bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex Differences in Cocaine Self‐Administration Behavior are Driven by Estrous Stage Dependent Changes in Dopamine Transporter Sensitivity to Cocaine
Authors: MAUTERER MADELYN , Jones Sara R. 
Published: June 2021

Traditionally, preclinical cocaine studies have focused primarily on male behavior and neurobiology, but recent work has suggested that there are distinct differences in male versus female cocaine responsivity. In humans, progression to cocaine dependence is faster in women compared to men. Women also exhibit greater craving and relapse following abstinence. Similar to humans, rodent literature suggests males and females have differential behavioral responses to cocaine, which appear to be estrous cycle dependent. For example, females exposed to cocaine during the estrous phase exhibit augmented behavioral responses, such as increased conditioned place preference and greater cocaine seeking. Furthermore, recent literature has uncovered neurobiological differences between the sexes, specifically related to estrogen, which suggest that differences within the dopamine system, specifically, may underlie the observed increase in cocaine abuse vulnerability in females.Here, we used intravenous cocaine self‐administration to assess differences in time to acquire and motivation to seek cocaine between not only sex but also stages of the estrous cycle. We found that female rats are most likely to achieve cocaine self‐administration acquisition parameters when they are in the estrus phase of the cycle; in fact, 90% of females tested were in the estrus phase at time of acquisition. We used the threshold schedule of reinforcement, a paradigm of behavioral economics, to assess motivation to take cocaine. Females in estrus exhibit greater motivation (increased “price” paid to maintain blood cocaine levels; Pmax) which is augmented further if their first exposure to cocaine occurred during estrus as well. Our observed behavioral differences were further shown to be correlated with changes in dopamine terminal sensitivity. Using ex vivo fast scan cyclic voltammetry (FSCV) in the nucleus accumbens (NAc), we found that females in estrus show greater terminal sensitivity to cocaine which may drive the increased cocaine taking behaviors.Support or Funding InformationR01 DA014030 T32 AA007565This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dissecting the Abuse Liability of Cathinone Derivative Psychomotor Stimulants in Female Rats
Authors: Taffe Michael A. , Harvey Eric L. , Javadi‐Paydar Mehrak , Nguyen Jacques D. , Grant Yanabel , Vandewater Sophia A. , Creehan Kevin M. , Dickerson Tobin J. 
Published: June 2021

RationaleUse of a diversity of synthetic psychoactive cathinone drugs (“bathsalts”) continues to expand worldwide despite legal control. The pyrrolidinophenones, 3,4‐methylenedioxypyrovalerone (MDPV) and α‐pyrrolidinopentiophenone (α‐PVP), cause violent and/or bizarre public behavior in some users and are potent reinforcers in rodent intravenous self‐administration (IVSA) models. Other cathinones with entactogen‐like pharmacology appear to be more efficacious reinforcers than the class‐defining 3,4‐methylenedioxymethamphetamine (MDMA).ObjectivesTo determine how modification of the aromatic ring and extension of the alpha carbon alkyl chain modifies the reinforcing properties of cathinone derivatives.MethodsFemale Wistar rats were trained in IVSA of α‐PVP (0.05 mg/kg/inf; 1 h sessions), MDMA (0.5 mg/kg/inf; 6 h) or Pentylone (0.5 mg/kg/inf; 6 h). Following acquisition, the groups were subjected to dose‐substitution under FR and PR response contingencies. Experiments evaluated: α‐PVP, α‐pyrrolidinohexiophenone, pentylone, methylone, pentedrone, 4‐methylpentedrone, MDMA and an MDMA analog.ResultsExtension of the carbon chain decreased potency, but increased efficacy, of MDMA and methylone. Removal of the pyrrolidino group decreased potency of α‐PVP or MDPV. Effects of 4‐methyl vs 3,4‐methylenedioxy substitution were not consistent across core structures.ConclusionsRecreational use of a wide variety of closely‐related cathinone derivatives drives structure‐activity inferences about abuse liability. IVSA studies in rats, however, show that predictions based on structure are often incomplete or in error. In vivo studies of abuse liability are therefore necessary to understand health risks of novel cathinone derivatives.Support or Funding InformationThese studies supported by USPHS Grant: R01 DA042211
Sex Differences in Antinociceptive Tolerance Development to Δ9‐THC and CP55,940 in Wild‐type and Desensitization‐Resistant S426A/S430A Mice
Authors: Henderson‐Redmond Angela N. , Sepulveda Diana E. , Ferguson Erin L. , Kline Aaron M. , Nealon Caitlin M. , Morgan Daniel J. 
Published: June 2021

