bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blueberry Supplementation Alters Biomarkers of Oxidative Stress in High‐fat Fed Rats
Authors: Keirsey Katherine I , Lee Sunhye , de La Serre Claire B , Fischer Joan G 
Published: November 2023

Obesity is associated with enhanced inflammation and oxidative stress. Blueberries contain high levels of anthocyanins, which may mitigate oxidative stress through direct antioxidant activity and/or alterations to antioxidant enzyme activities. Our objective was to determine if blueberry supplementation would decrease systemic, hepatic, and colonic oxidative stress in high fat fed rats. Wistar rats (n= 8/group) were fed low‐fat (LF, 10% fat), high‐fat (HF, 45% fat) or high‐fat with 10% blueberry (HF_BB) diets for 8 wks. HF and HF_BB diets were isocaloric and all diets were matched for sugar and fiber content. Levels of urinary F2‐isoprostanes, a marker of systemic lipid peroxidation, and hepatic and colonic malondialdehyde (MDA) were assessed. Activities of glutathione peroxidase (GPx) and glutathione reductase (GR), antioxidant enzymes that may be altered by anthocyanins, were also measured in liver. Unexpectedly, blueberry supplementation resulted in a small but significant increase in urinary F2‐isoprostanes in high fat fed rats. Hepatic MDA was elevated by HF feeding but was significantly lower in HF_BB fed animals compared to HF fed animals. Blueberry supplementation did not enhance hepatic GPx or GR activities, suggesting these enzymes did not account for the reduction in hepatic MDA. Although colonic MDA was lower in HF_BB animals compared to HF animals, the difference was not significant. These results suggest that blueberry supplementation may alter oxidative stress in high fat fed animals in a tissue‐specific manner.Support or Funding InformationThis material is based on work that is supported by the National Institute of Food and Agriculture, USDA, under award number 2014‐67017‐21757 & GA Agricultural Experiment Station.
Novel Gene Signature Classification Model for Predicting Severity of Skin Fibrosis
Authors: Yates Cecelia C. , Jones Jacqueline D , Feghali‐Bostwick Carol , Conley Yvette 
Published: November 2023

Scleroderma or systematic sclerosis (SSc) is a clinically heterogeneous disease with a complex phenotype. The disease is characterized by vascular dysfunction, tissue fibrosis, internal organ dysfunction, and immune dysfunction. Because it has no validated biomarkers or effective disease‐modifying therapies, scleroderma represents a major unmet medical need. Although a rare disease those afflicted with the systemic form of the disease suffer from severe vascular and other organ manifestations including pulmonary fibrosis. The leading cause of death is end‐organ dysfunction caused by fibrosis. An improved understanding of the molecular mechanisms involved in the initiation and perpetuation of fibrosis is mandatory to facilitate the rational design of new diagnostic and therapeutic strategies to detect earlier, arrest, and perhaps even reverse disease. We have also determined that chemokines, cytokines that help recruit immune cells to sites of infection and function in the migration of cells to aid in tissue repair, are key to ECM regulation. Diverse expressions of chemokine receptors on multiple dermal cellular populations are likely driven by inflammatory stimuli from excessive fibrosis. The contribution of chemokines to the human immune response is known, but its direct role on fibroblast‐induced ECM synthesis resulting in SSc disease severity is less clear.We three constructed classification models for making predictions on the severity of SSc, based on (1) gene expression profiles and (2) identifying marker gene sets that correlate with the classification. We utilized two existing genome‐wide microarray gene expression data from the Gene Expression Omnibus (GEO) database of SSc patients. Patients were divided into two groups based on skin score: low 0–17 (low‐mild) and high 18–51 (moderate‐sever modified Rodnan skin thickness score (mRSS), a predictor of disease outcome. In both the Group 1 and Group 2 dataset, random forest (RF) classifier combined with correlation‐based feature selection method (CFS) and naive bayes (NB) combined with CFS or support vector machine based recursive feature elimination method (SVM‐RFE) performed better than all other classification and feature selection methods. We then perform DAVID‐based GO enrichment analysis to evaluate if the chemokine pathways are enriched among differentially expressed genes. First, these data support the feasibility of accurately aligning the phenotype of each subset of patients and individual patient mRSS to generate gene signatures. Second, we uncovered differential expression of chemokine and ECM genes profiles that could potentially predict diseases severity
Individual Differences in the Relative Reinforcing Effects of 3,4‐Methylenedioxypyrovalerone (MDPV) Under Fixed and Progressive Ratio Schedules of Reinforcement in Rats
Authors: Gannon Brenda M. , Galindo Kayla I. , Rice Kenner C. , Collins Gregory T. 
Published: November 2023

