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https://www.readbyqxmd.com/read/29203576/dimethoxy-etomidate-a-non-hypnotic-etomidate-analog-that-potently-inhibits-steroidogenesis
#1
Megan McGrath, Celena Ma, Douglas 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 for 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...
December 4, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29200913/developmental-changes-in-gabaa-tonic-inhibition-are-compromised-by-multiple-mechanisms-in-preadolescent-dentate-gyrus-granule-cells
#2
Sudip Pandit, Gyu Seung Lee, Jin Bong Park
The sustained tonic currents (Itonic) generated by γ-aminobutyric acid A receptors (GABAARs) 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 GABAAR α5 subunit, resulted in various Itonic in the dentate gyrus granule cells (DGGCs) of preadolescent rats...
November 2017: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/29193847/genetic-loss-of-diazepam-binding-inhibitor-in-mice-impairs-social-interest
#3
A L Ujjainwala, C D Courtney, S G Rhoads, J S Rhodes, C A Christian
Neuropsychiatric disorders in which reduced social interest is a common symptom, such as autism, depression, and anxiety, are frequently associated with genetic mutations affecting GABAergic transmission. Benzodiazepine treatment, acting via GABAA receptors, improves social interaction in male mouse models with autism-like features. The protein diazepam binding inhibitor (DBI) can act as an endogenous benzodiazepine, but a role for DBI in social behavior has not been described. Here we investigated the role of DBI in the social interest and recognition behavior of mice...
November 28, 2017: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/29167116/medullary-raphe-nuclei-activate-the-lumbosacral-defecation-center-through-the-descending-serotonergic-pathway-to-regulate-colorectal-motility-in-rats
#4
Hiroyuki Nakamori, Kiyotada Naitou, Yuuki Horii, Hiroki Shimaoka, Kazuhiro Horii, Hiroki Sakai, Akihiro Yamada, Hidemasa Furue, Takahiko Shiina, Yasutake Shimizu
Colorectal motility is regulated by two defecation centers located in the brain and spinal cord. In previous studies, we have shown that administration of serotonin into the lumbosacral spinal cord causes enhancement of colorectal motility. Since spinal serotonin is derived from neurons of the medullary raphe nuclei including the raphe magnus, raphe obscurus and raphe pallidus, we examined whether stimulation of the medullary raphe nuclei enhances colorectal motility via the lumbosacral defecation center. Colorectal pressure was recorded with a balloon in vivo in anesthetized rats...
November 22, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/29146941/developmental-excitatory-to-inhibitory-gaba-polarity-switch-is-disrupted-in-22q11-2-deletion-syndrome-a-potential-target-for-clinical-therapeutics
#5
Hayder Amin, Federica Marinaro, Davide De Pietri Tonelli, Luca Berdondini
Individuals with 22q11.2 microdeletion syndrome (22q11.2 DS) show cognitive and behavioral dysfunctions, developmental delays in childhood and risk of developing schizophrenia and autism. Despite extensive previous studies in adult animal models, a possible embryonic root of this syndrome has not been determined. Here, in neurons from a 22q11.2 DS mouse model (Lgdel (+/-)), we found embryonic-premature alterations in the neuronal chloride cotransporters indicated by dysregulated NKCC1 and KCC2 protein expression levels...
November 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29131576/pharmacological-characterization-of-3h-atpca-as-a-substrate-for-studying-the-functional-role-of-the-betaine-gaba-transporter-1-and-the-creatine-transporter
#6
Anas Al-Khawaja, Anne S Haugaard, Ales Marek, Rebekka Löffler, Louise Thiesen, Monica Santiveri, Maria Damgaard, Christoffer Bundgaard, Bente Frølund, Petrine Wellendorph
The betaine/γ-aminobutyric acid (GABA) transporter 1 (BGT1) is one of the four GABA transporters (GATs) involved in the termination of GABAergic neurotransmission. Although suggested to be implicated in seizure management, the exact functional importance of BGT1 in the brain is still elusive. This is partly owing to the lack of potent and selective pharmacological tool compounds that can be used to probe its function. We previously reported the identification of 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid (ATPCA), a selective substrate for BGT1 over GAT1/GAT3, but also an agonist for GABAA receptors...
