bluuebunny/crossref_metadata_2025_split huggingface dataset:
Buspirone Does Not Alter the Reinforcing, Subjective or Physiological Effects of Intranasal Cocaine
Authors: Stoops William , Bolin B , Lile Joshua , Rush Craig 
Published: June 2021

Despite extensive research efforts, no effective medications have been identified for managing cocaine use disorder. The purpose of this study was to evaluate buspirone, a dopamine D3/ D4 receptor antagonist and serotonin 5‐HT1A receptor partial agonist, as a candidate cocaine pharmacotherapy using human laboratory methods. To this end, nine current cocaine users completed a repeated measures, inpatient protocol in which they were maintained on placebo and buspirone (30 mg/day) in counterbalanced order for 3 days before completing experimental sessions. The reinforcing, subjective and physiological effects of placebo and intranasal cocaine (15 and 45 mg) were assessed during those sessions. Cocaine functioned as a reinforcer and produced other prototypic effects (i.e., increased ratings of good effects and heart rate in a dose‐ and time‐related manner). Although cocaine was well tolerated during buspirone maintenance, there were no systematic differences observed in these outcome measures as a function of buspirone condition. These data indicate that this dosing regimen of buspirone did not change the pharmacodynamic effects of cocaine, consistent with clinical trial data suggesting that buspirone does not reduce cocaine use. However, longer dosing periods and higher buspirone doses should be tested to more fully determine the potential utility of buspirone for managing cocaine use disorder.Supported by R21DA034095.
Interactions of Modafinil or Methylphenidate with the Reinforcing and Neurochemical Effects of Cocaine
Authors: Tanda Gianluigi , Mereu Maddalena , Hiranita Takato , Chun Lauren , Lopez Jessica , Coggiano Mark , Quarterman Juliana , Newman Amy , Katz Jonathan 
Published: June 2021

Modafinil (MOD) and methylphenidate (MPH) are FDA‐approved wakefulness‐promoting agents, and MPH is also approved as a medication to treat attention deficit disorders. College students, who misuse MOD and MPH as “smart drugs” to increase cognitive performance, are also likely a population at high risk for abuse of illicit stimulants, such as cocaine (COC). Since MOD and MPH like COC target the dopamine (DA) transporter, and their interactions have not yet been fully described, it is critical to determine the effects of MOD on the reinforcing effects of COC. In the present study MOD (0.1‐10 mg/kg iv) failed to maintain self‐administration (SA) behavior above vehicle levels in rats trained with COC (0.1‐1 mg/kg iv), whereas MPH SA was maintained above vehicle levels at doses comparable to those for COC SA (0.1‐1 mg/kg iv). However, both MOD (10‐32 mg/kg ip) and MPH (1‐10 mg/kg ip) pre‐treatments dose‐dependently potentiated COC SA, shifting the dose‐response curve to the left. COC, at doses that maintain SA, also produced dose‐related stimulation of DA levels in the nucleus accumbens shell, a brain area involved in drug reinforcement. While MPH enhanced this cocaine‐dependent increase in DA, MOD had no significant effects. In summary, MOD had an unusual stimulant profile compared to COC and MPH. The results suggest MOD may enhance reinforcing effects when combined with sub‐threshold doses of COC. Further the results indicate a basis for clinical use of MOD as an agonist substitution therapy for stimulant abuse, as it shares many pharmacological effects of COC, but appears to have low abuse liability of its own.Support: NIDA/IRP
RGS Regulation of Gαi2 in the Mouse Hippocampus Modulates 5‐HT1A Receptor Mediated Antidepressant‐Like Activity
Authors: Senese Nick , Jutkiewicz Emily , Traynor John 
Published: June 2021

