Molecular and behavioral mechanisms mediating paclitaxel-induced changes in affect-like behavior in mice

The antineoplastic paclitaxel is associated with negative affective outcomes, such as depression, anxiety, and decreased quality of life during treatment and convalescence. With the Baby Boomer population approaching peak cancer age, it is dire that the mechanisms behind paclitaxel-induced changes in mood are uncovered. Cancer-free male and female C57BL/6J mice were treated with one set of four injections of vehicle or paclitaxel (32mg/kg cumulative), or two sets of four injections of vehicle or paclitaxel (64mg/kg cumulative), and periodically assessed for depression-like behaviors. Paclitaxel caused significant, time-dependent deficits in sucrose preference and operant responding for palatable food. Because there is growing evidence to support the role of kappa opioid receptors (KORs) in stress-mediated depression and reward dysfunction, we investigated KOR signaling as a putative mechanism of paclitaxel-induced depression-like behaviors. The selective KOR antagonist norbinaltorphimine (norBNI) reversed paclitaxel-induced attenuation of sucrose preference. At the molecular level, paclitaxel time-dependently induced an increase in the expression of Prodynorphin mRNA, the precursor for endogenous KOR agonists, in the nucleus accumbens (NAc). Using the [35S]GTPγS assay, we discovered that a history of paclitaxel time-dependently attenuated activation of dopamine D2 receptors (D2R) and KORs in the NAc but not caudate putamen. These data suggest that paclitaxel-induced changes in affect-like behavior may be due to time- and region-dependent dysregulation of KOR and D2R signaling. These observations help to establish the roles of KOR and D2R systems in paclitaxel-induced disruption of behavioral reward, thus revealing potential neurochemical targets for therapeutic intervention in cancer survivors with treatment-resistant depression.https://scholarscompass.vcu.edu/gradposters/1038/thumbnail.jp

Cannabinoid receptor interacting protein suppresses agonist-driven CB1 receptor internalization and regulates receptor replenishment in an agonist-biased manner

Cannabinoid receptor interacting protein 1a (CRIP1a) is a CB1 receptor (CB1R) distal C-terminus-associated protein that modulates CB1R signaling via G proteins, and CB1R down-regulation but not desensitization (Blume et al. [2015] Cell Signal., 27, 716-726; Smith et al. [2015] Mol. Pharmacol., 87, 747-765). In this study, we determined the involvement of CRIP1a in CB1R plasma membrane trafficking. To follow the effects of agonists and antagonists on cell surface CB(1)Rs, we utilized the genetically homogeneous cloned neuronal cell line N18TG2, which endogenously expresses both CB1R and CRIP1a, and exhibits a well-characterized endocannabinoid signaling system. We developed stable CRIP1a-over-expressing and CRIP1a-siRNA-silenced knockdown clones to investigate gene dose effects of CRIP1a on CB1R plasma membrane expression. Results indicate that CP55940 or WIN55212-2 (10 nM, 5 min) reduced cell surface CB1R by a dynamin-and clathrin-dependent process, and this was attenuated by CRIP1a over-expression. CP55940-mediated cell surface CB1R loss was followed by a cycloheximide-sensitive recovery of surface receptors (30120 min), suggesting the requirement for new protein synthesis. In contrast, WIN55212-2-mediated cell surface CB(1)Rs recovered only in CRIP1a knockdown cells. Changes in CRIP1a expression levels did not affect a transient rimonabant (10 nM)mediated increase in cell surface CB(1)Rs, which is postulated to be as a result of rimonabant effects on \u27non-agonist-driven\u27 internalization. These studies demonstrate a novel role for CRIP1a in agonist-driven CB1R cell surface regulation postulated to occur by two mechanisms: 1) attenuating internalization that is agonist-mediated, but not that in the absence of exogenous agonists, and 2) biased agonist-dependent trafficking of de novo synthesized receptor to the cell surface

Vasodilator effect of glucagon: receptorial crosstalk among glucagon, GLP-1, and receptor for glucagon and GLP-1

