23 results on '"Wolinsky T"'
Search Results
2. The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia
- Author
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Wolinsky, T. M., Swanson, C. M., Smith, K. M., Zhong, H., Borowsky, B., Seeman, P., Branchek, T., and Gerald, C. M.
- Published
- 2007
Catalog
3. Autoradiographic identification of estradiol-concentrating cells in the spinal cord of the female rat
- Author
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Morrell, J. I., Wolinsky, T. D., Krieger, M. S., and Pfaff, D. W.
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- 1982
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4. Positive modulation of delta-subunit containing GABAA receptors in mouse neurons
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Vardya, Irina, Hoestgaard-Jensen, Kirsten, Nieto-Gonzalez, Jose Luis, Boddum, Kim, Dósa, Zita, Holm, Mai Marie, Wolinsky, T, Jones, K, Dalby, NO, Ebert, B, and Jensen, Kimmo
- Subjects
nervous system - Abstract
δ-subunit containing extrasynaptic GABA(A) receptors are potential targets for modifying neuronal activity in a range of brain disorders. With the aim of gaining more insight in synaptic and extrasynaptic inhibition, we used a new positive modulator, AA29504, of δ-subunit containing GABA(A) receptors in mouse neurons in vitro and in vivo. Whole-cell patch-clamp recordings were carried out in the dentate gyrus in mouse brain slices. In granule cells, AA29504 (1 μM) caused a 4.2-fold potentiation of a tonic current induced by THIP (1 μM), while interneurons showed a potentiation of 2.6-fold. Moreover, AA29504 (1 μM) increased the amplitude and prolonged the decay of miniature inhibitory postsynaptic currents (mIPSCs) in granule cells, and this effect was abolished by Zn²⁺ (15 μM). AA29504 (1 μM) also induced a small tonic current (12.7 ± 3.2 pA) per se, and when evaluated in a nominally GABA-free environment using Ca²⁺ imaging in cultured neurons, AA29504 showed GABA(A) receptor agonism in the absence of agonist. Finally, AA29504 exerted dose-dependent stress-reducing and anxiolytic effects in mice in vivo. We propose that AA29504 potentiates δ-containing GABA(A) receptors to enhance tonic inhibition, and possibly recruits perisynaptic δ-containing receptors to participate in synaptic phasic inhibition in dentate gyrus. more...
- Published
- 2012
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5. The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia
- Author
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Wolinsky, T. D., primary, Swanson, C. J., additional, Smith, K. E., additional, Zhong, H., additional, Borowsky, B., additional, Seeman, P., additional, Branchek, T., additional, and Gerald, C. P., additional more...
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- 2006
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6. Diabetes alters and kappa opioid binding in rat brain regions: comparison with effects of food restriction
- Author
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Wolinsky, T. D., Abrahamsen, G. C., and Carr, K. D.
- Published
- 1996
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- View/download PDF
7. Effects of chronic food restriction on mu and kappa opioid binding in rat forebrain: a quantitative autoradiographic study
- Author
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Wolinsky, T. D., Carr, K. D., Hiller, J. M., and Simon, E. J.
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- 1994
- Full Text
- View/download PDF
8. The effects of chronic food restriction on MU and kappa opioid receptors in the rat
- Author
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Wolinsky, T. D., Carr, K. D., Hiller, J. M., and Simon, E. J.
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- 1994
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- View/download PDF
9. Chronic food restriction and weight loss produce opioid facilitation of perifornical hypothalamic self-stimulation
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Carr, K. D. and Wolinsky, T. D.
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- 1993
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10. Rapid-Acting Insulin Used to Treat a Case of Early Cystic Fibrosis-Related Diabetes Complicated by Post Prandial Hypoglycemia.
- Author
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Wolinsky T and Simon B
- Abstract
Background/objective: Cystic fibrosis-related diabetes (CFRD) is one of the most common nonrespiratory complications of cystic fibrosis (CF). There is a lack of clinical research to provide guidance on optimal treatment regimens for various subtypes of CFRD., Case Report: This case describes an 18-year-old woman, diagnosed with CF in infancy, who presented to our clinic for evaluation of possible CFRD and episodes of hypoglycemia. Subsequent testing revealed normal fasting glucose with elevated blood glucose levels on oral glucose tolerance test, consistent with the diagnosis of CFRD without fasting hyperglycemia. She was found to have large glycemic excursions after carbohydrate-containing meals, followed by delayed postprandial hypoglycemia., Discussion: We initiated low-dose mealtime rapid-acting analog insulin and saw both a decrease in her postprandial hyperglycemia as well as resolution of her hypoglycemic episodes., Conclusion: This case highlights the spectrum of pancreatic dysfunction and insulin dysregulation in CFRD as well as the benefit of prandial insulin alone as a treatment option., Competing Interests: The authors have no multiplicity of interest to disclose., (© 2023 AACE. Published by Elsevier Inc.) more...
