scholarly journals Antagonism of GluK1-containing Kainate Receptors Reduces Ethanol Consumption by Modulating Ethanol Reward and Withdrawal

2021 ◽  
Author(s):  
Natalia Quijano-Carde' ◽  
Erika E. Perez ◽  
Richard Feinn ◽  
Henry R. Kranzler ◽  
Mariella De Biasi
Keyword(s):  
Association Studies ◽  
Genetic Association Studies ◽  
Ethanol Consumption ◽  
In Vivo Microdialysis ◽  
Ethanol Withdrawal ◽  
Kainate Receptors ◽  
Dependent Manner ◽  
Receptor System ◽  
Acute Ethanol

Alcohol use disorder (AUD) is a neuropsychiatric condition affecting millions of people worldwide. Topiramate (TPM) is an antiepileptic drug that has been shown to reduce ethanol drinking in humans. However, TPM is associated with a variety of adverse effects due to its interaction with many receptor systems and intracellular pathways. Thus, a better understanding of the role of TPM's main molecular targets in AUD could yield better therapeutic tools. GluK1-containing kainate receptors (GluK1*KARs) are non-selectively inhibited by TPM, and genetic association studies suggest that this receptor system could be targeted to reduce drinking in AUD patients. We examined the efficacy of LY466195, a selective inhibitor of GluK1*KAR, in reducing ethanol consumption in the intermittent two-bottle choice paradigm in mice. The effect of LY466195 on various ethanol-related phenotypes was investigated by quantification of alcohol intake, physical signs of withdrawal, conditioned place preference (CPP) and in vivo microdialysis in the nucleus accumbens. Selective GluK1*KAR inhibition reduced ethanol intake and preference in a dose-dependent manner. LY466195 treatment attenuated the physical manifestations of ethanol withdrawal and influenced the rewarding properties of ethanol. Interestingly, LY466195 injection also normalized changes in dopamine levels in response to acute ethanol in ethanol-dependent mice, but had no effect in ethanol-naive mice, suggesting ethanol state-dependent effects. The data point to GluK1*KARs as an attractive pharmacological target for the treatment of AUD.

scholarly journals (R)-Ketamine Induces a Greater Increase in Prefrontal 5-HT Release Than (S)-Ketamine and Ketamine Metabolites via an AMPA Receptor-Independent Mechanism

2019 ◽  
Vol 22 (10) ◽  
pp. 665-674 ◽  
Author(s):  
Yukio Ago ◽  
Wataru Tanabe ◽  
Momoko Higuchi ◽  
Shinji Tsukada ◽  
Tatsunori Tanaka ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Ampa Receptor ◽  
Dopamine Release ◽  
Molecular Mechanisms ◽  
In Vivo Microdialysis ◽  
Serotonin Release ◽  
Dependent Manner ◽  
Independent Mechanism ◽  
Dose Dependent

Abstract Background Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites is not fully understood. In view of the involvement of mechanisms other than the N-methyl-D-aspartate receptor in ketamine’s action, we investigated the effects of (R)-ketamine, (S)-ketamine, (R)-norketamine [(R)-NK], (S)-NK, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], and (2S,6S)-HNK on monoaminergic neurotransmission in the prefrontal cortex of mice. Methods The extracellular monoamine levels in the prefrontal cortex were measured by in vivo microdialysis. Results (R)-Ketamine and (S)-ketamine acutely increased serotonin release in a dose-dependent manner, and the effect of (R)-ketamine was greater than that of (S)-ketamine. In contrast, (S)-ketamine caused a robust increase in dopamine release compared with (R)-ketamine. Both ketamine enantiomers increased noradrenaline release, but these effects did not differ. (2R,6R)-HNK caused a slight but significant increase in serotonin and noradrenaline but not dopamine release. (S)-NK increased dopamine and noradrenaline but not serotonin release. Differential effects between (R)-ketamine and (S)-ketamine were also observed in a lipopolysaccharide-induced model of depression. An α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4- tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), attenuated (S)-ketamine-induced, but not (R)-ketamine-induced serotonin release, whereas NBQX blocked dopamine release induced by both enantiomers. Local application of (R)-ketamine into the prefrontal cortex caused a greater increase in prefrontal serotonin release than that of (S)-ketamine. Conclusions (R)-Ketamine strongly activates the prefrontal serotonergic system through an AMPA receptor-independent mechanism. (S)-Ketamine-induced serotonin and dopamine release was AMPA receptor-dependent. These findings provide a neurochemical basis for the underlying pharmacological differences between ketamine enantiomers and their metabolites.