The abuse of “designer drugs” such as “bath salts” over the past 10 years has reached epidemic proportions. 3,4‐Methylenedioxypyrovalerone (MDPV), a synthetic cathinone and common “bath salt” constituent, is classified by the US Drug Enforcement Agency as Schedule I. MDPV has a cocaine‐like mechanism of action and the present study aimed to directly compare the reinforcing effects of MDPV and cocaine in male Sprague‐Dawley rats. When available under a fixed ratio (FR) 1 schedule, a rapid acquisition of responding was observed for both MDPV (0.032 mg/kg/inf; n=28 of 32) and cocaine (0.32 mg/kg/inf; n=13 of 16). Upon increasing the response requirement to an FR5, two distinct patterns of responding for MDPV emerged, with 0.032 mg/kg/inf MDPV maintaining relatively low rates (~35 infusions/90 min) in approximately half of the rats and significantly higher rates of responding (~85 infusions/90 min) in the other rats. These differential patterns of responding were observed across a range of doses of MDPV (0.0032–0.1 mg/kg/inf), as well as when cocaine (0.032–1 mg/kg/inf) was substituted for MDPV. Unlike in rats trained to self‐administer MDPV, the pattern of responding in cocaine‐trained rats was much more homogenous, regardless of whether they responded for cocaine, or MDPV. In order to determine if these differences in FR responding for MDPV were due to individual differences in the reinforcing effectiveness of MDPV, dose‐response curves (n=16) for MDPV (0.001–0.32 mg/kg/inf) were generated under a progressive ratio (PR) schedule, and compared to those obtained for cocaine (0.032–1.78 mg/kg/inf), methamphetamine (0.01–0.178 mg/kg/inf), and caffeine (0.032–1.78 mg/kg/inf). MPDV was the most potent (MDPV > methamphetamine > cocaine >> caffeine) and effective (MDPV > methamphetamine = cocaine >> caffeine) reinforcer. Although the potency of these drugs to maintain PR responding did not differ between the two sub‐sets of rats, those that self‐administered more MDPV under the FR5 schedule also earned significantly more infusions when MDPV was available under a PR schedule. Moreover, these differences were also apparent when methamphetamine, cocaine, and to a lesser degree, caffeine were available for responding under the PR schedule. Although the factors that contributed to unusually high rates of MDPV‐maintained responding, observed in a sub‐set of rats, are unclear, they might be related to individual differences in human drug‐taking behavior.Support or Funding InformationThis study was supported by an NIH research grant (R01 DA039146) from NIDA, as well as the NIH Intramural Research Programs of NIDA and NIAAA.
Revisiting the Tamoxifen Scaffold for Therapeutics Against Amphetamine Abuse
Authors: Carpenter Colleen , Altshuler Rachel , Zestos Alexander , Sorenson Roderick , Kennedy Robert , Jutkiewicz Emily , Showalter Hollis , Gnegy Margaret 
Published: November 2023

