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Marwa Y Sallam, Sahar M El-Gowilly, Abdel-Galil A Abdel-Galil, Mahmoud M El-Mas
We have previously shown that cyclosporine (CSA) counteracts cardiovascular manifestations induced by endotoxemia (lipopolysaccharide, LPS) such as hypotension and cardiac autonomic dysfunction in conscious rats. In this study we investigated whether the facilitation of central γ-amino butyric acid (GABA) neurotransmission blunts these favorable influences of CSA. The LPS-CSA interaction was determined in the absence and presence of drugs that activate GABAA or GABAB receptors or elevate synaptic GABA levels in the central nervous system...
April 18, 2018: Fundamental & Clinical Pharmacology
Valentina Vengeliene, Tatiane T Takahashi, Olga A Dravolina, Irina Belozertseva, Edwin Zvartau, Anton Y Bespalov, Rainer Spanagel
RATIONALE: Preclinical studies suggest that the GABAB receptor is a potential target for treatment of substance use disorders. However, recent clinical trials report adverse effects in patients treated with the GABAB receptor agonist baclofen and even question efficacy. How can the discrepancy between preclinical and clinical findings be explained? OBJECTIVE: To test efficacy and adverse effects of baclofen and the novel GABAB positive allosteric modulator (PAM) CMPPE in rat addiction models, which were developed in accordance with DSM...
April 12, 2018: Psychopharmacology
Oswaldo Pérez, Hugo Merchant
Extensive research has described two key features of interval timing. The bias property is associated with accuracy and implies that time is overestimated for short intervals and underestimated for long intervals. The scalar property is linked to precision and states that the variability of interval estimates increases as a function of interval duration. The neural mechanisms behind these properties are not well understood. Here we implemented a recurrent neural network that mimics a cortical ensemble and includes cells that show paired-pulse facilitation and slow inhibitory synaptic currents...
April 3, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Jinqin Chen, Li Liang, Huying Ning, Fengtao Cai, Zhuguo Liu, Longxiao Zhang, Liangyi Zhou, Qiuyun Dai
α-Conotoxins (α-CTxs) are small peptides composed of 11 to 20 amino acid residues with two disulfide bridges. Most of them potently and selectively target nicotinic acetylcholine receptor (nAChR) subtypes, and a few were found to inhibit the GABAB receptor (GABAB R)-coupled N-type calcium channels (Cav2.2). However, in all of α-CTxs targeting both receptors, the disulfide connectivity arrangement "C¹-C³, C²-C⁴" is present. In this work, a novel α4/7-CTx named Lt1.3 (GCCSHPACSGNNPYFC-NH₂) was cloned from the venom ducts of Conus litteratus ( C...
March 31, 2018: Marine Drugs
John O Clarke, Nielsen Q Fernandez-Becker, Kirsten A Regalia, George Triadafilopoulos
Baclofen has been shown to decrease reflux events and increase lower esophageal sphincter pressure, yet has never established a clear role in the treatment of gastroesophageal reflux disease (GERD). Lei and colleagues have shown in a recent elegant study that baclofen reduces the frequency and initiation of secondary peristalsis and heightens esophageal sensitivity to capsaicin-mediated stimulation. These findings may help explain both the benefit of baclofen in conditions such as rumination and supragastric belching, as well as the apparent lack of benefit of baclofen and other GABAB agonists in long-term treatment of GERD...
March 29, 2018: Clinical and Translational Gastroenterology
Anjan Nibber, Edward O Mann, Philippa Pettingill, Patrick Waters, Sarosh R Irani, Dimitri M Kullmann, Angela Vincent, Bethan Lang
GABAB receptor (GABAB R) autoantibodies have been detected in the serum of immunotherapy-responsive patients with autoimmune encephalitis. This study aimed to investigate the effect of immunoglobulin G (IgG) from a patient with GABAB R antibodies on primary neuronal cultures and acute slices of entorhinal cortex. Primary hippocampal neuronal cultures were incubated with serum immunoglobulin from patients with GABAB R or AMPA receptor (AMPAR) antibodies for up to 72 h to investigate their effect on receptor surface expression...