The mechanism of low molecular weight heparin (LMWH) inhibition of tumor growth

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13093-13093 ◽  
Author(s):  
S. L. Smiley ◽  
D. O. Henry ◽  
M. K. Wong
Keyword(s):  
Endothelial Cells ◽  
Tumor Growth ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Receptor System ◽  
Fgf Receptor ◽  
Tumor Inhibition ◽  
Inhibition Of Tumor Growth

13093 Background: Clinical studies show that LMWHs improve survival in cancer patients. There is compelling and mounting evidence that non-anticoagulation factors are at play, and that these may be contributing in a major way to improved patient outcome. Methods and Results: Dalteparin, enoxaparin, and tinzaparin were tested for their in vivo ability to inhibit tumor lines engineered for aggressive angiogenesis-driven growth. Therapeutic daily doses of drug administered the day following tumor inoculation resulted in significant angiogenesis and tumor inhibition. We previously showed that LMWHs inhibit fibroblast growth factor (FGF) -induced mitogenesis of Tumor Derived Endothelial Cells (TDECs) in a time and concentration dependent manner in vitro. We now show that this endothelial inhibition occurs through LMWHs-mediated reduction of phosphorylation and down stream signaling through ERK. The potency of LMWH was significantly reduced when TDECs were pretreated with heparinase- suggesting that the molecular target for LMWH may be the cell surface, low affinity FGF receptor system. Both our in vivo and in vitro studies demonstrate that angiogenesis and tumor inhibition are greatest for dalteparin > tinzaparin > enoxaparin. Clues to the heparin-TDECs interaction comes from tracking the real-time movement of FGF using a highly fluorescent nanocrystal bead decorated on its surface with FGF. High resolution video-microscopy shows FGF binding onto TDEC surfaces, but once heparin enters the environment, FGF detaches from the TDECs and migrates to the heparin. This ultimately results in significant TDEC growth inhibition as compared to controls. Conclusion: LMWH treatment at pharmacologic doses significantly blunts tumor growth and angiogenesis. This inhibition resides in part via heparin’s ability to sequester FGF from the low affinity receptor system on tumor endothelial cells. No significant financial relationships to disclose.

Effects of acute ethanol on opioid peptide release in the central amygdala: an in vivo microdialysis study

2008 ◽  
Vol 201 (2) ◽  
pp. 261-271 ◽  
Author(s):  
Minh P. Lam ◽  
Peter W. Marinelli ◽  
Li Bai ◽  
Christina Gianoulakis
Keyword(s):  
Opioid Peptide ◽  
In Vivo Microdialysis ◽  
Central Amygdala ◽  
Peptide Release ◽  
Acute Ethanol ◽  
Microdialysis Study

scholarly journals Solitary Nitric Oxide Signaling Mediates Mild Stress-Induced Anxiety and Norepinephrine Release in the Bed Nucleus of the Stria Terminalis during Protracted Ethanol Withdrawal

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Zhenglin Zhao ◽  
Sang Chan Kim ◽  
Yu Jiao ◽  
Yefu Wang ◽  
Bong Hyo Lee ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Elevated Plus Maze ◽  
In Vivo Microdialysis ◽  
Ethanol Withdrawal ◽  
Mild Stress ◽  
Stria Terminalis ◽  
Bed Nucleus ◽  
Nitric Oxide Signaling ◽  
Plus Maze