Glucagon is known for its insulin-antagonist effect in the blood glucose homeostasis, while it also reduces vascular resistance. The mechanism of the vasoactive effect of glucagon has not been studied before; thereby we aimed to investigate the mediators involved in the vasodilatation induced by glucagon. The vasoactive effect of glucagon, insulin, and glucagon-like peptide-1 was studied on isolated rat thoracic aortic rings using a wire myograph. To investigate the mechanism of the vasodilatation caused by glucagon, we determined the role of the receptor for glucagon and the receptor for GLP-1, and studied also the effect of various inhibitors of gasotransmitters, inhibitors of reactive oxygen species formation, NADPH oxidase, prostaglandin synthesis, protein kinases, potassium channels, and an inhibitor of the Na(+)/Ca(2+)-exchanger. Glucagon causes dose-dependent relaxation in the rat thoracic aorta, which is as potent as that of insulin but greater than that of GLP-1 (7-36) amide. Vasodilatation by GLP-1 is partially mediated by the glucagon receptor. The vasodilatation due to glucagon evokes via the glucagon-receptor, but also via the receptor for GLP-1, and it is endothelium-independent. Contribution of gasotransmitters, prostaglandins, the NADPH oxidase enzyme, free radicals, potassium channels, and the Na(+)/Ca(2+)-exchanger is also significant. Glucagon causes dose-dependent relaxation of rat thoracic aorta in vitro, via the receptor for glucagon and the receptor for GLP-1, while the vasodilatation evoked by GLP-1 also evolves partially via the receptor for glucagon, thereby, a possible crosstalk between the 2 hormones and receptors could occur

Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization

Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR-CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized a series of bivalent ligands targeting the putative CCR5-MOR heterodimer. To understand how these bivalent ligands may interact with the heterodimer, biological studies including calcium mobilization inhibition, binding affinity, HIV-1 invasion, and cell fusion assays were applied. In particular, HIV-1 infection assays using human peripheral blood mononuclear cells, macrophages, and astrocytes revealed a notable synergy in activity for one particular bivalent ligand. Further, a molecular model of the putative CCR5-MOR heterodimer was constructed, docked with the bivalent ligand, and molecular dynamics simulations of the complex was performed in a membrane-water system to help understand the biological observation