The abuse liability of amphetamine (AMPH) is largely due to its ability to act as a substrate at the dopamine transporter and significantly increase extracellular dopamine in the brain. Protein kinase C (PKC) activation contributes to this process and blocking PKC reduces AMPH activities. Tamoxifen remains the only available brain‐permeant PKC inhibitor and data from our lab show that tamoxifen reduces AMPH‐stimulated dopamine release from synaptosomal preparations. However, tamoxifen is also a selective estrogen receptor modulator and though effective against the recurrence of breast cancer, it also causes side effects such as hotflashes that affect patient compliance. Therefore, revisiting the tamoxifen scaffold may be an essential first step towards filling the current need for a therapeutic against AMPH abuse.Our goal is to use information from previous structure‐activity relationship studies to create a new generation of tamoxifen analogs with increased selectivity for PKC inhibition and reduced affinity at the estrogen receptor. Here we evaluated the extent to which our lead compound, C091, reduced AMPH‐stimulated dopamine release and AMPH‐reinforcing effects in rats. We also investigated more thoroughly the effects of C091 at the dopamine transporter.C091 inhibits PKC activity with an IC50 of 0.2 μM in our cellular assay and does not bind to estrogen receptor α at concentrations up to 1 μM. Suprafusion of rat striatal synaptosomes with concentrations from 0.3 μM to 3 μM C091 robustly and significantly reduces dopamine efflux stimulated by 10 μM AMPH. Similarly, direct administration of 1 μM C091 into the nucleus accumbens reduces both dopamine release and locomotion induced by 2 mg/kg i.p. AMPH by ~40% as measured during microdialysis in freely‐moving rats. Initial data show that administering 6 mg/kg s.c. C091 reduces i.v. AMPH self‐administration (0.032 mg/kg AMPH per infusion) by ~40% but does not affect food self‐administration in rats. 3 μM C091 significantly inhibits [3H]dopamine uptake in rat striatal synaptosomes. Yet, unlike classical dopamine transporter inhibitors, such as cocaine, C091 does not increase basal dopamine or locomotion in vivo, suggesting C091 will not have an abuse potential. Interestingly, C091 does not displace [3H]WIN 35428 binding at the dopamine transporter showing that it does not bind near the active site. This suggests that C091's effects on AMPH action could be due to allosteric modulation of the transporter and/or its interaction with a mediator of dopamine transporter functioning, such as PKC.Support or Funding InformationNIH grant 1R01 DA11697, HHMI International Student Research Fellowship, Rackham Graduate Student Research Grant
Cocaine‐like Discriminative Stimulus Effects of Amphetamine, Cathinone, and Alpha‐Pyrrolidinovalerophenone Analogs in Male Rhesus Monkeys
Authors: Smith Douglas , Negus Steve , Blough Bruce , Banks Matthew 
Published: November 2023

Synthetic cathinones, popularized as “bath salts,” are beta‐ketone amphetamine analogs and have emerged worldwide as a diverse class of abused compounds that are classified as either monoamine transporter inhibitors or monoamine transporter substrates. Chemical structure modifications have been shown to dramatically impact a drug's abuse liability. Preclinical drug discrimination procedures are useful for determining structure activity relationships (SAR) and the behavioral pharmacology of an abused drug's subjective‐like effects. However, the SAR of synthetic cathinones using a drug discrimination procedure in nonhuman primates is unknown. The first aim of the present study was to determine whether amphetamine vs. cathinone analogs were differentially sensitive to a 3,4‐methylenedioxy moiety. The second aim was to determine whether the monoamine transporter inhibitor alpha‐pyrrolidinovalerophenone (alpha‐PVP) and the monoamine transporter substrate methcathinone were differentially sensitive to 4‐methyl and 3,4‐methylenedioxy moieties. Male rhesus monkeys (n=4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two‐key food‐reinforced discrimination procedure. Potency and time course of cocaine‐like discriminative stimulus effects were determined for (±)‐amphetamine, (±)‐cathinone, (±)‐methamphetamine, (±)‐methcathinone, (±)‐alpha‐PVP, and their 3,4‐methylenedioxy analogs. Additionally, the behavioral effects of (±)‐4‐methylPVP and (±)‐4‐methylmethcathinone were determined to examine SAR differences between monoamine transporter inhibitors and substrates. Amphetamine, cathinone, methamphetamine, and methcathinone all produced dose‐dependent cocaine‐like effects. Despite similar potencies to produce cocaine‐like effects, cathinone and methcathinone displayed a shorter time course compared to their respective amphetamine derivatives. The addition of a 3,4‐methylenedioxy moiety attenuated the cocaine‐like discriminative stimulus effects of the monoamine transporter substrate cathinone to a greater extent than amphetamine and methamphetamine but not for methcathinone; however, the effects of methcathinone were reduced by the 4‐methyl moiety. The monoamine transporter inhibitor alpha‐PVP also substituted completely for cocaine, and neither the 3,4‐methylenedioxy nor the 4‐methyl moiety altered the potency or efficacy of alpha‐PVP to produce cocaine‐like effects. Overall, these results suggest that phenyl ring substitutions can differentially affect the pharmacology of amphetamine‐ and cathinone‐based monoamine releasers while exhibiting lesser effects on the pharmacology of structurally related monoamine uptake inhibitors.Support or Funding InformationFunding for this study was supported by National Institutes of Health grants R01‐DA026946, R01‐DA012970, R01‐DA033930, and institutional professional funds.
Blockade of striatal mu opioid receptors attenuates methamphetamine‐induced conditioned place preference
Authors: Logan Mary Caroline , Fisher Trevor J. , Logue Jordan B. , Horner Kristen Ashley 
Published: November 2023

