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https://www.readbyqxmd.com/read/28536867/suppressing-effect-of-cor659-on-alcohol-sucrose-and-chocolate-self-administration-in-rats-involvement-of-the-gabab-and-cannabinoid-cb1-receptors
#1
Paola Maccioni, Giancarlo Colombo, Irene Lorrai, Alessandro Zaru, Mauro A M Carai, Gian Luigi Gessa, Antonella Brizzi, Claudia Mugnaini, Federico Corelli
RATIONALE AND OBJECTIVES: COR659 [methyl2-(4-chlorophenylcarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate] is a new, positive allosteric modulator (PAM) of the GABAB receptor. This study evaluated whether COR659 shared with previously tested GABAB PAMs the capacity to reduce alcohol self-administration in rats. RESULTS: Treatment with non-sedative doses of COR659 (2.5, 5, and 10 mg/kg; i.p.) suppressed lever-responding for alcohol (15% v/v) in Sardinian alcohol-preferring (sP) rats under the fixed ratio (FR) 4 (FR4) and progressive ratio (PR) schedules of reinforcement; COR659 was more potent and effective than the reference GABAB PAM, GS39783...
May 24, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28534145/alterations-in-gene-expression-after-gamma-hydroxybutyric-acid-intake-a-pilot-study
#2
Lena-Maria Mehling, Annika Spottke, Anna Heidbreder, Peter Young, Burkhard Madea, Cornelius Hess, Cornelius Courts
Gamma-hydroxybutyric acid (GHB) acts as an agonist of the GABAB receptor, where GHB induces a depressant effect in the central nervous system. Besides its therapeutic application, GHB is also used as a date rape drug. However, the detection of GHB ingestion proves to be difficult due to its narrow detection window. The aim of this pilot study was to assess differential gene expressions after GHB intake to identify potential biomarkers for the detection of GHB intake. To this aim, alteration in gene expression of ALDH5A1, AKR7A2, EREG, and PEA15 was investigated via quantitative PCR (qPCR)...
May 22, 2017: International Journal of Legal Medicine
https://www.readbyqxmd.com/read/28533165/analgesic-conopeptides-targeting-g-protein-coupled-receptors-reduce-excitability-of-sensory-neurons
#3
REVIEW
Mahsa Sadeghi, Jeffrey R McArthur, Rocio K Finol-Urdaneta, David J Adams
Conotoxins (conopeptides) are a diverse group of peptides isolated from the venom of marine cone snails. Conus peptides modulate pain by interacting with voltage-gated ion channels and G protein-coupled receptors (GPCRs). Opiate drugs targeting GPCRs have long been used, nonetheless, many undesirable side effects associated with opiates have been observed including addiction. Consequently, alternative avenues to pain management are a largely unmet need. It has been shown that various voltage-gated calcium channels (VGCCs) respond to GPCR modulation...
May 19, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28510727/alternative-splicing-in-the-c-terminal-tail-of-cav2-1-is-essential-for-preventing-a-neurological-disease-in-mice
#4
Tomonori Aikawa, Takaki Watanabe, Taisuke Miyazaki, Takayasu Mikuni, Minoru Wakamori, Miyano Sakurai, Hidenori Aizawa, Nobutaka Ishizu, Masahiko Watanabe, Masanobu Kano, Hidehiro Mizusawa, Kei Watase
Alternative splicing (AS) that occurs at the final coding exon (exon 47) of the Cav2.1 voltage-gated calcium channel (VGCC) gene produces two major isoforms in the brain, MPI and MPc. These isoforms differ in their splice acceptor sites; human MPI is translated into a polyglutamine tract associated with spinocerebellar ataxia type 6 (SCA6), whereas MPc splices to an immediate stop codon, resulting in a shorter cytoplasmic tail.To gain insight into the functional role of the AS in vivo and whether modulating the splice patterns at this locus can be a potential therapeutic strategy for SCA6, here we created knockin mice that exclusively express MPc by inserting the splice-site mutation...
May 16, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28504122/gabab-receptors-and-pain
#5
REVIEW
Marzia Malcangio
Over the past three decades the research on GABAB receptor biology and pharmacology in pain processing has been a fascinating experience. Norman Bowery's fundamental discovery of the existence of the GABAB receptor has led the way to the definition of GABAB molecular mechanisms; patterns of receptor expression in the peripheral and central nervous system; GABAB modulatory functions within the pain pathways. We are now harnessing this acquired knowledge to develop innovative approaches to the therapeutic management of chronic pain through allosteric modulation of the GABAB...