Regulators of G‐protein signaling (RGS) are negative regulators of heterotrimeric G protein coupled receptor signaling. A single point mutation (G184S) in Gαi2 abolishes the RGS negative regulatory effects. Mice expressing two knock‐in copies of this RGS insensitive (RGSi) Gαi2 protein display a robust antidepressant‐like phenotype due to increased 5‐HT1A receptor (5‐HT1AR) signaling. The objective of this study was to test the hypothesis that the 5‐HT1ARs in the hippocampus are critical determinants of the phenotype.Mice (C57BL6) expressing RGSi‐Gαi2 and their wild‐type littermates were implanted with intra‐hippocampal drug infusion cannulae. Antidepressant‐like activity was evaluated by measuring time spent immobile in the tail suspension test (TST). The RGSi‐Gαi2 mice showed decreased immobility in the TST and this was reversed by infusion of the selective 5‐HT1AR antagonist WAY‐100635 (WAY) directly into the hippocampus. Conversely, direct hippocampal infusion of the 5‐HT1AR agonist 8‐OH‐DPAT produced decreased immobility in wild type mice that was reversed by the peripheral administration of WAY. Peripheral, but not hippocampal, administration of 8‐OH‐DPAT to wild‐type mice caused a 5‐HT1AR‐mediated hypothermia. The mutant mice showed no differences in 5‐HT1AR or Gα protein expression in the hippocampus compared with their wild‐type littermates.These results are consistent with the hypothesis that the antidepressant‐like phenotype in the RGSi‐Gαi2 knock‐in mice is due to altered 5‐HT1AR signaling in the hippocampus. These findings identify hippocampal 5‐HT1AR specifically coupled to Gαi2, and the RGS proteins that regulate them, as potential targets for antidepressant medications. Supported by MH097012 and GM007767.
The Use of Thalidomide in Treating PTSD and Co‐morbid Pain in an Animal Model of PTSD
Authors: Dib Patrick , Standifer Kelly 
Published: June 2021

Single‐prolonged stress (SPS) is an established animal model for post‐traumatic stress disorder (PTSD). We have previously reported that SPS induces increases in serum TNF‐α levels as well as long‐lasting mechanical allodynia and thermal hyperalgesia at day 3 post SPS. The aim of this study was to determine the effects of TNF‐α blockade on development of PTSD and co‐morbid pain symptoms. To achieve this, male Sprague‐Dawley rats were subjected to SPS; half of the SPS and control group rats were immediately presented with 50 mg/kg thalidomide (THL), a potent TNF‐α blocker, in 10% DMSO vehicle, daily, i.p for 5 days; non‐SPS rats received vehicle injections. THL almost completely prevented mechanical allodynia and reduces thermal hyperalgesia associated with SPS (p<0.05) that is normally noted as early as day 3 post SPS, without altering baseline sensitivity itself. Using a 2‐way ANOVA, a significant interaction was observed between THL and SPS (p<0.0001). Additionally, utilizing the elevated plus maze test, THL treatment reduces anxiety like behaviors, specifically mobility time, immobility time, open entries and time spent in open arms (p<0.05). Also, using a 2‐way ANOVA, a significant interaction was observed between THL and SPS (p<0.05) This suggests that immunomodulatory drugs such as THL, may offer a novel therapeutic method to prevent or reduce symptoms of PTSD and co‐morbid pain if administered shortly after the traumatic event.SupportDepartment of the Army DMRDP W81XWH‐11‐2‐0077
Mechanisms Contributing to Lack of Antidepressant Efficacy in Juveniles and Adolescents
Authors: Mitchell Nathan , Fraser Rheaclare , Owens W.Anthony , Horton Rebecca , Vitela Melissa , Gould Georgianna , Koek Wouter , Daws Lynette 
Published: June 2021

Depression is a major health problem where most patients are not effectively treated. This problem is compounded in children where only two antidepressants are clinically approved. Both are selective serotonin (5‐HT) reuptake inhibitors (SSRIs), which are often less efficacious in young populations compared to adults. We found the antidepressant‐like effects of SSRIs in juvenile mice (21 days post‐partum) was reduced relative to adult mice; however, there was no difference in expression of hippocampal 5‐HT transporter (SERT), the target protein of SSRIs, to account for the reduced SSRI efficacy. Increased extracellular 5‐HT after SSRI treatment is thought to trigger downstream events for therapeutic response. Our data suggests transporters capable of 5‐HT uptake other than SERT, such as organic cation transporters (OCTs) and the plasma membrane monoamine transporter (PMAT), may be preventing extracellular 5‐HT from climbing to therapeutically relevant levels after SSRI treatment. The binding site density of [3H]decynium‐22 (D22), an OCTs/PMAT blocker, was greater in juvenile mice than adults. Western blots revealed the greater [3H]D22 binding was likely driven by greater PMAT protein expression in juvenile mice. In our preliminary studies, D22 (0.01mg/kg) produced antidepressant‐like effects in juvenile but not adult mice. Using in vivo chronoamperometry, a technique which measures region specific 5‐HT clearance in brain, studies are underway to determine whether the antidepressant‐like effects of D22 in juvenile and adolescent mice are related to its ability to inhibit 5‐HT clearance.Support: NIH MH093320 / MH064489
The Effects of Siwu Mixture on Chemotherapy‐induced Rat's Ovary
Authors: Zhang Yu‐li , Xie Wei , Xue Xiao‐ou 
Published: June 2021

