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Gabaa receptor

Sheila Sharp, Scott J Mitchell, Monique Vallée, Elena Kuzmanova, Michelle Cooper, Delia Belelli, Jeremy J Lambert, Jeffrey T-J Huang
Neurosteroids are brain-derived steroids, capable of rapidly modulating neuronal excitability in a non-genomic manner. Dysregulation of their synthesis, or metabolism has been implicated in many pathological conditions. Here, we describe an isotope dilution based targeted and non-targeted (ID-TNT) profiling of carbonyl neurosteroids/steroids. The method combines stable isotope dilution, hydroxylamine derivatization, high-resolution MS scanning and data dependent MS/MS analysis, allowing absolute quantification of pregnenolone, progesterone, 5α-dihydroprogesterone, 3α,5α-tetrahydroprogesterone and 3β,5α-tetrahydroprogesterone, and relative quantification of other carbonyl containing steroids...
March 21, 2018: Analytical Chemistry
S Meis, T Endres, T Munsch, V Lessmann
Tonic inhibition mediated by ambient levels of GABA that activate extrasynaptic GABAA receptors emerges as an essential factor that tunes neuronal network excitability in vitro and shapes behavioral responses in vivo. To address the role of neuromodulatory transmitter systems on this type of inhibition, we employed patch clamp recordings in mouse amygdala slice preparations. Our results show that the current amplitude of tonic inhibition (Itonic ) in projection neurons of the basal amygdala (BA) is increased by preincubation with the neurosteroid THDOC, while the benzodiazepine diazepam is ineffective...
March 20, 2018: Molecular Neurobiology
Chun-Kuei Su, Yi-Yin Chen, Chiu-Ming Ho
Nitric oxide (NO) is a diffusible gas and has multifarious effects on both pre- and postsynaptic events. As a consequence of complex excitatory and inhibitory integrations, NO effects on neuronal activities are heterogeneous. Using in vitro preparations of neonatal rats that retain the splanchnic sympathetic nerves and the thoracic spinal cord as an experimental model, we report here that either enhancement or attenuation of NO production in the neonatal rat spinal cords could increase, decrease, or not change the spontaneous firing behaviors recorded from splanchnic sympathetic single fibers...
2018: Frontiers in Physiology
Alan L Pehrson, Christian S Pedersen, Kirstine Sloth Tølbøl, Connie Sanchez
Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine's effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected vortioxetine's cognitive effects to those on GABA and glutamate neurotransmission...
2018: Frontiers in Pharmacology
Ki Jin Kim, Sang Nam Lee, Bong Hyo Lee
RATIONALE: Morphine is a representative pain killer. However, repeated use tends to induce addiction. Music therapy has been gaining interest as a useful type of therapy for neuropsychiatric diseases. OBJECTIVES: The present study examined whether Korean traditional music (KT) could suppress morphine-seeking behavior and anxiety-like behavior induced by extinction from chronic morphine use and additionally investigated a possible neuronal mechanism. MATERIAL & METHODS: Male Sprague-Dawley rats were trained to intravenously self-administer morphine hydrochloride (1...
March 17, 2018: Neuroscience Letters
Masato Kasagi, Tomokazu Motegi, Kosuke Narita, Kazuyuki Fujihara, Yusuke Suzuki, Minami Tagawa, Koichi Ujita, Hirotaka Shimada, Masato Fukuda
BACKGROUND: Although recent studies have suggested that the γ-aminobutyric acid type A (GABAA) receptor binding affinity can be a more sensitive marker of age-related neuronal loss than regional gray matter (GM) volume, knowledge about the relationship between decreased GABAA receptor binding affinity and cognitive decline during normal aging is still limited. METHODS: Thirty-seven healthy elderly individuals (aged 50-77 years (mean, 64.5 ± 7.3 years); 15 males and 22 females) were enrolled in this study...
March 21, 2018: International Psychogeriatrics
Hua Tao, Xu Zhou, Bin Zhao, Keshen Li
According to an update from the World Health Organization, approximately 50 million people worldwide suffer from epilepsy, and nearly one-third of these individuals are resistant to the currently available antiepileptic drugs, which has resulted in an insistent pursuit of novel strategies for seizure treatment. Recently, methylglyoxal (MG) was demonstrated to serve as a partial agonist of the gamma-aminobutyric acid type A (GABAA ) receptor and to play an inhibitory role in epileptic activities. However, MG is also a substrate in the generation of advanced glycation end products (AGEs) that function by activating the receptor of AGEs (RAGE)...
2018: Frontiers in Molecular Neuroscience
Xiaodong Li, Hiroshi Ishimoto, Azusa Kamikouchi
In birds and higher mammals, auditory experience during development is critical to discriminate sound patterns in adulthood. However, the neural and molecular nature of this acquired ability remains elusive. In fruit flies, acoustic perception has been thought to be innate. Here we report, surprisingly, that auditory experience of a species-specific courtship song in developing Drosophila shapes adult song perception and resultant sexual behavior. Preferences in the song-response behaviors of both males and females were tuned by social acoustic exposure during development...
March 20, 2018: ELife
Leila Dehestani, Nematollah Ahangar, Seyedeh Mahdieh Hashemi, Hamid Irannejad, Patrick Honarchian Masihi, Aidin Shakiba, Saeed Emami
A series of phenacyl triazole hydrazones 3 have been designed based on the hybridization of (arylalkly)triazole and aroyl hydrazone scaffolds as new anticonvulsant agents. The target compounds 3 were easily synthesized from appropriate phenacyl triazoles and aryl acid hydrazides and characterized by IR, NMR and Mass spectroscopy. The in vivo anticonvulsant evaluation of synthesized compounds by using MES and PTZ tests revealed that they are more effective in MES model respect to PTZ test. All compounds showed 33-100% protection against MES-induced seizures at the dose of 100 mg/kg...