May 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28491031/control-of-absence-seizures-by-the-thalamic-feed-forward-inhibition
#6
Mingming Chen, Daqing Guo, Yang Xia, Dezhong Yao
As a subtype of idiopathic generalized epilepsies, absence epilepsy is believed to be caused by pathological interactions within the corticothalamic (CT) system. Using a biophysical mean-field model of the CT system, we demonstrate here that the feed-forward inhibition (FFI) in thalamus, i.e., the pathway from the cerebral cortex (Ctx) to the thalamic reticular nucleus (TRN) and then to the specific relay nuclei (SRN) of thalamus that are also directly driven by the Ctx, may participate in controlling absence seizures...
2017: Frontiers in Computational Neuroscience
https://www.readbyqxmd.com/read/28469569/eliminating-absence-seizures-through-the-deep-brain-stimulation-to-thalamus-reticular-nucleus
#7
Zhihui Wang, Qingyun Wang
Deep brain stimulation (DBS) can play a crucial role in the modulation of absence seizures, yet relevant biophysical mechanisms are not completely established. In this paper, on the basis of a biophysical mean-field model, we investigate a typical absence epilepsy activity by introducing slow kinetics of GABAB receptors on thalamus reticular nucleus (TRN). We find that the region of spike and slow-wave discharges (SWDs) can be reduced greatly when we add the DBS to TRN. Furthermore, we systematically explore how the corresponding stimulation parameters including frequency, amplitude and positive input duration suppress the SWDs under certain conditions...
2017: Frontiers in Computational Neuroscience
https://www.readbyqxmd.com/read/28466358/differential-surface-density-and-modulatory-effects-of-presynaptic-gabab-receptors-in-hippocampal-cholecystokinin-and-parvalbumin-basket-cells
#8
Sam A Booker, Daniel Althof, Claudius E Degro, Masahiko Watanabe, Ákos Kulik, Imre Vida
The perisomatic domain of cortical neurons is under the control of two major GABAergic inhibitory interneuron types: regular-spiking cholecystokinin (CCK) basket cells (BCs) and fast-spiking parvalbumin (PV) BCs. CCK and PV BCs are different not only in their intrinsic physiological, anatomical and molecular characteristics, but also in their presynaptic modulation of their synaptic output. Most GABAergic terminals are known to contain GABAB receptors (GABABR), but their role in presynaptic inhibition and surface expression have not been comparatively characterized in the two BC types...
May 2, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/28462453/preclinical-screening-for-treatments-for-infantile-spasms-in-the-multiple-hit-rat-model-of-infantile-spasms-an-update
#9
Aristea S Galanopoulou, Wenzhu B Mowrey, Wei Liu, Qianyun Li, Oleksii Shandra, Solomon L Moshé
Infantile spasms are the typical seizures of West syndrome, an infantile epileptic encephalopathy with poor outcomes. There is an increasing need to identify more effective and better tolerated treatments for infantile spasms. We have optimized the rat model of infantile spasms due to structural etiology, the multiple-hit rat model, for therapy discovery. Here, we test three compounds administered after spasms induction in the multiple hit model for efficacy and tolerability. Specifically, postnatal day 3 (PN3) male Sprague-Dawley rats were induced by right intracerebral injections of doxorubicin and lipopolysaccharide...
May 2, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28450542/neuronal-chloride-regulation-via-kcc2-is-modulated-through-a-gabab-receptor-protein-complex
#10
Rebecca Wright, Sarah E Newey, Andrei Ilie, Winnie Wefelmeyer, Joseph V Raimondo, Rachel Ginham, R A Jeffrey Mcllhinney, Colin J Akerman
GABAB receptors are G-protein coupled receptors that mediate inhibitory synaptic actions through a series of downstream target proteins. It is increasingly appreciated that the GABAB receptor forms part of larger signalling complexes, which enable the receptor to mediate multiple different effects within neurons. Here we report that GABAB receptors can physically associate with the potassium-chloride cotransporter protein, KCC2, which sets the driving force for the chloride permeable ionotropic GABAA receptor in mature neurons...