ObjectiveTo observe the influence of Siwu Mixture on structure changes of ovary and ovarian granulose cell apoptosis in rat model.MethodThirty female SD rats were randomly divided into siwu , model and normal group.The former 2 groups were respectively given Siwu Mixture and purified water intragastrically after the intraperitoneal injection of Cisplatin, and the normal group was given purified water intragastrically after the injection of saline solution. The vaginal secretion smears were taken everyday. On the 8th experimental morning, serum hormones were assayed and bilateral ovaries were taken. We observed the ultra‐structure and microstructure changes of ovary,imaged micro measurement the particles cell layer maximum thickness at Image Analyzer and use TUNEL method to detecte particles cell apoptosis.Result1. Compared with normal group,the FSH was elevated statistically (7.06±1.88 vs 9.19±0.55 U·L‐1, P<0.05) in model group rats while there was no statistical differences in serum hormones between normal and siwu group,the apoptosis index was elevated statistically (0.03±0.01 vs 0.37±0.09 %, P<0.05) in model group rats, while the particles cell layer maximum thickness was decreased statistically(16.16±5.35 vs 10.87±1.45 μm, P<0.05) in model group rats.Compared with model group, the apoptosis index was lower statistically in siwu group rats(0.37±0.09 vs 0.23±0.1%, P<0.05)while there was no statistical difference in the particles cell layer maximum thickness between the two groups(10.87±1.45 vs 16.16±5.35 μm, P>0.05),and the microstructure and ultra‐structure changes of siwu group's ovary demonstrated the lower degree of injury .ConclusionSiwu Mixture could promote the recovery of ovarian function ,but cannot afford complete fix.
Ferulic Acid Methylester from Tamarix aucheriana, Shows Anticancer Activity against Human Colorectal Cancer Cells: Underlying Molecular Mechanisms
Authors: Abaza Mohamed , Afzal Mohammad , Al‐Attiyah Rajaa , Guleri Radhika 
Published: June 2021

Natural products have long been used to treat many diseases, including cancer and therefore, these are good candidates for drug development.The present study focuses onthe isolation and identification of potential chemo‐therapeutic/preventive constituents from Tamarix aucheriana using bioactivity guided fractionation. Ferrulic acid methylester (FAME) was identified as an active agent. The potential of FAME to control the growth of human colorectal cancer cells, enhance their sensitivity to conventional chemotherapeutic drugs and the potential biological targets and molecular mechanisms of FAME action were investigated. FAME showed time‐ and dose‐dependent anti‐mitogenic effect on colorectal cancer cells with little cytotoxicity for normal human fibroblasts. FAME inhibited the colony formation, induced morphological changes, induced apoptosis, and inhibited DNA‐binding activity of NFkB, the various proteolytic activities of proteasome and invasion in colorectal cancer cells. FAME up‐regulated p15, p18, p19, p21, p27, p53, and p57, pro‐apoptotic gene expression and down‐regulated Cdk1, Cdk2, Cdk4, and Cdk6, anti‐apoptotic gene expression. FAME showed differential potential to enhance the sensitivity of colorectal cancer cells to conventional chemotherapeutic drugs. These results indicate the chemo‐therapeutic potential of FAME.Acknowledgment: This study was supported by Kuwait University, Research Grant # SL05‐04
Renal Effects of Glucose Transporter 4 in Nω‐nitro‐L‐arginine /High Salt Induced‐Hypertensive Rats
Authors: igbe ighodaro , Omogbai Eric , Oyekan Adebayo 
Published: June 2021

The aim of study was to determine the renal effects of glucose transporter 4 (GLUT4) in a hypertensive nephropathy rat model. GLUT4 has been implicated in insulin resistance and hypertension in several animal models, however its role in hypertensive nephropathy still remain unclear. Hypertensive nephropathy was induced by Nω‐nitro‐L‐arginine (L‐NNA), a nitric oxide (NO) synthase inhibitor, 100 mg/ml in drinking water and high salt (HS) diet (4 % NaCl), for 15 days in the presence of insulin, a GLUT 4 agonist (1 U/day) and indinavir, a GLUT4 inhibitor (80 mg/kg/day). Decreased basal renal medullary and cortical blood flow was enhanced in LNNA/HS/indinavir group (p<0.01) but attenuated (p<0.05) by insulin. Proteinuria was increased (p<0.01) in LNNA/HS/indinavir group but attenuated (p<0.01) by insulin. Insulin‐treated rats decreased urine NO (p<0.01) and urine Na2+ (p<0.01) compared to other treated animals. In indinavir‐treated animals, urine Na2+ was increased by benzamil, an epithelial sodium channel (ENaC) inhibitor (p<0.01) and hydrochlorothiazide, a sodium/chloride co‐transporter (NCC) inhibitor (p<0.05). GLUT4 exerts a renoprotective role which may be related to increase NO production. The antinatriuretic effects of GLUT4 appear to be due to enhancement of ion transport activity of ENaC and NCC at the renal tubules.This study was supported by National Institutes of Health grant HL03674.
Pregnancy‐Related Hormones Modulate Protein Expression of Hepatic DMEs and Transporters in HepaRG Cells
Authors: Farooq Muhammad , Vrana Marc , Parsad Bhagwat , Unadkat Jashvant 
Published: June 2021