Tolerance to the antinociceptive effects of cannabinoid agonists limit their therapeutic potential. Male mice expressing a desensitization‐resistant form of the CB1 receptor (S426A/S430A) show delayed tolerance development to the hypothermic and antinociceptive effects of Δ9‐THC, a strongly desensitizing partial CB1 agonist. However, it remains unknown what effect this mutation might have on altering tolerance to the synthetic full CB1 agonist CP55,940 and whether tolerance development to Δ9‐THC and CP55,940 differ in a sex‐specific manner. The purpose of the current study was to investigate whether the S426A/S430A mutation alters antinociceptive and/or hypothermic tolerance to CP55,940 and Δ9‐THC and whether these effects are sex‐specific. Tolerance to Δ9‐THC (30 mg/kg) and CP55,940 (0.3–0.6 mg/kg) was assessed in two ways: following once‐daily injections across 7–10 consecutive days and via shifts in the cumulative dose response curves following 3–7 days of treatment with each agonist in both male and female wild‐type and S426A/S430A mice. Once‐daily drug administration resulted in slower tolerance development to the effects of CP55,940 versus Δ9‐THC in male and female wildtype mice. The S426A/S430A mutation delayed tolerance to the antinociceptive effect of CP55,940 in male mice and delayed tolerance to both the antinociceptive and hypothermic effects of CP55,940 and Δ9‐THC in female mice. In our cumulative dose responses, we found that the S426A/S430A mutation rendered both male and female mice more sensitive to the effects of Δ9‐THC compared to wild‐type mice. Overall, our results demonstrate that sex and agonist specific mechanisms may mediate cannabinoid tolerance. These studies showcase the antinociceptive therapeutic potential of cannabinoid agonists and offer potential avenues to better understand tolerance to their analgesic effects following prolonged exposure.Support or Funding InformationNIH grants DA036385 (DJM), DA037355 (DJM), Pennsylvania Department of Health using CURE Tobacco Settlement Funds (DJM), Penn State University College of Medicine Department of Anesthesiology and Perioperative Medicine Start Up FundsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
An Internal Pool of β‐Adrenergic Receptors Activates PLC‐mediated PI4P Hydrolysis in Cardiac Myocytes
Authors: Nash Craig , Wenhui Wei , Smrcka Alan 
Published: June 2021

Cardiac hypertrophy and subsequent heart failure is a leading cause of morbidity and mortality in the USA. Previously, our laboratory identified a new prohypertrophic pathway where PLCɛ, scaffolded to mAKAPβ at the nuclear envelope, hydrolyzes phosphatidylinositol 4‐phosphate (PI4P) at the Golgi, locally generating DAG and drive hypertrophic gene expression. This pathway is activated by multiple upstream signals including the Epac‐selective cAMP analogue, cpTOME. However, stimulation of β‐adrenergic receptors with Isoproterenol does not activate this pathway, despite strongly raising cAMP. We were able to uncover Iso stimulated PI4P hydrolysis only in the presence of a cAMP phosphodiesterase 3 inhibitor. Irannejad et al 2 demonstrated that β1‐adrenergic receptors are present in the Golgi membrane of Hela cells and can generate cAMP there. Also, Boivin et al 3 demonstrated that β1‐adrenergic receptors are present in the perinuclear region of adult cardiomyocytes. To determine if internal β‐adrenergic receptors can stimulate PI4P hydrolysis, we treated NRVMs with the membrane permeable β‐adrenergic agonist, dobutamine. In contrast to the membrane impermeable Iso, dobutamine induced rapid and sustained PI4P hydrolysis that was at least partially blocked by the cell permeable β‐adrenergic antagonist, metoprolol (10 μM). The cell impermeable βAR antagonist, sotalol (5 mM) could not block dobutamine effects, suggesting that a pool of internal β‐adrenergic receptors can induce PI4P hydrolysis. Over expression of the RA1 domain of PLCɛ, which competes PLCɛ away from the mAKAPβ scaffold, also inhibited dobutamine stimulation of PI4P hydrolysis. These data suggest that β‐adrenergic stimulation in internal membranes, potentially at the Golgi apparatus or nuclear envelope, can stimulate PI4P hydrolysis. These observations demonstrate a novel mechanism for PLC activation through an internal GPCR which may be responsible for cardiac hypertrophy and heart failure. Targeting internal β‐adrenergic receptors may allow for the development of selective therapies which can treat heart failure with little to no effect on other cardiac functions.Support or Funding InformationThis research was supported by National Institutes of Health Grants R01GM53536 and R01GM81772.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Synergistic Effect of Dopamine and Norepinephrine Transporter Inhibition on Cognitive Enhancement
Authors: Pantoni Madeline M. , Anagnostaras Stephan G. 
Published: June 2021

