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Neuropharmacology

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https://www.readbyqxmd.com/read/28527758/modulation-of-cb1-cannabinoid-receptor-by-allosteric-ligands-pharmacology-and-therapeutic-opportunities
#1
REVIEW
Leepakshi Khurana, Ken Mackie, Daniele Piomelli, Debra A Kendall
Cannabinoid pharmacology has been intensely studied because of cannabis' pervasive medicinal and non-medicinal uses as well as for the therapeutic potential of cannabinoid-based drugs for the treatment of pain, anxiety, substance abuse, obesity, cancer and neurodegenerative disorders. The identification of allosteric modulators of the cannabinoid receptor 1 (CB1) has given a new direction to the development of cannabinoid-based therapeutics due to the many advantages offered by targeting allosteric site(s)...
May 17, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28526611/alcohol-induces-input-specific-aberrant-synaptic-plasticity-in-the-rat-dorsomedial-striatum
#2
Tengfei Ma, Britton Barbee, Xuehua Wang, Jun Wang
Accumulated evidence suggests that the dorsomedial striatum (DMS) of the basal ganglia plays an essential role in pathological excessive alcohol consumption. The DMS receives multiple glutamatergic inputs. However, whether and how alcohol consumption distinctly affects these excitatory afferents to the DMS remains unknown. Here, we used optogenetics to selectively activate the rat medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) inputs in DMS slices, and measured the effects of alcohol consumption on glutamatergic transmission in these corticostriatal and amygdalostriatal circuits...
May 16, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28526610/11-12-epoxyeicosatrienoic-acid-11-12-eet-reduces-excitability-and-excitatory-transmission-in-the-hippocampus
#3
Nandkishor K Mule, Anette C Orjuela Leon, John R Falck, Michael Arand, Anne Marowsky
Recent studies suggest a role for the arachidonic acid-derived epoxyeicosatrienoic acids (EETs) in attenuating epileptic seizures. However, their effect on neurotransmission has never been investigated in detail. Here, we studied how 11,12- and 14,15 EET affect excitability and excitatory neurotransmission in mouse hippocampus. 11,12 EET (2 μM), but not 14,15 EET (2 μM), induced the opening of a hyperpolarizing K(+) conductance in CA1 pyramidal cells. This action could be blocked by BaCl2, the G protein blocker GDPβ-S and the GIRK1/4 blocker tertiapin Q and the channel was thus identified as a GIRK channel...
May 16, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28526609/effects-of-l-dopa-benserazide-co-treatment-on-colonic-excitatory-cholinergic-motility-and-enteric-inflammation-following-dopaminergic-nigrostriatal-neurodegeneration
#4
C Pellegrini, L Antonioli, R Colucci, E Tirotta, D Gentile, C Ippolito, C Segnani, G Levandis, S Cerri, R F Blandini, E Barocelli, V Ballabeni, N Bernardini, C Blandizzi, M Fornai
INTRODUCTION: The mainstay therapy for Parkinson's disease (PD) relies on L-3,4- dihydroxyphenylalanine (L-DOPA) plus a DOPA-decarboxylase inhibitor. However, their effects on colonic dysmotility and inflammation observed in PD are undetermined. This study examined the effects of L-DOPA plus benserazide (BE) on colonic motility and inflammation in rats with central nigrostriatal dopaminergic denervation. METHODS: Neurodegeneration was induced by 6-hydroxydopamine (6-OHDA) injection into the median forebrain bundle (MFB)...
May 16, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28522313/neurotensin-in-the-nucleus-accumbens-reverses-dopamine-supersensitivity-evoked-by-antipsychotic-treatment
#5
Alice Servonnet, Ellie-Anna Minogianis, Claude Bouchard, Anne-Marie Bédard, Daniel Lévesque, Pierre-Paul Rompré, Anne-Noël Samaha
Long-term exposure to antipsychotics like haloperidol can increase sensitivity to dopamine agonist stimulation. This could contribute to treatment failure and increase relapse to psychosis. Chronic antipsychotic treatment elevates neurotensin levels in the nucleus accumbens (NAc), where the neuropeptide modulates dopamine function by signalling through NTS1 receptors. We hypothesized that increasing neurotensin activity in the NAc attenuates the expression of antipsychotic-induced dopamine supersensitivity, which is indicated by a potentiated psychomotor response to amphetamine...