Pregnancy modulates the activity of a variety of drug metabolising enzymes (DMEs) and some transporters (TRs) resulting in altered clearance of their respective substrate drugs. Previously, we have demonstrated that the in vivo induction of CYP3A activity could be replicated in HepaRG cells exposed to pregnancy‐related hormones (PRHs). However, data on the effect of PRHs on the protein expression of other DMEs and TRs is lacking. The aim of the current study was to fill this gap in knowledge.Terminally differentiated HepaRG cells were treated for 72h (n=3) with cortisol (C), estradiol (E2), placental growth hormone and pituitary growth hormone (GHs) individually or in combination (PRHs) at their 10X plasma concentrations observed during the third trimester. Then, the cells were lysed, membrane fraction isolated, and target proteins were quantified using surrogate peptide based LC‐MS/MS methods.C caused 蠅100% increase in CYP3A4, CYP2C9, OATP2B1 and OCT1 protein expression and 蠅 50% decrease in UGT2B7, UGT2B15, MRP2 and P‐gp protein expression. Identical trend was observed with the combination of hormones (PRHs).Our findings predict that the clearance of some drugs (e.g. by CYP3A4) will be increased during pregnancy while that of others (e.g. by UGT2B7) will be decreased. While additional studies with PRHs at their plasma concentrations (1X and 10X) observed during all three trimesters are needed, HepaRG cells appear to be an excellent in vitro model to elucidate the mechanism by which the expression (and therefore activity) of various DMEs and TRs is modulated during pregnancy.Supported by NIH grant P01DA032507
Multidrug and toxin extrusion transporters play a key role in natriuresis as a dopamine transporter
Authors: Kajiwara Moto , Ban Tsuyoshi , Hanada Yuki , Matsubara Kazuo , Masuda Satohiro 
Published: June 2021

Background and aimThe intrarenal dopaminergic system is likely responsible for regulating over 50% of net renal salt and water excretion when salt intake increases. Although dopamine synthesis is localized at proximal tubular cells, the molecular mechanism underlying dopamine secretion into urine remains unknown. Multidrug and toxin extrusion (MATE, SLC47A) is expressed in high levels in the brush border membrane of proximal tubular cells mediating the efflux of organic cations, such as metformin and cisplatin, from epithelial cells into urine. Therefore, we hypothesized that MATE mediates secretion of dopamine, a cationic catecholamine, into tubule lumen and consequently regulates natriuresis.MethodsUrinary Na+ and dopamine concentration were respectively measured with an ion‐selective electrode (cobas6000, Roche) and a liquid chromatography‐tandem mass spectrometry.ResultsUptake of [3H]dopamine by HEK293 cells expressing human (h) MATE1, hMATE2‐K, and mouse MATE1 exhibited saturable kinetics showed that dopamine is a substrate of MATE transporters. After acute saline‐loading experiments, urinary dopamine was detected in wild‐type mice (WT), but was hardly present in MATE1‐knockout mice (KO). Another experiment showed that the amount of urinary Na+ excretion in WT increased to 12.3‐fold than that of the control group, although the amount in MATE1‐KO increased to only 1.5‐fold than that of the control group.ConclusionIn conclusion, our results indicated a critical role of MATE in dopamine secretion into tubular lumen, along with MATE's regulation of Na+ excretion into urine.
Dobutamine Stress Testing as an Early Diagnostic for Radiation‐Induced Heart Disease
Authors: Lieblong Benjamin , Bhatti Sabha , Mulkey Robin , Fletcher Terry , Rusch Nancy , Boerma Marjan 
Published: June 2021