November 13, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29129792/the-hypoxia-mimetic-protocatechuic-acid-ethyl-ester-inhibits-synaptic-signaling-and-plasticity-in-the-rat-hippocampus
#7
Sinead M Lanigan, John J O'Connor
During hypoxia a number of physiological changes occur within neurons including the stabilization of hypoxia-inducible factors (HIFs). The activity of these proteins is regulated by O2, Fe(2+), 2-OG and ascorbate-dependant hydroxylases which contain prolyl-4-hydroxylase domains (PHDs). PHD inhibitors have been widely used and have been shown to have a preconditioning and protective effect against a later and more severe hypoxic insult. In this study we have investigated the neuroprotective effects of the PHD inhibitor, protocatechuic acid ethyl ester (ethyl 3,4, dihydroxybenzoate: EDHB) as well as its effects on synaptic transmission and plasticity in the rat hippocampus using electrophysiological techniques...
November 10, 2017: Neuroscience
https://www.readbyqxmd.com/read/29093445/blood-meal-acquisition-enhances-arbovirus-replication-in-mosquitoes-through-activation-of-the-gabaergic-system
#8
Yibin Zhu, Rudian Zhang, Bei Zhang, Tongyan Zhao, Penghua Wang, Guodong Liang, Gong Cheng
Mosquitoes are hematophagous insects that carry-on and transmit many human viruses. However, little information is available regarding the common mechanisms underlying the infection of mosquitoes by these viruses. In this study, we reveal that the hematophagous nature of mosquitoes contributes to arboviral infection after a blood meal, which suppresses antiviral innate immunity by activating the GABAergic pathway. dsRNA-mediated interruption of the GABA signaling and blockage of the GABAA receptor by the specific inhibitors both significantly impaired arbovirus replication...
November 2, 2017: Nature Communications
https://www.readbyqxmd.com/read/29089046/the-novel-isoxazoline-ectoparasiticide-lotilaner-credelio%C3%A2-a-non-competitive-antagonist-specific-to-invertebrates-%C3%AE-aminobutyric-acid-gated-chloride-channels-gabacls
#9
Lucien Rufener, Vanessa Danelli, Daniel Bertrand, Heinz Sager
BACKGROUND: The isoxazolines are a novel class of parasiticides that are potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and, to a lesser extent, of inhibitory glutamate-gated chloride channels (GluCls). Lotilaner (Credelio™), a novel representative of this chemical class, is currently evaluated for its excellent ectoparasiticide properties. METHODS: In this study, we investigated the molecular mode of action and pharmacology of lotilaner...
November 1, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/28919062/progress-and-challenges-in-anti-obesity-pharmacotherapy
#10
REVIEW
Daniel H Bessesen, Luc F Van Gaal
Obesity is a serious and growing worldwide health challenge. Healthy lifestyle choices are the foundation of obesity treatment. However, weight loss can lead to physiological adaptations that promote weight regain. As a result, lifestyle treatment alone typically produces only modest weight loss that is difficult to sustain. In other metabolic diseases, pharmacotherapy is an accepted adjunct to lifestyle. Several anti-obesity drugs have been approved in the USA, European Union, Australia, and Japan including sympathomimetics, pancreatic lipase inhibitors, GABAA receptor activators, a serotonin 2C receptor agonist, opioid antagonist, dopamine-norepinephrine reuptake inhibitor, and glucagon-like peptide-1 (GLP-1) receptor agonists...