EC94-872-S Nebraska Crop Budgets

Resource Persons • Crops Budgeting Procedure • Prices Used for 1994 Panhandle • Gravity Irrigated Crops • Sugar Beets • Dry Edible Beans • Corn for Grain • Corn for Silage • Establish Alfatfa with Oats • Alfalfa Hay Gravity Irrigated • Center Pivot Irrigated Crops • Sugar Beets • Dry Edible Beans • Corn for Grain • Winter Wheat • Alfalfa Hay • Non-Irrigated Crops • Winter Wheat Stubble Much Fallow • Winter Wheat, Eco-Fallow (Chemical and Tillage Combination) • Sunflower, Wheat-Sunflower-Fallow Rotation • Millet, Wheat, Fallow, Millet, Fallow Southwest • Corn for Grain, Gravity Irrigated • Corn for Silage, Gravity Irrigated • Corn for Grain, Ditch Irrigated, Platte Valley • Corn for Grain, Ridge Planted, Gravity Irrigated • Corn for Grain, Center Pivot Irrigated, Fine Texture Soil • Corn for Grain, Center Pivot Irrigated, Sandy Soil • Pinto Beans, Center Pivot Irrigated • Soybeans, Center Pivot Irrigated • Fall Seed Alfalfa, Center Pivot Irrigated • Alfalfa Hay, Center Pivot Irrigated • Alfalfa Hay, Sub-Irrigated, Platte Valley • Fall Seed Grass, Center Pivot Irrigated • Pasture, Center Pivot Irrigated • Wheat, Center Pivot Irrigated • Wheat, Stubble Mulch Fallow • Wheat, Clean Till Fallow • Wheat, Continuous, Chemical Weed Control • Wheat, Followed by Corn, 3 Year Rotation, Eco-Fallow • Corn, Following Eco-Fallow Wheat • Grain Sorghum, Non-Irrigated • Grain Sorghum, Non-Irrigated, No-TUI Continuous • Cane Hay, Non-Irrigated North • Corn for Grain, Center Pivot Irrigated • Corn for Silage, Center Pivot Irrigated • Establish Alfalfa, Center Pivot Irrigated • Alfalfa Hay, Center Pivot Irrigated • Establish Grass, Center Pivot Irrigated • Pasture, Center Pivot Irrigated • Native Hay, Wet Meadow • Native Hay, Upland Central • Corn for Grain Center Pivot Irrigated • Corn for Silage Center Pivot Irrigated • Grain Sorghum for Grain, Limited Irrigation, Center Pivot • Corn for Grain, Gravity Irrigated • Corn for Silage Gravity Irrigated • Soybeans, Gravity Irrigated , • Establish Alfalfa, Gravity Irrigated • Alfalfa for Hay, Gravity Irrigated • Corn for Grain, Non-Irrigated • Corn for Grain, Eco-Fallow, Follows Wheat in 3 Year Rotation • Corn for Silage, Non-Irrigated • Grain Sorghum for Grain, Non-Irrigated • Grain Sorghum for Grain, Eco-Fallow, Follows Wheat in 3 Year Rotation • Grain Sorghum for Grain, Continuous, No Till, Non-Irrigated • Soybeans, Non-Irrigated • Wheat for Grain, Continuous Cropped, Non-Irrigated • Wheat for Grain, Continuous, No Till, Non-Irrigated • Wheat for Grain, Fallow Every Third Year • Establish Alfalfa, Non-Irrigated • Alfalfa for Hay, Non-Irrigated • Establish and Maintain Cover Crop on Set Aside Acres Northeast • Corn for Grain, Center Pivot Irrigated, Sandy Soils • Corn for Grain, Center Pivot Irrigated, Rolling Hills • Corn for Grain, Till-Plant, Rolling Hills • Soybeans, Non-Irrigated • Soybeans, Center Pivot Irrigated • Oats, Non-Irrigated 8 • Oats With Spring Alfalfa Seeding • Alfalfa Seeding • Establish Alfalfa, Sandy Soil, Fall Seeding • Alfalfa Hay, Large Round Baler • Alfalfa Hay Small Square Baler • East Central • Corn for Grain, Center Pivot Irrigated • Soybeans, Center Pivot Irrigated • Corn tor Grain, Non-Irrigated • No-Till Com in Soybean Residue • Grain Sorghum, Non-Irrigated • Soybeans, Non-Irrigated • Soybeans, After Corn Reduced Till • Wheat • Establish Alfalfa, Fall Seeded • Establish Alfalfa, Spring With Herbicide • Alfalfa Hay, Large Round Baler • Alfalfa Hay, Field Stacker • Oats, Non-Irrigated Southeast • Corn for Grain, Center Pivot Irrigated • Corn for Silage, Center Pivot Irrigated • Corn for Grain, Non-Irrigated • Grain Sorghum, Non-Irrigated • Forage Sorghum Silage, Non-Irrigated • Soybeans, Non-Irrigated • Wheat • Alfalfa Hay, Large Round Bale

Serum methylarginines and spirometry-measured lung function in older adults

Rationale: Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in animal models of lung disease but have not previously been examined for their association with spirometric measures of lung function in humans. Objectives: This study measured serum concentrations of asymmetric and symmetric dimethylarginine in a representative sample of older community-dwelling adults and determined their association with spirometric lung function measures. Methods: Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and L-arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults from the Hunter Community Study. The five key lung function measures included as outcomes were Forced Expiratory Volume in 1 second, Forced Vital Capacity, Forced Expiratory Volume in 1 second to Forced Vital Capacity ratio, Percent Predicted Forced Expiratory Volume in 1 second, and Percent Predicted Forced Vital Capacity. Measurements and Main Results: In adjusted analyses there were statistically significant independent associations between a) higher asymmetric dimethylarginine, lower Forced Expiratory Volume in 1 second and lower Forced Vital Capacity; and b) lower L-arginine/asymmetric dimethylarginine ratio, lower Forced Expiratory Volume in 1 second, lower Percent Predicted Forced Expiratory Volume in 1 second and lower Percent Predicted Forced Vital Capacity. By contrast, no significant associations were observed between symmetric dimethylarginine and lung function. Conclusions: After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum asymmetric dimethylarginine was independently associated with a reduction in key measures of lung function. Further research is needed to determine if methylarginines predict the decline in lung function

Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects