Gabra1 expression after chronic ethanol exposure is still unknown. We found that chronic ethanol exposure using either ethanol gavage or two-bottle choice voluntary access paradigms decreased Gabra1 expression and increased Hdac2 and Hdac3 expression...
February 27, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Kyle J Brymer, Erin Y Fenton, Lisa E Kalynchuk, Hector J Caruncho
Depression is a serious psychiatric disorder frequently comorbid with autoimmune disorders. Previous work in our lab has demonstrated that repeated corticosterone (CORT) injections in rats reliably increase depressive-like behavior, impair hippocampal-dependent memory, reduce the number and complexity of adult-generated neurons in the dentate gyrus, decrease hippocampal reelin expression, and alter markers of GABAergic function. We hypothesized that peripheral injections of the TNF-α inhibitor etanercept could exert antidepressant effects through a restoration of many of these neurobiological changes...
2018: Frontiers in Pharmacology
Kara R Vogel, Garrett R Ainslie, Dana C Walters, Alice McConnell, Sameer C Dhamne, Alexander Rotenberg, Jean-Baptiste Roullet, K Michael Gibson
We present an update to the status of research on succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD), a rare disorder of GABA metabolism. This is an unusual disorder featuring the accumulation of both GABA and its neuromodulatory analog, gamma-hydroxybutyric acid (GHB), and recent studies have advanced the potential clinical application of NCS-382, a putative GHB receptor antagonist. Animal studies have provided proof-of-concept that enzyme replacement therapy could represent a long-term therapeutic option...
February 19, 2018: Journal of Inherited Metabolic Disease
Chantalle Briggs, Michiru Hirasawa, Kazue Semba
Glutamate transporter 1 (GLT1) is the main astrocytic transporter that shapes glutamatergic transmission in the brain. However, whether this transporter modulates sleep/wake regulatory neurons is unknown. Using quantitative immunohistochemical analysis, we assessed perisomatic GLT1 apposition with sleep/wake neurons in the male rat following 6-h sleep deprivation (SD) or following 6-h undisturbed conditions when animals were mostly asleep (Rest). We found that SD decreased perisomatic GLT1 apposition with wake-promoting orexin (ORX) neurons in the lateral hypothalamus (LH) compared to Rest...
February 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Martin Berger, Yong Chen, Konstantina Bampali, Margot Ernst, Nuno Maulide
Classical synthetic approaches to highly unsaturated polyene/yne natural products rely on iterative cross-coupling of linear fragments. Herein, we present an expeditious and unified approach to the unsaturated backbone of polyacetylenes via domino cuprate addition/4π-electrocyclic ring opening of a stereodefined cyclobutene intermediate. This sets the stage for a detailed biological assessment of the role of Virol A and Cicutoxin as inhibitors of GABA induced chloride currents, providing further insight into the interaction of these highly potent toxins towards the GABAA receptor, including the structure-activity relationship of the derivatives...
February 7, 2018: Chemical Communications: Chem Comm
Zahra Dargaei, Jee Yoon Bang, Vivek Mahadevan, C Sahara Khademullah, Simon Bedard, Gustavo Morrone Parfitt, Jun Chul Kim, Melanie A Woodin
Huntington's disease (HD) is classically characterized as a movement disorder, however cognitive impairments precede the motor symptoms by ∼15 y. Based on proteomic and bioinformatic data linking the Huntingtin protein (Htt) and KCC2, which is required for hyperpolarizing GABAergic inhibition, and the important role of inhibition in learning and memory, we hypothesized that aberrant KCC2 function contributes to the hippocampal-associated learning and memory deficits in HD. We discovered that Htt and KCC2 interact in the hippocampi of wild-type and R6/2-HD mice, with a decrease in KCC2 expression in the hippocampus of R6/2 and YAC128 mice...
January 30, 2018: Proceedings of the National Academy of Sciences of the United States of America
Jose I Juncosa, Kenji Takaya, Hoang V Le, Matthew J Moschitto, Pathum M Weerawarna, Romila Mascarenhas, Dali Liu, Stephen L Dewey, Richard B Silverman
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. Inhibition of GABA aminotransferase (GABA-AT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme that degrades GABA, has been established as a possible strategy for the treatment of substance abuse. The raised GABA levels that occur as a consequence of this inhibition have been found to antagonize the rapid release of dopamine in the ventral striatum (nucleus accumbens) that follows an acute challenge by an addictive substance...