September 14, 2017: Lancet Diabetes & Endocrinology
https://www.readbyqxmd.com/read/28916137/oxytocin-induces-penile-erection-and-yawning-when-injected-into-the-bed-nucleus-of-the-stria-terminalis-involvement-of-glutamic-acid-dopamine-and-nitric-oxide
#11
Fabrizio Sanna, Jessica Bratzu, Antonio Argiolas, Maria Rosaria Melis
Oxytocin (5-100ng), but not Arg(8)-vasopressin (100ng), injected unilaterally into the bed nucleus of the stria terminalis (BNST) induces penile erection and yawning in a dose-dependent manner in male rats. The minimal effective dose was 20ng for penile erection and 5ng for yawning. Oxytocin responses were abolished not only by the oxytocin receptor antagonist d(CH2)5Tyr(Me)(2)-Orn(8)-vasotocin (1μg), but also by (+) MK-801 (1μg), an excitatory amino acid receptor antagonist of the N-methyl-d-aspartic acid (NMDA) subtype, SCH 23390 (1μg), a D1 receptor antagonist, but not haloperidol (1μg), a D2 receptor antagonist, and SMTC (40μg), an inhibitor of neuronal nitric oxide synthase, injected into the BNST 15min before oxytocin...
September 18, 2017: Hormones and Behavior
https://www.readbyqxmd.com/read/28900387/social-isolation-in-early-versus-late-adolescent-mice-is-associated-with-persistent-behavioral-deficits-that-can-be-improved-by-neurosteroid-based-treatment
#12
Andrea Locci, Philippe Geoffroy, Michel Miesch, Ayikoe-Guy Mensah-Nyagan, Graziano Pinna
Early trauma and stress exposure during a critical period of life may increase the risk of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) in adulthood. The first-choice treatment for MDD and PTSD are selective serotonin reuptake inhibitor (SSRI) antidepressants. Unfortunately, half of MDD and PTSD patients show resistance to the therapeutic effects of these drugs and more efficient treatments are essential. Both MDD and PTSD patients present reduced levels of allopregnanolone (Allo), a potent endogenous positive allosteric modulator of GABA action at GABAA receptors which are normalized by SSRIs in treatment responders...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28855287/gaba-transporters-regulate-tonic-and-synaptic-gabaa-receptor-mediated-currents-in-the-suprachiasmatic-nucleus-neurons
#13
Michael G Moldavan, Olga Cravetchi, Charles N Allen
GABA is a principal neurotransmitter in the hypothalamic suprachiasmatic nucleus (SCN) that contributes to intercellular communication between individual circadian oscillators within the SCN network and the stability and precision of the circadian rhythms. GABA transporters (GAT) regulate the extracellular GABA concentration and modulate GABAA receptor (GABAAR)-mediated currents. GABA transport inhibitors were applied to study how GABAAR-mediated currents depend on the expression and function of GAT. Nipecotic acid inhibits GABA transport and induced an inward tonic current in concentration-dependent manner during whole-cell patch clamp recordings from SCN neurons...
August 30, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28807671/selective-inhibition-of-extra-synaptic-%C3%AE-5-gabaa-receptors-by-s44819-a-new-therapeutic-agent
#14
Lori-An Etherington, Balázs Mihalik, Adrienn Pálvölgyi, István Ling, Katalin Pallagi, Szabolcs Kertész, Péter Varga, Ben G Gunn, Adam R Brown, Matthew R Livesey, Olivia Monteiro, Delia Belelli, József Barkóczy, Michael Spedding, István Gacsályi, Ferenc A Antoni, Jeremy J Lambert
In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABAAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits α5-subunit-containing GABAARs (α5-GABAARs)...
August 12, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28780039/disruption-of-5-ht2a-pdz-protein-interaction-differently-affects-the-analgesic-efficacy-of-ssri-snri-and-tca-in-the-treatment-of-traumatic-neuropathic-pain-in-rats
#15
Anne-Sophie Wattiez, Amandine Dupuis, Anne-Marie Privat, Maryse Chalus, Eric Chapuy, Youssef Aissouni, Alain Eschalier, Christine Courteix
Antidepressants remain one of the first line treatments prescribed to neuropathic pain patients despite their limited efficacy and/or their numerous side effects. More and more, pharmacotherapy for neuropathic pain has evolved towards the use of therapeutic combinations. The goal of the present study was to assess the efficacy of the combination of antidepressants - selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors-with a peptide (TAT-2ASCV) able to disrupt the interaction between serotonin type 2A (5-HT2A) receptors and associated PDZ proteins...