September 2017: Epilepsia Open
Yevgen Yudin, Tibor Rohacs
Primary sensory neurons in the dorsal root ganglia and trigeminal ganglia are responsible for sensing mechanical and thermal stimuli, as well as detecting tissue damage. These neurons express ion channels that respond to thermal, mechanical, or chemical cues, conduct action potentials, and mediate transmitter release. These neurons also express a large number of G-protein coupled receptors, which are major transducers for extracellular signaling molecules, and their activation usually modulates the primary transduction pathways...
January 2018: Molecular Pain
Xiang Liu, Shaolin Liu
Neuropeptides including cholecystokinin (CCK) are important for many brain functions including sensory processing. CCK is predominantly present in a subpopulation of excitatory neurons and activation of CCK receptors is implicated in olfactory signal processing in the olfactory bulb (OB). However, cellular and circuit mechanisms underlying CCK actions in the OB remain elusive. Here we characterized CCK effects on synaptic inhibition of the principal OB output neurons mitral/tufted cells (MTCs) followed by mechanistic analyses at the circuit and cellular levels with the following findings...
March 23, 2018: Journal of Physiology
Isabella Premoli, Julia Király, Florian Müller-Dahlhaus, Carl M Zipser, Pierre Rossini, Christoph Zrenner, Ulf Ziemann, Paolo Belardinelli
BACKGROUND: Inhibition in the human motor cortex can be probed by means of paired-pulse transcranial magnetic stimulation (ppTMS) at interstimulus intervals of 2-3 ms (short-interval intracortical inhibition, SICI) or ∼100 ms (long-interval intracortical inhibition, LICI). Conventionally, SICI and LICI are recorded as motor evoked potential (MEP) inhibition in the hand muscle. Pharmacological experiments indicate that they are mediated by GABAA and GABAB receptors, respectively. OBJECTIVE/HYPOTHESIS: SICI and LICI of TMS-evoked EEG potentials (TEPs) and their pharmacological properties have not been systematically studied...
March 15, 2018: Brain Stimulation
Paula Cristina Bianchi, Paulo Eduardo Carneiro de Oliveira, Paola Palombo, Rodrigo Molini Leão, Hugo Cogo-Moreira, Cleopatra da Silva Planeta, Fábio Cardoso Cruz
BACKGROUND: The high rate of relapse to drug use remains a central challenge to treating drug addiction. In human and rat models of addiction, environmental stimuli in contexts associated with previous drug use can provoke a relapse of drug seeking. Pre-clinical studies have used the ABA renewal procedure to study context-induced reinstatement of drug seeking. In the current study, we studied the role of the orbitofrontal cortex (OFC) in context-induced reinstatement to alcohol. METHODS: We trained male and female rats to self-administer alcohol in context A, extinguished drug-reinforced responding in a distinct context B, and assessed context-induced reinstatement in context A or B (control group)...
March 2, 2018: Drug and Alcohol Dependence
Mo Chen, Maíra C Lixandrão, Cecília N Prudente, Rebekah L S Summers, Teresa J Kimberley
BACKGROUND: The extent to which short interval intracortical inhibition (SICI) responds to low-frequency repetitive transcranial magnetic stimulation (rTMS) remains inconclusive with reports of increased, decreased and unchanged response following modulation. The aim of this study was to systematically investigate if the variability of SICI following rTMS is explained by the interstimulus interval (ISI) and/or the conditioning stimulus intensity (CSI). METHODS: Two experiments with pretesting/posttesting and an rTMS session (1 Hz, 90% RMT, 900 pulses) were done...
March 22, 2018: Neuromodulation: Journal of the International Neuromodulation Society
Meng-Yi Xu, Albert H C Wong
Schizophrenia is considered primarily as a cognitive disorder. However, functional outcomes in schizophrenia are limited by the lack of effective pharmacological and psychosocial interventions for cognitive impairment. GABA (gamma-aminobutyric acid) interneurons are the main inhibitory neurons in the central nervous system (CNS), and they play a critical role in a variety of pathophysiological processes including modulation of cortical and hippocampal neural circuitry and activity, cognitive function-related neural oscillations (eg, gamma oscillations) and information integration and processing...