April 27, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28449268/ventral-but-not-dorsal-hippocampus-inactivation-impairs-reward-memory-expression-and-retrieval-in-contexts-defined-by-proximal-cues
#11
Sadia Riaz, Anett Schumacher, Seyon Sivagurunathan, Matthijs Van Der Meer, Rutsuko Ito
The hippocampus (HPC) has been widely implicated in the contextual control of appetitive and aversive conditioning. However, whole hippocampal lesions do not invariably impair all forms of contextual processing, as in the case of complex biconditional context discrimination, leading to contention over the exact nature of the contribution of the HPC in contextual processing. Moreover, the increasingly well-established functional dissociation between the dorsal (dHPC) and ventral (vHPC) subregions of the HPC has been largely overlooked in the existing literature on hippocampal-based contextual memory processing in appetitively-motivated tasks...
April 27, 2017: Hippocampus
https://www.readbyqxmd.com/read/28444246/lateral-orbitofrontal-cortical-modulation-on-medial-prefrontal-cortex-amygdala-pathway-differential-regulation-of-intra-amygdala-gabaa-and-gabab-receptors
#12
Chun-Hui Chang
Background: The basolateral complex of the amygdala receives inputs from neocortical areas, including the medial prefrontal cortex (mPFC) and lateral orbitofrontal cortex (lOFC). Earlier studies have shown that lOFC activation exerts an inhibitory gating on mPFC-amygdala information flow. Here we examined the individual role of GABAA and GABAB receptors in this process. Methods: In vivo extracellular single-unit recordings were done in anesthetized rats. We searched amygdala neurons that fire in response to mPFC activation, tested lOFC gating at different delays (lOFC-mPFC delays: 25, 50, 100, 250, 500, and 1000 ms), and examined differential contribution of GABAA and GABAB receptors with iontophoresis...
April 22, 2017: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28438833/g-protein-gi1-exhibits-basal-coupling-but-not-preassembly-with-g-protein-coupled-receptors
#13
Alexey Bondar, Josef Lazar
The Gi/o protein family transduces signals from a diverse group of G protein-coupled receptors (GPCRs). The observed specificity of Gi/o-GPCR coupling and high rate of Gi/o signal transduction have been hypothesized to be enabled by existence of stable associates between Gi/o proteins and their cognate GPCRs in the inactive state (Gi/o-GPCR preassembly). To test this hypothesis, we applied the recently developed technique of two-photon polarization microscopy (2PPM) to Gαi1 subunits labeled with fluorescent proteins and four GPCRs (the α2A-adrenergic receptor (α2A-AR), γ-aminobutyric acid receptor B (GABAB), cannabinoid receptor type 1 (CB1R) and dopamine receptor type 2 (D2R))...
April 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28424564/new-developments-in-the-management-of-narcolepsy
#14
REVIEW
Vivien C Abad, Christian Guilleminault
Narcolepsy is a life-long, underrecognized sleep disorder that affects 0.02%-0.18% of the US and Western European populations. Genetic predisposition is suspected because of narcolepsy's strong association with HLA DQB1*06-02, and genome-wide association studies have identified polymorphisms in T-cell receptor loci. Narcolepsy pathophysiology is linked to loss of signaling by hypocretin-producing neurons; an autoimmune etiology possibly triggered by some environmental agent may precipitate hypocretin neuronal loss...
2017: Nature and Science of Sleep
https://www.readbyqxmd.com/read/28424220/gababr-induced-egfr-transactivation-promotes-migration-of-human-prostate-cancer-cells
#15
Shuai Xia, Cong He, Yini Zhu, Suyun Wang, Huiping Li, Zhongling Zhang, Xinnong Jiang, Jianfeng Liu
G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABAB receptor (GABABR) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABABR has been detected in human cancer tissues and cancer cell lines, but the role of GABABR in these cells is controversial and the underlying mechanism remains poorly understood. Here, we investigated whether GABABR hijacks RTK signaling to modulate the fates of human prostate cancer cells...
