bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relative Contribution of Dopamine, Norepinephrine, and Serotonin to the Discriminative Stimulus Effects of MDPV
Authors: Seaman Robert W , Doyle Michelle R , Sulima Agnieszka , Rice Kenner C , Collins Gregory T 
Published: June 2021

The abuse of synthetic cathinones (“bath salts”) has increased worldwide over the past decade. Bath salt preparations often contain multiple synthetic cathinones in addition to other stimulants such as cocaine or caffeine. Synthetic cathinones are known to interact with dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively). Although recent studies suggest that interactions with DAT are crucial for the reinforcing effects of synthetic cathinones, actions at SERT were found to negatively modulate reinforcing effectiveness. The goal of the current study was to characterize the relative contributions of dopamine, norepinephrine, and serotonin to the discriminative stimulus effects of MDPV by evaluating the substitution profiles of 1) a series of structurally related cathinones (MDPBP, MDPPP, α‐PPP, and α‐PVP) and cocaine, and 2) direct‐acting dopamine (quinpirole [D2/3], SKF 82958 [D1/5], and apomorphine [D1‐5]), and norepinephrine (phenylephrine [α1], and clonidine [α2]) receptor agonists in male Sprague‐Dawley rats (n=8) trained to discriminate 1.0 mg/kg MDPV from saline under a fixed ratio 10 schedule of sucrose pellet delivery. The mu‐opioid receptor agonist fentanyl served as a negative control. As expected, each of the cathinones and cocaine produced dose‐dependent increases in MDPV‐appropriate responding, whereas fentanyl failed to increase MDPV‐appropriate responding at doses smaller than those that suppressed responding. The rank order potency of the synthetic cathinones to increase MDPV‐appropriate responding is positively correlated with their potency to inhibit DAT and NET, but not SERT, and is consistent with the rank order to maintain self‐administration. The D2/3 receptor‐preferring agonist quinpirole dose‐dependently increased MDPV‐appropriate responding whilst SKF 82958 [D1/5], apomorphine [D1‐5], phenylephrine [α1], and clonidine [α2] failed to increase MDPV‐appropriate responding at doses smaller than those that suppressed responding. Together, these data provide evidence that the discriminative stimulus effects of MDPV are primarily mediated by its capacity to inhibit DAT, and the subsequent activation of dopamine D2 and/or D3 receptors. Moreover, these studies suggest do not support a role for serotonergic or adrenergic systems in mediating/modulating the discriminative stimulus effects of MDPV. Future studies will utilize antagonists of dopamine, adrenergic, and serotoninergic receptors to better characterize their relative contributions to the discriminative stimulus effects of MDPV.Support or Funding InformationThis work was supported by NIH/NIDA grant (R01 DA039146; GTC) and NIDA‐ and NIAAA‐IRPs (KCR)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effects of Eating a High Fat Diet on Methamphetamine‐Induced Conditioned Place Preference
Authors: Serna Paloma , Galindo Kayla I , Serafine Katherine M 
Published: June 2021

Eating a high fat diet can cause several negative health consequences, including dysfunction to dopamine systems. For example, eating a high fat diet enhances sensitivity of rats to methamphetamine‐induced locomotion. However, it is not known if sensitivity to the rewarding effects of methamphetamine are similarly enhanced in rats eating a high fat diet. Females are more sensitive than males to the behavioral effects of stimulants in general, and therefore might also be particularly vulnerabile to high fat diet‐induced enhanced sensitivity to stimulant drugs. To test the hypothesis that eating high fat chow enhances sensitivity of rats to the rewarding effects of methamphetamine, female Sprague‐Dawley rats were fed standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat) for 4 weeks prior to conditioned place preference (CPP) training, using a biased design. Rats were trained on alternating days rats with saline or methamphetamine (0.32 or 1.0 mg/kg, i.p.) and were restricted to one of two sides (wire mesh vs rod flooring) of a CPP apparatus. After 8 alternating training days, rats had free access to the entire apparatus, and time spent in the drug‐paired side versus the saline‐paired side was examined. Methamphetmaine induced a significant CPP in all rats, regardless of diet or dose of methamphetamine; however, there were no differences in magnitude of CPP between rats eating high fat chow and rats eating standard chow. Previous literature suggests that females might be more sensitive to the rewarding effects of methamphetamine, necessitating the use of smaller doses. As such, future studies will examine a wider range of doses of methamphetamine, as well as other conditioned behavior (i.e., self‐administration) and will include male subjects to study potential sex differences.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A selective phosphodiesterase 4D inhibitor BPN14770 reverses beta amyloid‐induced memory impairment in humanized PDE4D mice
Authors: Xu Ying , Yang Mingxin , Zhang Han‐Ting , Gurney Mark , O'Donnell James 
Published: June 2021