Psychostimulants such as amphetamine and methylphenidate are highly effective cognitive enhancing medications, yet have a high potential for abuse and addiction. Evidence suggests that both norepinephrine transporter (NET) and dopamine transporter (DAT) inhibition is required for the procognitive effects of psychostimulants. Although DAT inhibition is also responsible for the addictive potential of psychostimulants, drugs with low activity at DAT may not produce addiction. In the present study, we examined the cognitive and reinforcing effects of various DAT inhibitors (e.g., bupropion, GBR‐12909, GBR‐12935) and NET inhibitors (e.g., atomoxetine, nisoxetine) alone and in combination, using Pavlovian fear conditioning and conditioned place preference. We found that certain dose combinations of these DAT and NET inhibitors produced enhancements in immediate and/or long‐term fear memory acquisition, but did not produce reinforcement or behavioral sensitization. We propose that a pharmaceutical combination of DAT and NET inhibition could lead to the development of a non‐stimulating, non‐addictive, and non‐controlled, yet highly effective cognitive enhancer.Support or Funding InformationNIH DA020041 (SGA)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Investigating Arrestin‐3 Recruitment to Nociceptin/Orphanin FQ Opioid Receptor (NOPR)
Authors: Hansen Marissa M. , Spangler Skylar M. , Bruchas Michael R. 
Published: June 2021

Nociceptin/orphanin FQ opioid receptor (NOPR) has therapeutic potential for treating drug addiction as demonstrated by the FDA‐approved drug Buprenorphine, a NOPR partial agonist, and recent studies show NOPR agonism blocks reward seeking behavior in rodents across multiple drug classes. Despite this, little is known about the signaling dynamics by which NOPR exerts these effects. It has been previously determined that the endogenous ligand nociceptin induces recruitment of arrestin‐3, a scaffolding protein which mediates GPCR desensitization and internalization, through NOPR c‐terminal tail phosphorylation. This study proposes that NOPR c‐terminal tail phosphorylation encodes arrestin functionality, as the specific phosphorylation patterns that recruit arrestin‐3 and 2 remain unknown. The biased signaling of NOPR in arrestin‐3 recruitment was explored using NOPR phospho‐mutants and biased ligands (reported in Chang et al., 2015) 3‐endo‐8‐[bis(2‐methylphenyl)methyl]‐3‐phenyl‐8‐azabicyclo[3.2.1]octan‐3‐ol (SCH 221,510) and 11‐[1‐(1‐methylcyclooctyl)‐4‐piperidinyl]‐2‐(3R)‐3‐piperidinyl‐1H‐benzimidazole trihydrochloride (MCOPPB) in order to dissect the molecular mechanisms of NOPR‐arrestin recruitment. Bioluminescence resonance energy transfer (BRET) assays were conducted to quantify real‐time binding between NOPR and arrestin to construct concentration response curves as a means of identifying signaling bias. This study shows that arrestin‐3 recruitment is not dependent on phosphorylation of c‐terminal tail sites as indicated by NOPR‐arrestin interaction with the NOPR c‐terminal phospho‐null mutant, however is absent in the 10A mutant which includes the 3rd intracellular loop. Further decoding of phosphorylation sites on the third intracellular loop could reveal the mechanism by which NOPR phosphorylation initiates downstream signaling via arrestin and thus the pathways by which the receptor controls neuronal function in dopamine neurons.Support or Funding InformationThis work was funded and supported by the National Institutes of Health Blueprint Program for Enhancing Neuroscience Diversity through Undergraduate Research Education Experiences (R25) and Washington University in St. Louis.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Systems Approach to Assign Expression Based Signatures to Adrenergic Drugs
Authors: McGregor Brett Anthony , Guo Kai , Porter James E. , Hur Junguk 
Published: June 2021