Ethanol withdrawal (EtOHW) alters the pattern of neurohormonal and behavioral response toward internal and external stimuli, which mediates relapse to alcohol use even after a long period of abstinence. Increased noradrenergic signaling from the nucleus tractus solitarius (NTS) to the bed nucleus of the stria terminalis (BNST) during EtOHW underlies withdrawal-induced anxiety, while nitric oxide synthase (NOS) inhibitors injected into the periaqueductal area attenuate EtOHW-induced anxiety. Therefore, this study investigated the involvement of NOS within the NTS in anxiety and increased norepinephrine (NE) release in the BNST during protracted EtOHW in rats exposed to a mild stress. Rats were intraperitoneally administered 3 g/kg/day EtOH for 21 days followed by 28 days of withdrawal, and on the 28th day of withdrawal, the rats were subjected to restraint stress for 7 minutes. The elevated plus maze test was employed to evaluate anxiety-like behavior in rats, and in vivo microdialysis was used to measure the extracellular NE level in the BNST. In elevated plus maze tests, EtOHW rats but not EtOH-naive rats exhibited anxiety-like behavior when challenged with 7-minute mild restraint stress, which was, respectively, mitigated by prior intra-NTS infusion of the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME), or selective neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI). Each of these agents also decreased the plasma corticosterone levels in EtOHW rats. In in vivo microdialysis, prior intra-NTS infusion of carboxy-PTIO, L-NAME, or 7-NI attenuated the mild stress-induced NE release in the BNST of EtOHW rats. Additionally, EtOHW rats showed increased solitary nNOS gene and protein expression. Moreover, the anxiolytic effect of intra-NTS administration of 7-NI was abolished by subsequent intra-NTS administration of sodium nitroprusside. These results suggest that elevation of solitary nitric oxide signaling derived from nNOS mediates stress-precipitated anxiety and norepinephrine release in the BNST during protracted EtOHW.

scholarly journals Functional analysis of a common BAG3 allele associated with protection from heart failure

2021 ◽  
Author(s):  
Juan A Perez-Bermejo ◽  
Luke M Judge ◽  
Christina L Jensen ◽  
Kenneth Wu ◽  
Annie Truong ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Interaction ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Interaction Network ◽  
Dependent Manner ◽  
Protein Variant ◽  
Preferential Binding ◽  
Induced Pluripotent ◽  
Immortalized Cell

AbstractMultiple genetic association studies have correlated a common allelic block linked to the BAG3 gene with a decreased incidence of heart failure, but the molecular mechanism for such protection remains elusive. One of the variants in this allele block is coding, changing cysteine to arginine at position 151 of BAG3 (rs2234962-BAG3C151R). Here, we use induced pluripotent stem cells (iPSC) to test if the BAG3C151R variant alters protein and cellular function in human cardiac myocytes. Quantitative protein interaction network analysis identified specific changes in BAG3C151R protein interaction partners in cardiomyocytes but not in iPSCs or an immortalized cell line. Knockdown of BAG3 interacting factors in cardiomyocytes followed by myofibrillar analysis revealed that BAG3C151R associates more strongly with proteins involved in the maintenance of myofibrillar integrity. Finally, we demonstrate that cardiomyocytes expressing the BAG3C151R variant have improved response to proteotoxic stress in an allele dose-dependent manner. This study suggests that the BAG3C151R variant increases cardiomyocyte protection from stress by enhancing the recruitment of factors critical to the maintenance of myofibril integrity, hinting that this variant could be responsible for the cardioprotective effect of the haplotype block. By revealing specific changes in preferential binding partners of the BAG3C151R protein variant, we also identify potential targets for the development of novel cardioprotective therapies.

Lack of effect of acute ethanol consumption on active cation fluxes of leucocytes and erythrocytes in healthy humans

1987 ◽  
Vol 73 (4) ◽  
pp. 387-393 ◽  
Author(s):  
Rachel J. Green ◽  
D. N. Baron
Keyword(s):  
Neutrophil Count ◽  
Serum Insulin ◽  
Ethanol Consumption ◽  
Electrolyte Excretion ◽  
Plasma Adrenaline ◽  
Healthy Humans ◽  
Human Volunteers ◽  
Acute Ethanol ◽  
Intracellular Electrolyte Concentrations

1. Acute ethanol consumption in human volunteers did not appear to alter active cation fluxes by Na+,K+-ATPase, or intracellular electrolyte concentrations, in peripheral leucocytes or erythrocytes. 2. Urinary electrolyte excretion was decreased after ethanol consumption, compared with controls. 3. Neither plasma glucose nor serum insulin was altered by ethanol. 4. After ethanol consumption there was an elevation of endogenous plasma adrenaline levels. This was accompanied by a leucocytosis, which could be attributed to a raised neutrophil count. 5. The raised adrenaline levels were not associated with hypokalaemia. 6. It is possible that in vivo ethanol may prevent adrenaline-induced hypokalaemia by fluidizing the membrane and/or decreasing the affinity of β-receptors for adrenaline.