Beta amyloid peptides (Aβ) are known risk factors involved in cognitive impairment in Alzheimer's disease (AD). Type 4 phosphodiesterase (PDE4) inhibitors such as rolipram could upregulate intracellular cAMP level, which further activate downstream target cAMP‐responsive‐ element‐binding protein (CREB), brain‐derived neurotrophic factor (BDNF) and nerve growth factor (VGF) signaling. Although conventional PDE4 inhibitors have benefits on memory enhancement in preclinical and clinical studies, they were prevented to be developed as a novel class of memory‐enhancing drugs due to their adverse effects such as GI irritation. BPN14770, a novel allosteric inhibitor of PDE4D, exhibits high selectivity on PDE4D based on its close interaction with a single amino acid present at primate PDE4D. The present study used the humanized PDE4D (hPDE4D) mice, which provide a unique and powerful genetic tool for assessing the PDE4D target engagement, to investigate the effects of BPN14770 on memory impairment induced by Ab1‐42. Results suggested that BPN14770‐treated mice exhibited significant learning and memory enhancement, as shown in Morris water maze and Y maze tests. The morphological analyses suggested that both the number of dendrites and the total length were significantly increased after treatment hPDE4D mice with BPN14770 for two weeks. The subsequent neurochemical assay indicated that neuroprotective proteins such as pCREB, BDNF and VGF in Ab‐treated hPDE4D mice were upregulated after treatment with BPN14770. These findings provide evidence that BPN14770 may be a potential therapeutic drug for treating cognitive deficits in Alzheimer's disease and its underlying mechanism may be involved in the cAMP‐pCREB‐BDNF/VGF signaling.Support or Funding InformationThis project was supported by R44 MH091791 to Drs. Mark Gurney and Ying Xu.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Overexpression of TIPE2, a Negative Regulator of Innate and Adaptive Immunity, Attenuates Cognitive Deficits in APP/PS1 Mice
Authors: Zhang Fang , Miao Yong‐zhen , Xu Zi‐han , Ju Chuan‐xia , Wang Lei , Wang Ke‐wei 
Published: June 2021

Neuroinflammation plays an early and prominent role in the pathology of Alzheimer's disease (AD). Tumor necrosis factor‐a‐induced protein 8‐like 2 (TIPE2) has been identified as a negative regulator of innate and adaptive immunity. However, whether TIPE2 affects cognitive functions in AD‐like mouse models remains unknown. In this study, we compared the gene and protein expressions of TIPE2 and β‐amyloid in the brain between the APP/PS1 mice and the age‐matched wild type (WT) mice at different stages of developments using assays of immunofluorescence, western blot and qPCR. Deposition of Aβ plaques appeared in the hippocampus from the 6‐month‐old APP/PS1 mice, and the hippocampal expression of the TIPE2 mRNA and protein in APP/PS1 mice were significantly higher than that of the WT mice starting from 6 months to 10 months. However, the difference of the TIPE2 expression between the APP/PS1 mice and the WT mice declined in a time‐dependent manner. The spatial learning and memory deficit from 8‐month‐old APP/PS1 mice was observed in the Y‐maze test and fear conditioning task. Interestingly, overexpression of TIPE2 by intra‐hippocampal injection of AAV‐TIPE2 into the 7‐month old APP/PS1 mice resulted in an improvement of learning and memory. Taken together, our findings show that the TIPE2 expression level was negatively correlated with the Alzheimer's disease, suggesting TIPE2 is a potential target for pharmacological intervention and improvement of cognitive deficits.Support or Funding InformationThis work was supported by research grants to Fang ZHANG from the Natural Science Foundation of Shandong Province of China, No. ZR2016 HM 46; Post doctoral application foundation of Qingdao Municipal Bureau of Social Sciences, No. 2016062; Qingdao science and technology bureau, No 18‐6‐1‐75‐nsh; Clinical medicine +X Project of Qingdao University Medical Department; Innovation and Entrepreneurship Training Program of undergraduate student in Qingdao University. No. 201711065152.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Molecular and behavioral mechanisms mediating paclitaxel‐induced changes in affect‐like behavior in mice
Authors: Meade Julie , Toma Wisam , Alkhlaif Yasmin , Bagdas Deniz , Obeng Samuel , Selley Dana E. , Damaj M. Imad 
Published: June 2021