Adrenergic receptors and associated drugs have been among the most thoroughly studied G‐protein coupled receptors involved in a wide variety of physiological processes. There are three main groups of adrenergic receptors (alpha1, alpha2, and beta) with each group having multiple receptor subtypes which involve different targets modulating various functions. Due to the highly conserved structures of these receptors, identifying specific and non‐specific binding partners as well as activity of the receptors have been a challenge to assign within this family. In this study, we used a systems approach, involving the use of high‐throughput drug‐perturbation profiling data from the Library of Integrated Network‐Based Cellular Signatures (LINCS) database, to assign drug receptor preference as well as downstream modulation of cellular functions. LINCS, aiming to create a network‐based understanding of gene expression when cells are exposed to different perturbing agents, have extensively profiled the transcriptomic perturbations of over 20,000 small‐molecules in various cell lines and primary cells. Existing information about receptor specificity of drugs from DrugBank for 113 adrenergic drugs was used to assign binding partners to these drugs based on the LINCS drug perturbation data. Perturbed gene expression signatures for specific receptors were then examined for enriched biological functions as well as gene expression similarities. The analysis of drugs specific for activating these receptors provides an expression‐based signature demonstrating each receptors influence on cellular functions. Defining the role different receptor subtypes have on cellular function would provide an alternative way to determine receptor preference of the more promiscuous drugs based on the similarity of their functional involvement. We used this method to identify separate classes of drugs with similar effects on our model system. As an example, we had previously been using Isoprenaline as a beta‐adrenergic agonist to modulate cytokine response in SIMA9 cells, a murine microglia cell line, and needed to identify an alternative non‐catechol drug that would also influence toll like receptor signaling pathways. Our method identified a quinolone, Procaterol, as an alternative drug, which also influences toll like receptor signaling pathways and yields a similar effect in the SIMA9 cell line. Using this systems pharmacology approach may provide a way to further elucidate receptor preference of certain drugs as well as identifying drugs with similar functional influences despite other characteristics.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
New Paradigms of Mass‐Action Law Based Bio‐Dynamics and Pharmacodynamics for New Drug Evaluations
Authors: Chou Ting‐Chao 
Published: June 2021

The Mass‐action law (MAL) based Median‐effect eq. (and its Combination‐index eq.) is the unified general biodynamics (BD) theory for biochemistry and biophysics (Chou TC, Pharmacol. Rev. 58: 621–681, 2006; Integr. Biol. 3: 548–559, 2011). Its eqs & algorithms provide efficient, quantitative, econo‐green, digital, automated computer simulations for bio‐medical research & development (R&D). This paper is to illustrate the fundamental principle of how the theory was derived during the 1967–1984 period, and how this theory, to date has been cited 27,594 times in >1,500 biomedical journals worldwide (Google Scholar Citations – Ting‐Chao Chou; Web of Science: www.researcherid.com/rid/B‐4111‐2009). One theoretical article alone, Chou TC & Talalay P, (Adv. Enz. Regul. 22: 27–55, 1984) has been cited 5,422 times in 1,102 journals, which is referred as “Makes History” [Elsevier News Release 3/16/2016]. The derived/proven theory reveals the following new basic paradigms: 1. “Dose” and “Effect” are interchangeable. 2. All dose‐effect curves (DEC) of MAL can be transformed into straight lines. 3. The theoretical minimum of only 2‐data points are required to simulate a DEC [and the practical minimum of 16, 10, and 10 data points for a DEC by computer simulation in vitro, animals and clinical trials, respectively]. This is the theoretical basis for simple, efficient, quantitative “econo‐green” bio‐R&D and regulations. 4. Explicit digital definition of “Synergism” of drug combination is established [in which “Synergism‐Claim” has scientific, regulatory, legal, ethical and economic consequences]. 5. Ki will never be greater than IC50. 6. The median‐dose (Dm) is the harmonic mean of kinetic constants, Kii and Kis. 7. The PD software, e.g., CompuSyn, allows 5 dynamic graphic transformations for diagnostic plots, illustrations automatically by computer simulation within 1 second after data entries. This theory/method has been cited 9,916 times during 2012 to 2017. The Scopus Analysis (11.18.2017) indicated that Chou's publications have been cited by the papers distributed in the follow disciplines: Medicine (56.2%), Biochem. (50.8%), Pharmacol. (25.3%), Chem. (15.6%), Immuno. (4.3%), Chemical Engineer. (3.5%), Mater. Sci. (2.1%), and Others (9.3%); and by number of citing papers from Institutions: Mem. Sloan‐Kettering CC (475), Harvard Med. Sch. (380), MD Anderson CC (325), NIH (305), NCI (251), Inserm (200), Chinese Aca. Sci. (155), UC‐SD (130) and Duke U. (127). The above indicate the broad utilities and high impact of the MAL based PD theory and applications.Support or Funding InformationPD Science LLC Fund‐17This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
p23 Modulates Aryl Hydrocarbon Receptor Protein Levels in Normal Cell Lines
Authors: Chen Jinyun , Yakkundi Poonam , Chan William K. 
Published: June 2021