scholarly journals Relevance of the COPI complex for Alzheimer’s disease progression in vivo

2016 ◽  
Vol 113 (19) ◽  
pp. 5418-5423 ◽  
Author(s):  
Karima Bettayeb ◽  
Basaraj V. Hooli ◽  
Antonio R. Parrado ◽  
Lisa Randolph ◽  
Dante Varotsis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Retrograde Transport ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Memory Impairments ◽  
Ad Mouse Model

Cellular trafficking and recycling machineries belonging to late secretory compartments have been associated with increased Alzheimer’s disease (AD) risk. We have shown that coat protein complex I (COPI)-dependent trafficking, an early step in Golgi-to-endoplasmic reticulum retrograde transport, affects amyloid precursor protein subcellular localization, cell-surface expression, as well as its metabolism. We present here a set of experiments demonstrating that, by targeting subunit δ-COP function, the moderation of the COPI-dependent trafficking in vivo leads to a significant decrease in amyloid plaques in the cortex and hippocampus of neurological 17 mice crossed with the 2xTg AD mouse model. Remarkably, an improvement of the memory impairments was also observed. Importantly, human genetic association studies of different AD cohorts led to the identification of 12 SNPs and 24 mutations located in COPI genes linked to an increased AD risk. These findings further demonstrate in vivo the importance of early trafficking steps in AD pathogenesis and open new clinical perspectives.

Abstract 5: Sortilin Regulates Hepatic VLDL Secretion and LDL Uptake in a Lysosome-Dependent Manner

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Alanna Strong ◽  
Qiurong Ding ◽  
Andrew Edmondson ◽  
Sumeet Khetarpal ◽  
Carlos Morales ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Plasma Cholesterol ◽  
Association Studies ◽  
Ldl Receptor ◽  
Genome Wide Association Studies ◽  
Dependent Manner ◽  
Ldl Particles ◽  
Vldl Secretion ◽  
Ldl Uptake

Sortilin, the protein product of the SORT1 gene, is a multi-ligand sorting receptor involved in Golgi to lysosome and plasma membrane to lysosome protein trafficking. Genome wide association studies for lipid traits have identified the 1p13 locus harboring the SORT1 gene as strongly associated both with plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) risk in humans. Adeno-associated virus (AAV)-mediated hepatic sortilin overexpression in LDL receptor deficient mice reduced plasma cholesterol by 30% at two weeks ( n = 6 mice per group, P = 0.02), with a concomitant reduction in LDL-C. In vivo VLDL production studies demonstrated a 50% reduction in the VLDL triglyceride secretion rate ( P = 0.007) and a 50% reduction in apoB secretion ( P = 0.02) with sortilin overexpression. In vivo LDL turnover studies demonstrated a 3-fold increase in the LDL fractional catabolic rate (FCR) with sortilin overexpression ( n = 6 mice per group, P = 0.00002). Sortilin deficiency both alone and on an LDL receptor deficient background led to a 40% and 50% reduction in FCR ( n = 6 mice per group, P = 0.002 and P = 0.01). The effect of sortilin on both VLDL secretion and LDL turnover is dependent on the ability of sortilin to traffic to the lysosome, as sortilin mutants that cannot traffic to the lysosome do not affect VLDL secretion or LDL uptake in vivo or in vitro . Surface plasmon reasonance demonstrated a high affinity interaction between sortilin and the apoB in LDL particles at physiological pH with a K d of ∼2 nM, and this affinity virtually disappears at the acidic lysosomal pH. In sum, these data are consistent with a model in which sortilin binds apoB-containing lipoprotein particles in the Golgi apparatus and at the plasma membrane and traffics them to the endolysosomal compartment for degradation, thereby reducing VLDL secretion and facilitating LDL uptake, explaining the strong association of hepatic sortilin overexpression in humans with reduced plasma cholesterol.

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