January 30, 2018: Journal of the American Chemical Society
Zhengchun Wang, Huan Wang, Tzvetomir Tzvetanov, Yifeng Zhou
Among the serious consequences of alcohol abuse is the reduced ability to process visual information. Diminished vision from excessive consumption of alcohol has been implicated in industrial, home, and automobile accidents. Alcohol is also generally recognized as an inhibitor in the brain by potentiating GABA-ergic transmission. In this study, we focused on visual motion processing and explored whether moderate alcohol intoxication induced changes in inhibitory mediated motion repulsion in a center-surround configuration...
January 25, 2018: Scientific Reports
Sara Valpione, Matteo S Carlino, Johanna Mangana, Meghan J Mooradian, Grant McArthur, Dirk Schadendorf, Axel Hauschild, Alexander M Menzies, Ana Arance, Paolo A Ascierto, AnnaMaria Di Giacomo, Francesco de Rosa, James Larkin, John J Park, Simone M Goldinger, Ryan J Sullivan, Wen Xu, Elisabeth Livingstone, Michael Weichenthal, Rajat Rai, Lydia Gaba, Georgina V Long, Paul Lorigan
BACKGROUND: Most metastatic melanoma patients treated with BRAF inhibitors (BRAFi) ± MEK inhibitors (MEKi) eventually progress on treatment. Along with acquired resistance due to genetic changes, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse retrospectively outcomes for patients retreated with BRAF-directed therapy. PATIENTS AND METHODS: One hundred sixteen metastatic melanoma patients who received BRAFi-based therapy and, after a break, were rechallenged with BRAFi ± MEKi at 14 centres in Europe, US and Australia were studied, respectively...
January 19, 2018: European Journal of Cancer
Cecilie Morland, Anne-Sofie Frøland, Mi Nyguyen Pettersen, Jon Storm-Mathisen, Vidar Gundersen, Frode Rise, Bjørnar Hassel
Propionic acidemia is the accumulation of propionate in blood due to dysfunction of propionyl-CoA carboxylase. The condition causes lethargy and striatal degeneration with motor impairment in humans. How propionate exerts its toxic effect is unclear. Here we show that intravenous administration of propionate causes dose-dependent propionate accumulation in the brain and transient lethargy in mice. Propionate, an inhibitor of histone deacetylase, entered GABAergic neurons, as could be seen from increased neuronal histone H4 acetylation in striatum and neocortex...
January 16, 2018: Biochemical Journal
Ankit Seth, Piyoosh A Sharma, Avanish Tripathi, Priyanka K Choubey, Pavan Srivastava, Prabhash N Tripathi, Sushant Kumar Shrivastava
BACKGROUND: Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial γ- aminobutyric acid (GABA) uptake in vitro. However nipecotic acid does not readily cross the blood-brain barrier (BBB) following peripheral administration, owing to its hydrophilic nature. OBJECTIVE: A series of substituted acetonaphthones tethered nipecotic acid derivatives were designed and synthesized with an aim to improve the lipophilicity and the blood-brain barrier (BBB) permeation...
January 15, 2018: Medicinal Chemistry
Man-Li Hu, Hong-Mei Zhu, Qiu-Lin Zhang, Jing-Jing Liu, Yi Ding, Ju-Ming Zhong, Vitaly Vodyanoy, Ming-Xing Ding
Electroacupuncture (EA) can relieve various pains. However, its mechanism in terms of the transcriptome is still not well-known. To explore the full profile of EA-induced molecular modification in the central nerve system, three twins of goats were selected for a match-paired experiment: EA stimulation (60 Hz, 30 min) and none-EA (control). Goats in the EA group showed an increased (p < 0.05) nociceptive threshold compared with the control goats. Experimental goats were sacrificed at 4 h of the experiment, and the periaqueductal grays were harvested for RNA sequencing...
December 25, 2017: International Journal of Molecular Sciences
Milena Jankowska, Justyna Rogalska, Joanna Wyszkowska, Maria Stankiewicz
Essential oils (EOs) are lipophilic secondary metabolites obtained from plants; terpenoids represent the main components of them. A lot of studies showed neurotoxic actions of EOs. In insects, they cause paralysis followed by death. This feature let us consider components of EOs as potential bioinsecticides. The inhibition of acetylcholinesterase (AChE) is the one of the most investigated mechanisms of action in EOs. However, EOs are rather weak inhibitors of AChE. Another proposed mechanism of EO action is a positive allosteric modulation of GABA receptors (GABArs)...
December 23, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Megan McGrath, Celena Ma, Douglas E Raines
Cushing's syndrome is characterized by the overproduction of adrenocortical steroids. Steroidogenesis inhibitors are mainstays of medical therapy for Cushing's syndrome; unfortunately, adverse side effects and treatment failures are common with currently available drugs. The general anesthetic induction agent etomidate is among the most potent inhibitors of adrenocortical steroidogenesis. However, its use as a treatment of Cushing's syndrome is complicated by its sedative-hypnotic activity and ability to produce myoclonus, central nervous system actions thought to be mediated by the GABAA receptor...
February 2018: Journal of Pharmacology and Experimental Therapeutics
Sudip Pandit, Gyu Seung Lee, Jin Bong Park
The sustained tonic currents (Itonic ) generated by γ-aminobutyric acid A receptors (GABAA Rs) are implicated in diverse age-dependent brain functions. While various mechanisms regulating Itonic in the hippocampus are known, their combined role in Itonic regulation is not well understood in different age groups. In this study, we demonstrated that a developmental increase in GABA transporter (GAT) expression, combined with gradual decrease in GABAA R α5 subunit, resulted in various Itonic in the dentate gyrus granule cells (DGGCs) of preadolescent rats...
November 2017: Korean Journal of Physiology & Pharmacology
Hussain N Alhamami, Ayed Alshamrani, Karen P Briski
The glucose polymer glycogen is a vital fuel reserve in the brain. The mediobasal hypothalamic energy sensor AMP-activated protein kinase (AMPK) maintains glucostasis via neurotransmitter mechanisms that suppress [ γ -aminobutyric acid; GABA] or stimulate [nitric oxide; steroidogenic factor-1 (SF1)] counter-regulatory outflow. This study investigated whether glycogen-derived fuel supply is a critical screened variable in ventromedial hypothalamic nucleus (VMN) monitoring of neuro-metabolic stability during glucostasis and/or insulin (I)-induced hypoglycemia...
December 2017: Physiological Reports
Tatiana Paschoalin-Maurin, Tayllon Dos Anjos-Garcia, Luiz Luciano Falconi-Sobrinho, Renato Leonardo de Freitas, Jade Pissamiglio Cysne Coimbra, Carlos Júlio Laure, Norberto Cysne Coimbra
Using an innovative approach to study the neural bases of psychiatric disorders, this study investigated the behavioral, morphological and pharmacological bases of panic attack-induced responses in a prey-versus-coral snake paradigm. Mesocricetus auratus was chronically treated with intraperitoneal administration of the selective serotonin uptake inhibitor paroxetine or the gamma aminobutyric acid (GABA)/benzodiazepine receptor agonist alprazolam at three different doses and were then confronted with a venomous coral snake (Micrurus frontalis, Reptilia, Elapidae)...
January 15, 2018: Neuroscience
George T Taylor, Sandra Lerch, Sabine Chourbaji
Marble burying is considered an, albeit controversial, animal model of the compulsive like behaviors of obsessive-compulsive disorder (OCD). Hallmark features of OCD patients are similarities and, more prominent, differences from anxiety disorders, e.g., the absence of sex differences and resistance to spontaneous remission. We report an experiment on marble burying by male and female C57/BL6/N mice. Animals were administered either the classic anxiolytic drug, diazepam, that targets the GABA receptor or a "pure" inhibitor of the serotonin transporter, escitalopram, that has been reported to be particularly effective in OCD...
2017: Acta Neurobiologiae Experimentalis
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