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.Support or Funding InformationSupported by: Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship to Promote Diversity in Health‐Related Research 1F31CA224930‐01A1; NIH grant 1R01‐CA206028‐01; NIHNCI Cancer Center Support Grant P30‐CA016059.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Lower Pain Sensitivity in Ovariectomized Mice Using HIV Gp120 and Chemotherapy‐induced Chronic Pain Models
Authors: Rodríguez Ismael Rodríguez Lugo , García Dianise Rodríguez , Brelsfoard Jennifer , Lilley Jennifer , Blanton Henry , Guindon Josee 
Published: June 2021

Pain is an uncomfortable sensation linked with a vast majority of health complications. It is a result of complex interactions involving the peripheral and central nervous system, which vary between different types of pain. It is important to improve the analgesic effects of drugs for different types of pain while maintaining patient well‐being. For this reason, our laboratory focused on understanding the behavioral antinociceptive effects of cisplatin (a chemotherapeutic drug) and HIV gp120 on both male and female mice. We also tested the analgesic effects of CP55, 940 (a cannabinoid CB1/CB2 receptor agonist) in an HIV‐gp120 mouse model after neuropathic effects were documented. Cannabinoid receptor agonists have been shown to be effective in pain animal models by inhibiting acute nociceptive responses and reversing the behavioral hypersensitivity. Because of this, we hypothesize that neuropathic pain on this HIV‐gp120 mouse model will also be reversed. All of this was experimented in ovariectomized mice in order to improve our understanding of pro‐ or anti‐ nociceptive processes and the potential role of sex hormones. We tested the effect of cisplatin (0.5 mg/kg intraperitoneal injection once a week for 4 weeks) or HIV‐gp120 (200 ng) treatment on mechanical (von Frey) and cold (acetone) allodynia in control (male and female) and ovariectomized mice. We also conducted daily vaginal lavages in the female mice. Our results suggest that both, cisplatin and HIV‐gp120 mouse models, induce mechanical and cold pain sensitivity in both male and female. Only HIV‐gp120 female mice show an increase in mechanical and cold pain sensitivity relative to male. Both, ovariectomized mice treated with cisplatin and ovariectomized HIV‐gp120 mice show a decrease in mechanical and cold pain sensitivity relative to control female mice. As for treatment with Cp55, 940 analgesic effects were clearly present at 10mg/kg for all mice. However, 1mg/kg had no analgesic effects. We also observed disturbance in the estrous cycle of the HIV‐gp120 mice group. As a conclusion, we confirm that hormonal changes are influencing pain sensitivity and therefore demonstrate the importance of sex‐hormones in pain transmission. Further studies are needed to better understand the mechanisms of action of these findings.Support or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Age‐dependent differences in pain‐related depression of nesting in mice
Authors: Miller Laurence , McPherson Sarah 
Published: June 2021

Pain‐related inference with behavior is a key clinical diagnostic indicator and target in the treatment of pain. Increasingly, preclinical studies on the expression, mechanisms, and treatment of pain have been aimed at improving understanding of pain‐related interference with behavior. Although there are well‐known changes to sensory, motor, and cognitive functions across the lifespan, no studies have examined the expression, mechanisms, and treatment of pain‐related depression of behavior from an aging perspective. The present studies compare the effects of a noxious pain stimulus and a clinically relevant analgesic on nesting behavior in 12‐, 18‐, and 48‐ week old mice. Nesting was operationally defined as the clearance of pieces of cotton nesting material from six zones within the home cage. This is the first step of consolidating the nesting material into a single zone for nest construction. Nesting was observed over the course of a 60‐minute session. First, the rate of nesting was compared across the age groups. Early in the nesting session, 12‐week old mice cleared more zones of nesting material than 18‐ and 48‐week old mice, but there were no differences in the number of zones cleared after 60 minutes. Next, the potency of intraperitoneal injection of lactic acid to depress nesting was determined in each age group. Lactic acid was more potent in the 48‐week old mice than the 18‐week old mice, but no other age related differences were observed. Finally, the effects of the nonsteroidal anti‐inflammatory drug (NSAID), ketoprofen, on lactic acid‐induced depression of nesting were determined. There were no age‐related differences in the potency or efficacy of ketoprofen. Together, these findings support the validity of assays of pain‐related depression of behavior to examine age‐related changes in the expression and treatment of functional impairment caused by pain. Moreover, these findings suggest that aging may result in increased susceptibility to pain‐related functional impairment, and that aging does not affect the ability of NSAIDs to treat pain‐related functional impairment.Support or Funding InformationSupport was provided by the Augusta University Center for Undergraduate Research and ScholarshipThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Molecular Mechanism of Rap1A‐Dependent Activation of PLCɛ
Authors: Sieng Monita , Garland‐Kuntz Elisabeth E. , Selvia Arielle F. , Chakravarthy Srinivas , Lyon Angeline M. 
Published: June 2021

Phospholipase C (PLC) enzymes hydrolyze phosphatidylinositol lipids to produce diacylglycerol (DAG) and inositol phosphates, leading to the activation of protein kinase C (PKC) and downstream signaling pathways, including cell growth and survival. The PLCɛ subfamily is a key player in cardiovascular function, where it contributes to maximum contractility. However, prolonged activation of PLCɛ results in cardiac hypertrophy and heart failure through its ability to regulate the expression of hypertrophic genes. This process is regulated by the small GTPase Rap1A, which is activated downstream of β‐adrenergic receptors. Rap1A binds to the C‐terminal Ras association (RA) domain of PLCɛ, simultaneously translocating the complex to the perinuclear region and activating PLCɛ. PLCɛ also contains an N‐terminal CDC25 domain, which has guanine nucleotide exchange factor (GEF) activity for Rap1A resulting in a feed forward activation loop and sustained lipid hydrolysis. However, the molecular mechanism of this process is not known. In this work, we seek to characterize the interactions between Rap1A and PLCɛ using structural and functional studies to map the Rap1A binding site on PLCɛ and determine whether activation results in conformational changes that release autoinhibition and/or increase membrane association. These studies provide the first molecular details of the Rap1A‐dependent activation of PLCɛ and open the door to the development of new therapeutic strategies for treating cardiac hypertrophy.Support or Funding InformationThis research is supported by the American Heart Association Predoctoral Fellowship 18PRE33990057 to M.S., American Heart Association Grant Scientist Development Grant 16SDG29920017 to A.M.L. and the NIH NLHBI 1R01HL 141076‐01 to A.M.L. SAXS data was collected and analyzed with the assistance of S. Chakravarthy at Argonne National Laboratory.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Building a Sound Wall in the Cochlea: Development of the Stria Vascularis
Authors: Basch Martin Leandro 
Published: June 2021

The stria vascularis is a specialized epithelial structure of the mammalian cochlea that produces endolymph, the potassium‐rich fluid responsible for the positive endocochlear potential of the cochlear lumen. This positive extracellular potential is the major driving force for proper signal transduction by sensory cells in the ear, and thus normal hearing. The stria vascularis is the “battery” of the auditory organ: it is localized in the lateral wall of the cochlea, and consists of a multilayered highly vascularized epithelium. It is composed of three main cell types with distinct embryonic origins: the marginal cells derived from the otic epithelium , the intermediate cells which are specialized melanocyte‐like cells derived from migratory neural crest cells, and the basal cells that are derived from otic mesenchyme. Mesoderm‐derived blood vessels are interspersed between these cells throughout the stria. Defects in the development of the stria vascularis are part of a number of inheritable deafness syndromes in humans, including Hirschsprung disease and Waardenburg, Jervell and Lange‐Nielsen, Bartter and SeSAME syndromes. Strial degeneration is estimated to cause more than 30% of age related hearing loss or presbycusis, which affects between 25–40% of the population over 65 years and over 60% of the population over 80 years old. The causes of strial atrophy remain poorly understood. Over the past decade, a great effort has been made to understand the development of the sensory cells in the mammalian cochlea with the aim of applying their developmental principles to regenerative therapies. By contrast, very little is known about the developmental potential of the stria vascularis, or even the mechanisms of strial degeneration due to aging. Our focus is to uncover the normal development of the stria, the cellular interactions that lead to its formation, and the potential for regeneration in cases of congenital strial deafness.Support or Funding InformationHearing Health FoundationThe Hartwell FoundationNIDCD R01DC015785This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.