April 19, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28419642/nicotine-induced-molecular-alterations-are-modulated-by-gabab-receptor-activity
#16
Andres P Varani, Valeria T Pedrón, Amira J Aon, Christian Höcht, Gabriela B Acosta, Bernhard Bettler, Graciela N Balerio
It has been demonstrated that GABAB receptors modulate nicotine (NIC) reward effect; nevertheless, the mechanism implicated is not well known. In this regard, we evaluated the involvement of GABAB receptors on the behavioral, neurochemical, biochemical and molecular alterations associated with the rewarding effects induced by NIC in mice, from a pharmacological and genetic approach. NIC-induced rewarding properties (0.5 mg/kg, subcutaneously, sc) were evaluated by conditioned place preference (CPP) paradigm...
April 17, 2017: Addiction Biology
https://www.readbyqxmd.com/read/28419057/gabaergic-modulation-of-noradrenaline-release-caused-by-blood-pressure-changes-in-the-rat-median-preoptic-area
#17
Makoto Takahashi, Junichi Tanaka
Experiments using in-vivo microdialysis methods were conducted to investigate whether blood pressure changes cause an alteration in the release of noradrenaline (NA) in the median preoptic nucleus (MnPO) and whether the γ-aminobutyric acid (GABA) receptor mechanism is involved in the modulation of the pressure response-induced alteration in the NA release. In urethane-anesthetized male rats, intravenous administration of metaraminol, an α-agonist, significantly produced an increase in dialysate NA concentration in the MnPO area accompanied by an elevation in the mean arterial pressure (MAP)...
June 14, 2017: Neuroreport
https://www.readbyqxmd.com/read/28416021/effects-of-gabab-receptors-in-the-insula-on-recognition-memory-observed-with-intellicage
#18
Nan Wu, Feng Wang, Zhe Jin, Zhen Zhang, Lian-Kun Wang, Chun Zhang, Tao Sun
BACKGROUND: Insular function has gradually become a topic of intense study in cognitive research. Recognition memory is a commonly studied type of memory in memory research. GABABR has been shown to be closely related to memory formation. In the present study, we used intellicage, which is a new intelligent behavioural test system, and a bilateral drug microinjection technique to inject into the bilateral insula, to examine the relationship between GABABR and recognition memory. METHODS: Male Sprague-Dawley rats were randomly divided into control, Sham, Nacl, baclofen and CGP35348 groups...
April 17, 2017: Behavioral and Brain Functions: BBF
https://www.readbyqxmd.com/read/28400257/phase-amplitude-coupled-persistent-theta-and-gamma-oscillations-in-rat-primary-motor-cortex-in%C3%A2-vitro
#19
Nicholas W Johnson, Mazhar Özkan, Adrian P Burgess, Emma J Prokic, Keith A Wafford, Michael J O'Neill, Stuart D Greenhill, Ian M Stanford, Gavin L Woodhall
In vivo, theta (4-7 Hz) and gamma (30-80 Hz) neuronal network oscillations are known to coexist and display phase-amplitude coupling (PAC). However, in vitro, these oscillations have for many years been studied in isolation. Using an improved brain slice preparation technique we have, using co-application of carbachol (10 μM) and kainic acid (150 nM), elicited simultaneous theta (6.6 ± 0.1 Hz) and gamma (36.6 ± 0.4 Hz) oscillations in rodent primary motor cortex (M1). Each oscillation showed greatest power in layer V...
April 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28395176/the-ketogenic-diet-metabolite-beta-hydroxybutyrate-%C3%AE-hb-reduces-incidence-of-seizure-like-activity-sla-in-a-katp-and-gabab-dependent-manner-in-a-whole-animal-drosophila-melanogaster-model
#20
Jinglu Li, Emma I O'Leary, Geoffrey R Tanner
The high-fat, low-carbohydrate ketogenic diet (KD) is an effective clinical treatment for epilepsy in juveniles, especially for drug-resistant seizures. The KD results in elevated production of ketone bodies (KB's), such as beta-hydroxybutyrate (β-HB), which are thought to have anticonvulsant properties; however, their exact mechanism of action is unknown. In vitro, KB effects on reducing neuronal firing rates are mediated in part by Katp channel activity and GABAb signaling. In order to study metabolic and pharmacological effects in a whole-animal model, we used the eas "bang-sensitive" (BS) mutant strain of Drosophila, which exhibits seizure-like activity (SLA) upon mechanical stimulation...
April 5, 2017: Epilepsy Research
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