March 7, 2018: Bioorganic Chemistry
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
Juan Francisco Rodríguez-Landa, Jonathan Cueto-Escobedo, Luis Ángel Flores-Aguilar, Gilberto Uriel Rosas-Sánchez, María de Jesús Rovirosa-Hernández, Francisco García-Orduña, Miguel Carro-Juárez
BACKGROUND: Montanoa frutescens and Montanoa grandiflora have been indistinctly used for centuries in traditional Mexican medicine for reproductive impairments, anxiety, and mood disorders. Preclinical studies support their aphrodisiac and anxiolytic properties, but their effects on mood are still unexplored. METHODS: The effects of 25 and 50 mg/kg of M frutescens and M grandiflora extracts were evaluated on days 1, 7, 14, 21, and 28 of treatment, and compared with fluoxetine (1 mg/kg) and Remotiv (7...
January 2018: J Evid Based Integr Med
Li-Yuan Chen, Maxime Lévesque, Mauro Cataldi, Massimo Avoli
The muscarinic receptor agonist carbachol (CCh) can induce activity in the theta range (4 - 15 Hz) in the entorhinal cortex (EC), but the underlying network mechanisms remain unclear. Here, we investigated the interplay between interneurons and principal cells in the EC during CCh-induced theta-like field oscillations in an in vitro brain slice preparation using tetrodes. Field oscillations at 10.1 Hz (IQR = 9.5 - 10.9 Hz) occurred during bath application of CCh (100 μM; n = 32 experiments) and were associated with single-unit (n = 189) firing...
March 10, 2018: Neuroscience
Amanda M Barkley-Levenson, Frances A Lagarda, Abraham A Palmer
BACKGROUND: Glyoxalase 1 (GLO1) is an enzyme that metabolizes methylglyoxal (MG), which is a competitive partial agonist at GABAA receptors. Inhibition of GLO1 increases concentrations of MG in the brain and decreases binge-like ethanol drinking. The present study assessed whether inhibition of GLO1, or genetic over expression of Glo1, would also alter the locomotor effects of ethanol, which might explain reduced ethanol consumption following GLO1 inhibition. We used the prototypical GABAA receptor agonist muscimol as a positive control...
March 12, 2018: Alcoholism, Clinical and Experimental Research
Pengmin Qin, Niall W Duncan, David Yen-Ting Chen, Chi-Jen Chen, Li-Kai Huang, Zirui Huang, Chien-Yuan E Lin, Christine Wiebking, Che-Ming Yang, Georg Northoff, Timothy Lane
Neural activity varies continually from moment to moment. Such temporal variability (TV) has been highlighted as a functionally specific brain property playing a fundamental role in cognition. We sought to investigate the mechanisms involved in TV changes between two basic behavioural states, namely having the eyes open (EO) or eyes closed (EC) in vivo in humans. To these ends we acquired BOLD fMRI, ASL, and [18 F]-fluoro-deoxyglucose PET in a group of healthy participants (n = 15), along with BOLD fMRI and [18 F]-flumazenil PET in a separate group (n = 19)...
March 9, 2018: Neuroscience
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
Travis T Mallard, James R Ashenhurst, K Paige Harden, Kim Fromme
GABRA2, the gene encoding the α2 subunit of the GABAA receptor, potentially plays a role in the etiology of problematic drinking, as GABRA2 genotype has been associated with subjective response to alcohol and other alcohol-related reward processes. The GABRA2 gene has also been associated with illicit drug use, but the extent to which associations with drug use are independent of associations with alcohol use remains unclear, partly because most previous research has used a cross-sectional design that cannot discriminate comorbidity at the between-person level and co-occurrence within-persons...
February 2018: Journal of Abnormal Psychology
Dilara Nemutlu Samur, Rana Arslan, Sule Aydın, Nurcan Bektas
The purpose of this study is to assess the possible anti-allodynic and antihyperalgesic effect of valnoctamide, an amide derivative of valproic acid, at the doses of 40, 70 and 100mg/kg (i.p.) in neuropathic pain model induced by chronic constriction injury in rats, by using dynamic plantar test and plantar test (Hargreaves method), and to evaluate that the possible role of certain serotonin, noradrenergic, opioid and GABAergic receptors by pre-treatment with 1mg/kg (i.p.) ketanserin, yohimbine, naloxone and 0...
March 6, 2018: European Journal of Pharmacology
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
Lih-Chu Chiou, Hsin-Jung Lee, Margot Ernst, Wei-Jan Huang, Jui-Feng Chou, Hon-Lie Chen, Akihiro Mouri, Liang-Chieh Chen, Marco Treven, Takayoshi Mamiya, Pi-Chuan Fan, Daniel E Knutson, Chris Witzigmann, James Cook, Werner Sieghart, Toshitaka Nabeshima
BACKGROUND AND PURPOSE: The pathophysiological role of α6 subunit-containing GABAA receptors (α6GABAA Rs), which are mainly expressed in cerebellar granule cells, remains unclear. Recently, we demonstrated that hispidulin, a flavonoid isolated from a local herb that remitted a patient's intractable motor tics, attenuated methamphetamine-induced hyperlocomotion in mice as a positive allosteric modulator (PAM) of cerebellar α6GABAA Rs. Here, using hispidulin and a selective α6GABAA R PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar α6GABAA Rs in disrupted prepulse inhibition (PPI), which reflects sensorimotor gating deficits manifested in several neuropsychiatric disorders...
March 8, 2018: British Journal of Pharmacology
Panos Zanos, Scott M Thompson, Ronald S Duman, Carlos A Zarate, Todd D Gould
Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites...
March 7, 2018: CNS Drugs
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