The behavioral effects of METH are mediated by the striatum, which is involved in habit learning and reward association. The striatum can be divided into the patch compartment, which mediates limbic and reward functions, and the matrix compartment, which mediates sensorimotor tasks. METH treatment results in repetitive behavior that is related to enhanced activation of the patch compartment relative to the matrix compartment. The patch compartment contains a high density of mu opioid receptors, while the matrix compartment expresses very few mu opioid receptors, and localized blockade of patch‐based mu opioid receptors prior to METH treatment attenuates enhanced activity of the patch compartment and reduces repetitive behavior. However, while numerous studies have examined patch‐enhanced activity and the contribution of patch‐associated mu opioid receptors to METH‐induced repetitive behavior, it is currently not known whether patch‐enhanced activity occurs during METH‐mediated reward, nor is it known if patch‐based mu opioid receptors contribute to METH reward. The goal of this study was to determine if blockade of patch‐based mu opioid receptors alters METH‐induced conditioned place preference (CPP). A biased conditioning paradigm was used to assess CPP, and conditioning occurred over an 8‐day period. Animals were bilaterally infused in the striatum with the mu‐specific antagonist CTAP (0.8 mg/ml) or vehicle prior to conditioning with METH (2 mg/kg) or saline. Animals were tested for preference 24h after the last day of conditioning, sacrificed and the brains processed for immunohistochemistry. Blockade of patch‐based mu opioid receptors reduced METH‐induced CPP, and reduced patch‐enhanced c‐Fos expression in the striatum following METH‐mediated CPP. These data indicate that patch‐enhanced activity is associated with METH‐mediated reward and patch‐based mu opioid receptors contribute to this phenomenon.Support or Funding InformationDA025303 (KAH)
Alternating Access to a Highly Palatable Diet Alters Amphetamine Sensitivity and Self‐Administration
Authors: Moore Catherine F , Sabino Valentina , Cottone Pietro 
Published: November 2023

Eating disorders and certain forms of obesity are associated with mesolimbic dopaminergic reward dysfunction. Overeating of diets rich in sugar and fat alter dopamine neurotransmission in the nucleus accumbens, likely contributing to the persistence of excessive intake. Amphetamine‐like drugs, which act in the mesolimbic pathway to enhance the release of dopamine, also confer long‐lasting neuroadaptations. However, it is not yet known if a history of disordered eating can alter sensitivity to these drugs. In this study, we investigated the effects of palatable food diet alternation on sensitivity to amphetamine (AMPH) and AMPH self‐administration. Ad libitum diet alternation occurred for 5 weeks prior to any testing. One group was provided a chow diet 7 days a week (‘Chow/Chow’), and a second group was provided chow 5 days a week followed by 2 days of access to a highly palatable, chocolate flavored, high‐sucrose diet (‘Chow/Palatable’). While continuing diet alternation, we measured locomotor activity following an AMPH challenge (0, 0.1, 0.5, 1.0 mg/kg) to test sensitivity during the 2 days of access to the palatable diet as well as when animals were withdrawn from palatable food. Following this within‐subject AMPH challenge schedule, animals were allowed to self‐administer AMPH in water (0.05 mg/ml) in the home cage. ‘Chow/Palatable’ rats exhibited excessive food intake when fed the palatable diet, and pronounced hypophagia when fed the chow diet. ‘Chow/Palatable’ rats also dramatically escalated the intake of the palatable diet during the first hour of renewed access, and during withdrawal, showed compulsive‐like eating as assessed in the light/dark conflict test. During access to palatable food, ‘Chow/Palatable’ rats showed decreased locomotor sensitivity to AMPH at the highest dose, but showed no differences from ‘Chow/Chow’ rats during palatable food withdrawal. When allowed to orally self‐administer AMPH in the home cage, ‘Chow/Palatable’ rats showed an increase in intake during palatable food access, with no differences from ‘Chow/Chow’ rats during withdrawal. These results show that palatable food diet alternation affects AMPH sensitivity and self‐administration, specifically during access to palatable food.Support or Funding InformationResearch was supported by grant numbers DA030425, MH091945, and MH093650 from NIH and NIMH, by the Peter Paul Career Development Professorship (PC), the McManus Charitable Trust (VS), and Boston University's Undergraduate Research Opportunities Program (UROP). CM is supported by the Burroughs Wellcome Fund through the Transformative Training Program in Addiction Sciences and the NIH/NIGMS Training in Biomolecular Pharmacology (GM008541‐17).
Anorexia Increases Sensitivity to Cocaine in Adolescent Rats: Implications for the Dopamine Transporter
Authors: Owens William Anthony , Daws Lynette C 
Published: November 2023