May 15, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28504123/erythropoietin-and-small-molecule-agonists-of-the-tissue-protective-erythropoietin-receptor-increase-fxn-expression-in-neuronal-cells-in-vitro-and-in-fxn-deficient-kiko-mice-in-vivo
#6
James L Miller, Myriam Rai, Normand L Frigon, Massimo Pandolfo, Juha Punnonen, Jeffrey R Spencer
Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease caused by reduced levels of the mitochondrial protein frataxin (FXN). Recombinant human erythropoietin (rhEPO) increased FXN protein in vitro and in early clinical studies, while no published reports evaluate rhEPO in animal models of FRDA. STS-E412 and STS-E424 are novel small molecule agonists of the tissue-protective, but not the erythropoietic EPO receptor. We find that rhEPO, STS-E412 and STS-E424 increase FXN expression in vitro and in vivo...
May 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28504122/gabab-receptors-and-pain
#7
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/28495376/gabaa-receptor-positive-allosteric-modulators-modify-the-abuse-related-behavioral-and-neurochemical-effects-of-methamphetamine-in-rhesus-monkeys
#8
Laís F Berro, Monica L Andersen, Sergio Tufik, Leonard L Howell
GABAA receptor positive allosteric modulators (GABAA receptor modulators) are commonly used for the treatment of insomnia. Nevertheless, the effects of these compounds on psychostimulant-induced sleep impairment are poorly understood. Because GABAA receptor modulators have been shown to decrease the abuse-related effects of psychostimulants, the aim of the present study was to evaluate the effects of temazepam (0.3, 1.0 or 3.0 mg/kg) and eszopiclone (0.3, 1.0 or 3.0 mg/kg), two GABAA receptor modulators, on the behavioral neuropharmacology of methamphetamine in adult rhesus macaques (n = 5)...
May 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28495375/methylene-blue-stimulates-substrate-level-phosphorylation-catalysed-by-succinyl-coa-ligase-in-the-citric-acid-cycle
#9
T Komlódi, L Tretter
Methylene blue (MB), a potential neuroprotective agent, is efficient in various neurodegenerative disease models. Beneficial effects of MB have been attributed to improvements in mitochondrial functions. Substrate-level phosphorylation (SLP) results in the production of ATP independent from the ATP synthase (ATP-ase). In energetically compromised mitochondria, ATP produced by SLP can prevent the reversal of the adenine nucleotide translocase and thus the hydrolysis of glycolytic ATP. The aim of the present study was to investigate the effect of MB on mitochondrial SLP catalysed by succinyl-CoA ligase...
May 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28495374/metyrapone-prevents-brain-damage-induced-by-status-epilepticus-in-the-rat-lithium-pilocarpine-model
#10
Luis García-García, Ahmed A Shiha, Rubén Fernández de la Rosa, Mercedes Delgado, Ágata Silván, Pablo Bascuñana, Jens P Bankstahl, Francisca Gomez, Miguel A Pozo
The status epilepticus (SE) induced by lithium-pilocarpine is a well characterized rodent model of the human temporal lobe epilepsy (TLE) which is accompanied by severe brain damage. Stress and glucocorticoids markedly contribute to exacerbate neuronal damage induced by seizures but the underlying mechanisms are poorly understood. Herein we sought to investigate whether a single administration of metyrapone (150 mg/kg, i.p.), an 11β-hydroxylase inhibitor, enzyme involved in the peripheral and central synthesis of corticosteroids, had neuroprotective properties in this model...