August 2, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28743598/decrease-in-endogenous-brain-allopregnanolone-induces-autism-spectrum-disorder-asd-like-behavior-in-mice-a-novel-animal-model-of-asd
#16
Ken Ebihara, Hironori Fujiwara, Suresh Awale, Dya Fita Dibwe, Ryota Araki, Takeshi Yabe, Kinzo Matsumoto
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABAA receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis...
July 22, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28655928/brain-activity-changes-in-a-macaque-model-of-oxaliplatin-induced-neuropathic-cold-hypersensitivity
#17
Kazuaki Nagasaka, Kazunori Yamanaka, Shinya Ogawa, Hiroyuki Takamatsu, Noriyuki Higo
The antineoplastic agent oxaliplatin induces a painful peripheral neuropathy characterized by an acute cold hypersensitivity. There is a lack of effective treatments to manage oxaliplatin-induced cold hypersensitivity which is due, in part, to a lack of understanding of the pathophysiology of oxaliplatin-induced cold hypersensitivity. Thus, brain activity in oxaliplatin-treated macaques was examined using functional magnetic resonance imaging (fMRI). Oxaliplatin treatment reduced tail withdrawal latency to a cold (10 °C) stimulus, indicating cold hypersensitivity and increased activation in the secondary somatosensory cortex (SII) and the anterior insular cortex (Ins) was observed...
June 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28635080/neuroadaptations-of-presynaptic-and-postsynaptic-gabab-receptor-function-in-the-paraventricular-nucleus-in-response-to-chronic-unpredictable-stress
#18
Yonggang Gao, Jing-Jing Zhou, Yun Zhu, Li Wang, Therese A Kosten, Xiangjian Zhang, De-Pei Li
BACKGROUND AND PURPOSE: Chronic stress impairs GABAA (GABA type A) receptor-mediated inhibition in the hypothalamic paraventricular nucleus (PVN). It is not clear whether GABAB receptor function is also altered. We hypothesize that chronic stress alters GABAB receptor function in PVN corticotrophin-releasing hormone (CRH) neurons to control hypothalamus-pituitary-adrenal axis activity. EXPERIMENTAL APPROACH: Whole-cell patch clamp recordings were made of PVN-CRH neurons expressing eGFP driven by CRH promoter in brain slices from unstressed rats and rats exposed to chronic unpredictable mild stress (CUMS)...
September 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28529139/psychopharmacology-of-combined-activation-of-the-serotonin1a-and-%C3%AF-1-receptors
#19
REVIEW
Yukio Ago, Shigeru Hasebe, Naoki Hiramatsu, Hitoshi Hashimoto, Kazuhiro Takuma, Toshio Matsuda
The selective serotonin (5-HT) reuptake inhibitors (SSRIs) are generally used for the treatment of major depressive disorders, and the 5-HT1A and σ1 receptors are considered to be targets for treatment of psychiatric disorders. Some SSRIs such as fluvoxamine have agonistic activity towards for the σ1 receptor, but it is not known whether the effect on the receptor plays a key role in the pharmacological effects. We have recently demonstrated that fluvoxamine shows an anti-anhedonic effect in picrotoxin-induced model of anxiety/depression, while the SSRI paroxetine, which have little affinity for the σ1 receptor, does not...
May 18, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28483674/the-postnatal-5-ht1a-receptor-regulates-adult-anxiety-and-depression-differently-via-multiple-molecules
#20
Chihiro Ishikawa, Takashi Shiga
Serotonin (5-HT) and the 5-HT1A receptor during development are known to modulate anxiety and depression in later life. However, the brain mechanisms linking the postnatal 5-HT system and adult behavior remain unknown. Here, we examined the effects of pharmacological 5-HT1A receptor activation during the postnatal period on anxiety and depression-like behavior in adult BALB/c male mice. To elucidate the underlying mechanisms, we measured mRNA expression of the 5-HT1A receptor, brain-derived neurotrophic factor (BDNF), GABAA receptor subunits, and AMPA receptor subunits in the medial prefrontal cortex (mPFC), amygdala, and hippocampus...
May 5, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
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