Aryl hydrocarbon receptor (AHR) is a transcription factor activated in response to exposure of environmental toxins. p23, a co‐chaperone of AHR, was found to be capable of regulating ligand‐dependent AHR activation and functions. Previous study from our laboratory showed that low expression of the p23 protein is associated with poor AHR protein stability and function in cancer cell lines. While in a p23 null mouse model, it was reported that p23 did not affect the AHR expression. To better understand this apparent dichotomy, we explored the possibility that the AHR expression may be regulated differently in cancer cells than in normal cells. We analyzed the AHR protein levels in three normal cell lines with either wild‐type or reduced p23 protein levels (55–62% of the wild‐type p23 protein levels), namely human breast epithelial cells (MCF‐10A), human bronchial tracheal epithelial cells (HBTEC), and mouse type I regulatory T cells (Tr1). We observed that the AHR expression was significantly reduced by about 38–57% compared to the controls after 72 hours transfection of p23‐specific shRNA in all three normal cells, indicating that p23 is more important for the control of AHR expression in normal conditions than previously expected. In conclusion, our data clearly support that p23 is necessary in maintaining the AHR protein levels in normal and cancer cells. Insights on underlying mechanisms and implications will be presented and discussed.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evaluation of non‐clinical safety of Frutalin in adult Zebrafish (Danio rerio)
Authors: Monteiro‐Moreira Ana Cristina Oliveira , Vieira‐Neto Antônio Eufrásio , Ferreira Maria Kueirislene Amâncio , Mendes Francisco Rogênio Silva , Barros Adriana Rolim Campos , Magalhães Francisco Ernani Alves , Moreira Renato Azevedo 
Published: June 2021

Our previous studies have shown several biotechnological and biomedical activities of Frutalin (FTL), a lectin from Artocarpus incisa seeds. Its multiple specificity for α‐D‐galactose and a‐D‐mannose promotes affinity for glycans present in various cell receptors, such as ion channels. FTL presents isoforms, according to its deconvolved mass spectrum, which increases the biotechnological potential of the molecule, allowing the prospection of new applications. This study was conducted to evaluate the nonclinical safety of FTL in adult Zebrafish (Danio rerio). The action of FTL (1.0 mg/mL; 20 μL; ip) on the locomotor activity of adult zebrafish (Danio rerio) (ZFa; n = 6/group) was evaluated in the open field test.1 As controls were used one group without treatment (Naive) and another with vehicle (Saline 0,9%, 20 μL, ip). After 24 h of treatments, mortality was analyzed and the concentration able to kill 50% (LC50) of the zebrafish was calculated.2 The experimental procedures were approved by the Ethics Committee for the Use of Animals (CEUA), under protocol no. 7210149/2016, of the State University of Ceará (UECE), Fortaleza, Ceará. Despite interacting with other cellular receptors and promoting other pharmacological activities, FTL, active in the physiological environment of Zebrafish, did not modify the locomotor activity nor did it prove to be toxic to the animals, suggesting that its lectin activity, capable of promoting pharmacological activities when recognizing glycans of several ion channels, and membrane protein receptors, can not be associated with toxicity or locomotor damage.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.