Radiation‐induced heart disease (RIHD) is a potentially severe side effect caused by irradiation of all or part of the heart in radiotherapy for intrathoracic and chest wall tumors. Currently, there is no recommended approach for early detection of the disease. However, dobutamine stress testing (DST) is used clinically to unmask other forms of heart disease. Our study sought to determine whether DST may represent an early diagnostic strategy to detect RIHD. Male Sprague‐Dawley rats received X‐irradiation locally to the heart via 5 fractions of 0 (sham), 6, or 9 Gy, and then animals were subjected to DST after 2, 3 and 6 months. Dobutamine was infused in increasing doses (10 ‐ 60 µg/kg/min i.v.) while echocardiography and electrocardiography were performed. At 3 months, radiation caused a dose‐dependent increase in myocardial collagen deposition and alterations in left ventricular function, both of which progressively worsened by 6 months. However, as early as 2 months after irradiation, DST dose‐dependently caused ST‐segment elevation on ECG in irradiated rats, while functional alterations were not present at this time point. The ST‐segment elevations may be an indication of myocardial ischemia. Our results suggest that DST may induce ST segment abnormalities in irradiated hearts prior to detection of functional or histological abnormalities, and thereby may represent a strategy to diagnose and treat myocardial ischemia during early RIHD to prevent later cardiac events.Supported by CA1487679 to MB (NIH/NCI)
Impaired Function in Rats Following Delayed Reversal of Volume Overload Heart Failure is Rescued by Levosimendan
Authors: Wilson Kristin , Guggilam Anuradha , Galantowicz Maarten , West T. , Cismowski Mary , Lucchesi Pamela 
Published: June 2021

ObjectivesThis study investigated if delayed surgical intervention in rats with aortocaval fistula (ACF)‐induced volume overload HF adversely impacts LV functional recovery and if pre or post‐surgical treatment with levosimendan (Levo, myofilament Ca2+ sensitizer) alters LV recovery.Methods and ResultsACF or Sham surgery was performed in male Sprague‐Dawley rats (200‐240 g) 4 or 8 weeks prior to reversing (REV) the shunt in a subset of rats. REV during established HF at 8 wks resulted in impaired LV systolic (%FS, Ees, PRSW: 31.7%, 0.428 mmHg/µL, 57.4 mmHg, respectively; p<0.05 vs Sham) and diastolic function (tau, dP/dtmin; 12.2 msec, ‐6294 mmHg/sec, respectively; p<0.05 vs Sham), while REV during pre‐HF at 4 wks resulted in delayed, but improved LV systolic (%FS, Ees, PRSW: 39.7%; 0.813 mmHg/µL; 87.4 mmHg, p<0.05 vs ACF) and diastolic function (tau, dP/dtmin; 10.8 msec; ‐7128 mmHg/sec, p<0.5). A subset of ACF rats reversed at 8 wks received Levo (1 mg/kg) for 4 wks prior to REV (Levo‐P) or for 11 wks following REV (Levo‐R). Levo‐P improved LV function prior to and after REV (%FS = 42% and 31.8% at Wks 8 & 19, respectively), while Levo‐R improved LV function through the end of the study (%FS, Ees, PRSW, tau, dP/dtmin: 42.4%, 0.859 mmHg/µL, 98.7 mmHg, 8.7 msec, ‐9583 mmHg/sec, respectively; p<0.05 vs Sham). Improved LV function in Levo‐R correlated with normalized α‐to‐β‐myosin heavy chain and increased cTnI Ser‐23/24 phosphorylation (2‐fold vs REV).ConclusionThese results demonstrate that LV dysfunction persisted when volume overload was reversed during established HF but was rescued if Levo was given continuously post‐REV.
The Role of Piezo1 in Regulating Cytosolic Calcium Level in Aortic Smooth Muscle Cells in Rats
Authors: Zhang Jinglin , Tjong Jeff , Tang Nelson Leung‐sang , Yao Xiaoqiang 
Published: June 2021

IntroductionPiezo1 proteins are large integral proteins with 24‐39 transmembrane domains. Piezos are expressed in several tissues. Piezo ion channel family is evolutionarily conserved in mechanotransduction. We examined the expression level of Piezo1 in rat aortic smooth muscle cells (ASMCs) and determined stretch induced cytosolic calcium rise in these cells.MethodmRNA and protein expressions of piezo 1 and 2 proteins in rat tissues were detected by RT‐PCR and western blot study, respectively. Stretch‐induced cytosolic calcium elevation in RASMC was determined by confocal microscopy.ResultsIn rats, Piezo1 mRNA and protein was highly expressed in aorta, aortic smooth muscle cells and mesenteric artery, but low in cerebral artery, nodose ganglion and petrosal ganglion. Stretch‐induced [Ca2+]i elevation was found to be increased in Piezo1 over‐expressing rat ASMCs compared with native rat ASMCs.ConclusionThe results indicated that Piezo1 may play a functional role in stretch induced [Ca2+]i elevation in rat arterial smooth muscle cell.