Anorexia is a major public health concern, compounded by a lack of effective treatments. Anorexia is most common in females and often manifests during adolescence. The etiology of anorexia remains unclear, however, dysregulation of dopamine (DA) neurotransmission is a consistent finding. The DA transporter (DAT) terminates DA neurotransmission by high‐affinity uptake of DA into neurons and because of this, it is a primary regulator of both the strength and duration of DA signaling. This critical function, together with strong evidence supporting dysregulation of DA neurotransmission in eating disorders, suggests that DAT function may be aberrant in individuals with anorexia. Surprisingly, however, few studies have investigated the relationship between DAT activity and anorexia.Here we use the activity based anorexia (ABA) model to interrogate the role of DAT in anorexia in male and female Sprague‐Dawley rats aged P30 or P90. The ABA model has many advantages over other models of eating disorders, primary among them is that rats must “choose” between eating and another rewarding condition, exercise. ABA also recapitulates key characteristics of anorexia including hyperactivity, reduced food intake and increased insulin sensitivity. To assay DAT function we assessed the dose‐dependency of the locomotor response to the DAT blocker, cocaine, and measured the kinetics of DA clearance in striatum using in vivo high‐speed chronoamperometry. Quantitative autoradiography was used to assess DAT expression.We found that ABA rats were more sensitive to the locomotor stimulant effects of cocaine, as evidenced by a marked shift to the left in the ascending limb of the dose response curve, compared with control rats. Correspondingly, the descending limb of the dose response curve was also shifted to the left. These effects were most pronounced in adolescent female rats. Preliminary analyses show that DAT expression does not differ between adolescent and adult rats, but that DAT activity is greater in adolescent rats than in adults, and that DAT activity is increased further in ABA rats, relative to control rats. As expected, ABA rats lost the most weight and exercised more than control groups.Together with our published studies showing that hyperinsulinemia increases DAT activity, these studies suggest that anorexia, particularly in the most prone clinical population, adolescent females, serves to ramp up DAT activity and increase sensitivity to cocaine. Combined, these studies support the idea that during adolescence, DAT function is especially sensitive to the amount of food consumed and exercise to which an individual engages. In turn, self‐imposed low food intake and increased exercise, may cause “cross sensitization” of response to drugs of abuse or to food addictions in later life. Our findings suggest that DAT may be a potential therapeutic target for the treatment of anorexia.Support or Funding InformationSupported by DA038504 (LCD)
Chronic cocaine exposure alters D1 medium spiny neuron activity to promote relapse
Authors: Calipari Erin S , Bagot Rosemary C , Purushothaman Immanuel , Pirpinias Stephen , Davidson Thomas J , Deisseroth Karl , Nestler Eric J 
Published: November 2023

Learned associations between environmental cues and experience are the basis of decision‐making and allow organisms to guide behavior towards advantageous outcomes. Dysfunction in the processes that regulate these associations, especially in the nucleus accumbens, is a critical factor in the underlying pathology of addiction. The nucleus accumbens is a heterogeneous region composed of both D1 and D2 medium spiny projection neurons (MSNs), and understanding the cell‐type specific signals that mediate learning processes has far reaching implications for treatment. Using fiber photometry calcium imaging we define D1 MSNs as the specific population of cells in the brain that encodes drug associations. Chronic cocaine exposure dysregulates the temporally specific D1 signals that encode contextual information to both prevent extinction and facilitate reinstatement of drug seeking to drive relapse. Further, manipulating the D1 signal using designer receptors exclusively activated by designer drugs (DREADD), even after associations have been formed, can eliminate these associations indefinitely. Together, these data elucidate the underlying neural processes that control associative learning and how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse following abstinence. Further, these processes have been localized to a single cell population in the nucleus accumbens that can be manipulated to attenuate the strength of these associations and prevent relapse.Support or Funding InformationThis work was supported by grants from the National Institute on Drug Abuse and Brain & Behavior Research Foundation.