May 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28495373/amyloid-beta-neurotoxicity-and-clearance-are-both-regulated-by-glial-group-ii-metabotropic-glutamate-receptors
#11
Daniela Durand, Lila Carniglia, Juan Turati, Delia Ramírez, Julieta Saba, Carla Caruso, Mercedes Lasaga
Astrocytes are now fully endorsed as key players in CNS functionality and plasticity. We recently showed that metabotropic glutamate receptor 3 (mGlu3R) activation by LY379268 promotes non-amyloidogenic cleavage of amyloid precursor protein (APP) in cultured astrocytes, leading to increased release of neuroprotective sAPPα. Furthermore, mGlu3R expression is reduced in hippocampal astrocytes from PDAPP-J20 mice, suggesting a role for these receptors in Alzheimer's disease. The present study enquires into the role of astroglial-derived neurotrophins induced by mGlu3R activation in neurotoxicity triggered by amyloid β (Aβ)...
May 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28487067/selective-and-interactive-effects-of-d2-receptor-antagonism-and-positive-allosteric-mglur4-modulation-on-waiting-impulsivity
#12
Sarah N Isherwood, Trevor W Robbins, Janet R Nicholson, Jeffrey W Dalley, Anton Pekcec
BACKGROUND: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity...
May 6, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28483393/activation-of-5-ht7-receptors-reverses-nmda-r-dependent-ltd-by-activating-pka-in-medial-vestibular-neurons
#13
Yan-Hai Li, Lei Han, Kenneth Lap-Kei Wu, Ying-Shing Chan
The medial vestibular nucleus (MVN) is a major output station for neurons that project to the vestibulo-spinal pathway. MVN neurons show capacity for long-term depression (LTD) during the juvenile period. We investigated LTD of MVN neurons using whole-cell patch-clamp recordings. High frequency stimulation (HFS) robustly induced LTD in 90% of type B neurons in the MVN, while only 10% of type A neurons were responsive, indicating that type B neurons are the major contributors to LTD in the MVN. The neuromodulator serotonin (5-HT) is known to modulate LTD in neural circuits of the cerebral cortex and the hippocampus...
May 5, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28479397/locomotor-sensitization-to-intermittent-ketamine-administration-is-associated-with-nucleus-accumbens-plasticity-in-male-and-female-rats
#14
C E Strong, K J Schoepfer, A M Dossat, S K Saland, K N Wright, M Kabbaj
Clinical evidence suggests superior antidepressant response over time with a repeated, intermittent ketamine treatment regimen as compared to a single infusion. However, the club drug ketamine is commonly abused. Therefore, the abuse potential of repeated ketamine injections at low doses needs to be investigated. In this study, we investigated the abuse potential of repeated exposure to either 0, 2.5, or 5 mg/kg ketamine administered once weekly for seven weeks. Locomotor activity and conditioned place preference (CPP) were assayed to evaluate behavioral sensitization to the locomotor activating effects of ketamine and its rewarding properties, respectively...
May 4, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28479396/trpc6-mediated-erk1-2-phosphorylation-prevents-dentate-granule-cell-degeneration-via-inhibiting-mitochondrial-elongation
#15
Ah-Reum Ko, Tae-Cheon Kang
Transient receptor potential canonical channel-6 (TRPC6) is one of Ca(2+)-permeable non-selective cation channels. In the rat hippocampus, TRPC6 expression is predominantly observed in dentate granule cells (DGC) rather than other hippocampal components. Interestingly, TRPC6 knockdown results in the massive DGC degeneration following status epilepticus (SE), although DGC is one of the resistant neuronal populations to various harmful stresses. However, the molecular events underlying the DGC degeneration induced by TRPC6 knockdown are still unclear...