March 22, 2018: Acta Pharmacologica Sinica
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
Lei Liu, Wataru Ito, Alexei Morozov
Region and cell-type restricted expression of light-activated ion channels is the indispensable tool to study properties of synapses in specific circuits and to monitor synaptic alterations by various stimuli including neuromodulators and behaviors, both ex vivo and in vivo . These analyses require the light-activated proteins or viral vectors for their delivery that do not interfere with the phenomenon under study. Here, we report a case of such interference in which the high-level expression of channelrhodopsin-2 introduced in the somatostatin-positive GABAergic neurons of the dorsomedial prefrontal cortex by an adeno-associated virus vector weakens the presynaptic GABAb receptor-mediated suppression of GABA release...
April 2018: Neurophotonics
Shane D Hellyer, Sabine Albold, Taide Wang, Amy Ny Chen, Lauren T May, Katie Leach, Karen J Gregory
Numerous positive and negative allosteric modulators (PAMs and NAMs) of Class C G protein-coupled receptors (GPCRs) have been developed as valuable preclinical pharmacological tools and therapeutic agents. While many Class C GPCR allosteric modulators have undergone subtype selectivity screening, most assay paradigms have failed to perform rigorous pharmacological assessment. Utilizing mGlu5 as a representative Class C GPCR, we tested the hypothesis that allosteric modulator selectivity was based on cooperativity rather than affinity...
March 7, 2018: Molecular Pharmacology
Kiyoto Kanbara, Yoshinori Otsuki, Masahito Watanabe, Syunichi Yokoe, Yoshiaki Mori, Michio Asahi, Masashi Neo
BACKGROUND: High-grade chondrosarcoma, which has a high incidence of local recurrence and pulmonary metastasis despite surgical resection, is associated with poor prognosis. Therefore, new and effective adjuvant therapies are urgently required for this disease. Gamma-aminobutyric acid (GABA), which acts as a neurotrophic factor during nervous system development, is related to the proliferation and migration of certain cancer cells. The GABAergic system, which is composed of GABA, the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD), and GABA receptors, has an important function in nerve growth and development of neural crest...
March 7, 2018: BMC Cancer
Bojana Kokinovic, Paolo Medini
Recovery after stroke is mediated by plastic changes largely occurring in the lesion periphery. However, little is known on the microcircuit changes underlying recovery, at which extent perilesional plasticity occurs at synaptic input vs. spike output level, and on the connectivity behind such synaptic plasticity. We combined intrinsic imaging with extra- and intra-cellular recordings and pharmacological inactivation in a focal stroke in mouse somatosensory cortex (S1). In vivo whole-cell recordings in hindlimb S1 (hS1) showed synaptic responses also to forelimb stimulation in controls, and such responses were abolished by stroke of neighboring forelimb area (fS1), suggesting that in normal conditions they originate via horizontal connections from neighboring fS1...
March 5, 2018: Journal of Physiology
Sima Dameni, Atousa Janzadeh, Mahmoud Yousefifard, Farinaz Nasirinezhad
BACKGROUND: and aim: Irisin is a new myokine that is secreted by myocytes during exercise, and plays a role in creating the beneficial effects of exercise on metabolism. Considering the benefits of exercise in reducing pain, this study was carried out to determine the probable effect of irisin on neuropathic pain in the chronic constriction injury (CCI) model in male rats. METHODS: To induce neuropathic pain CCI model was used. Animals were divided into groups of control, CCI, sham, CCI + vehicle, and CCI + irisin...
February 28, 2018: Journal of Chemical Neuroanatomy
Nurul H M Yusoff, Sharif M Mansor, Christian P Müller, Zurina Hassan
Mitragynine is the major alkaloid found in the leaves of M. speciosa Korth (Rubiaceae), a plant that is native to Southeast Asia. This compound has been used, either traditionally or recreationally, due to its psychostimulant and opioid-like effects. Recently, mitragynine has been shown to exert conditioned place preference (CPP), indicating the rewarding and motivational properties of M. speciosa. Here, the involvement of GABAB receptors in mediating mitragynine reward is studied using a CPP paradigm in rats...
February 27, 2018: Behavioural Brain Research
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