May 4, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28479395/effects-of-acute-alcohol-on-excitability-in-the-cns
#16
REVIEW
Neil L Harrison, Mary Jane Skelly, Emma P Grosserode, Daniel C Lowes, Tamara Zeric, Sara Phister, Michael C Salling
Alcohol has many effects on brain function and hence on human behavior, ranging from anxiolytic and mild disinhibitory effects, sedation and motor incoordination, amnesia, emesis, hypnosis and eventually unconsciousness. In recent years a variety of studies have shown that acute and chronic exposure to alcohol can modulate ion channels that regulate excitability. Modulation of intrinsic excitability provides another way in which alcohol can influence neuronal network activity, in addition to its actions on synaptic inputs...
May 4, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28479394/ampk-contributes-to-aerobic-exercise-induced-antinociception-downstream-of-endocannabinoids
#17
Tanya S King-Himmelreich, Christine V Möser, Miriam C Wolters, Julia Schmetzer, Yannik Schreiber, Nerea Ferreirós, Otto Q Russe, Gerd Geisslinger, Ellen Niederberger
Physical exercise has been repeatedly associated with decreased nociceptive responses but the underlying mechanisms have still not been fully clarified. In this study, we investigated exercise-induced effects after a single bout of treadmill running on the mouse model of formalin-induced inflammatory nociception. As potential molecular mediators, we focused on endogenous endocannabinoids as well as AMP-activated protein kinase (AMPK). Our results showed that wild type mice display a reduced nociceptive response in the formalin test after treadmill running, while exercise had no effect on inflammatory nociception in AMPKα2 knockout mice...
May 4, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28476644/autoantibody-mediated-diseases-of-the-cns-structure-dysfunction-and-therapy
#18
REVIEW
James Varley, Jennifer Taylor, Sarosh R Irani
The field of neuronal autoantibody associated diseases of the central nervous system has expanded dramatically in the last few years. The range of identified neuronal and glial antibody targets has led to the accurate classification of a number of syndromes which each associate with characteristic clinical features. These diseases are especially important due to their frequent response to immunotherapies. Antibodies against the N-methyl, d-aspartate receptor (NMDAR) and leucine-rich glioma inactivated 1 (LGI1) are the commonest autoantibodies known in patients with autoimmune forms of encephalitis...
May 3, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28476643/in-vivo-assessment-of-neurological-channelopathies-application-of-peripheral-nerve-excitability-studies
#19
REVIEW
Susan E Tomlinson, James Howells, David Burke
With the rapid evolution of understanding of neurological channelopathies comes a need for sensitive tools to evaluate patients in clinical practice. Neurological channelopathies with a single-gene basis can manifest as seizures, headache, ataxia, vertigo, confusion, weakness and neuropathic pain and it is likely that other genetic factors contribute to the phenotype of many of these disorders. Ion channel dysfunction can result in abnormal cell membrane excitability but utilisation of advanced neurophysiology techniques has lagged behind developments in clinical, genetic and imaging evaluation of channelopathies...
May 2, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28476642/properties-of-the-corticostriatal-long-term-depression-induced-by-medial-prefrontal-cortex-high-frequency-stimulation-in%C3%A2-vivo
#20
Barbara Y Braz, Juan E Belforte, M Gustavo Murer, Gregorio L Galiñanes
Repetitive stimulation of cognitive forebrain circuits at frequencies capable of inducing corticostriatal long term plasticity is increasingly being used with therapeutic purposes in patients with neuropsychiatric disorders. However, corticostriatal plasticity is rarely studied in the intact brain. Our aim was to study the mechanisms of corticostriatal long term depression (LTD) induced by high frequency stimulation (HFS) of the medial prefrontal cortex in vivo. Our main finding is that the LTD induced in the dorsomedial striatum by medial prefrontal cortex HFS in vivo (prefrontostriatal LTD) is not affected by manipulations that block or reduce the LTD induced in the dorsolateral striatum by motor cortex HFS in brain slices, including pharmacological dopamine receptor and CB1 receptor blockade, chronic nigrostriatal dopamine depletion, CB1 receptor genetic deletion and selective striatal cholinergic interneuron (SCIN) ablation...
May 2, 2017: Neuropharmacology
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