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- 2023
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11. Multifocal primary neuroblastoma tumor heterogeneity in siblings with co-occurring PHOX2B and NF1 genetic aberrations.
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Rybinski B, Wolinsky T, Brohl A, Moerdler S, Reed DR, Ewart M, and Weiser D
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- Child, Preschool, Computational Biology methods, DNA Copy Number Variations, Genes, Neurofibromatosis 1, Genetic Heterogeneity, Genetic Predisposition to Disease, Homeodomain Proteins metabolism, Humans, Infant, Loss of Heterozygosity, Male, Mutation, Neurofibromin 1 metabolism, Polymorphism, Single Nucleotide, Siblings, Transcription Factors metabolism, Exome Sequencing methods, Homeodomain Proteins genetics, Neuroblastoma genetics, Neurofibromin 1 genetics, Transcription Factors genetics
- Abstract
Neuroblastoma, the most common extracranial solid tumor of childhood, can present in multiple primary sites, but the extent of genetic heterogeneity among tumor foci, as well as the presence or absence of common oncogenic drivers, remains unknown. Although PHOX2B genetic aberrations can cause familial neuroblastoma, they demonstrate incomplete penetrance with respect to neuroblastoma pathogenesis, suggesting that additional undescribed oncogenic drivers are necessary for tumor development. We performed comprehensive molecular characterization of neuroblastoma tumors from two siblings affected by familial multifocal neuroblastoma, including whole exome sequencing and single-nucleotide polymorphism (SNP) arrays of tumor and matched blood samples. Data were processed and analyzed using established bioinformatics algorithms to evaluate for germline and somatic mutations and copy number variations (CNVs). We confirmed the presence of a PHOX2B deletion and NF1 mutation across all tumor samples and the germline genome. Matched tumor-blood whole exome sequencing also identified 365 genes that contained nonsilent coding mutations across all tumor samples, with no recurrent mutations across all tumors. SNP arrays also showed significant heterogeneity with respect to CNVs. The only common CNV across all tumors was 17q gain, with differing chromosomal coordinates across samples but a common region of overlap distal to 17q21.31, suggesting this adverse prognostic biomarker may offer insight about additional drivers for multifocal neuroblastoma in patients with germline PHOX2B or NF1 aberrations. Molecular characterization of all tumors from patients with multifocal primary neuroblastoma has potential to yield novel insights on neuroblastoma pathogenesis., (© 2019 Wiley Periodicals, Inc.) more...
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- 2020
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12. Physician perspectives on compassionate use in pediatric oncology.
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Moerdler S, Zhang L, Gerasimov E, Zhu C, Wolinsky T, Roth M, Goodman N, and Weiser DA
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- Child, Humans, Neoplasms psychology, Oncologists psychology, Surveys and Questionnaires, Attitude of Health Personnel, Clinical Competence, Drugs, Investigational therapeutic use, Health Knowledge, Attitudes, Practice, Neoplasms drug therapy, Oncologists ethics, Practice Patterns, Physicians' ethics
- Abstract
Background: Targeted cancer treatments are almost always first studied in adults, even when there is a biologically plausible potential for efficacy in children. Through compassionate use programs, children who are not eligible for a clinical trial and for whom there are no known effective therapies may obtain access to investigational agents, including drugs under development for adults. However, little is known about pediatric oncologists' experiences with applying for and obtaining compassionate use agents., Methods: This study surveyed 132 pediatric oncologists to assess awareness and utilization of compassionate use programs, to identify barriers to their use, and to evaluate available institutional support and resources., Results: We found that the process of applying for access to drugs in development is poorly understood, which presents a barrier to obtaining investigational drugs. Fifty-seven percent of the pediatric oncologists applied for compassionate use. Providers from larger institutions or with more than 15 years of clinical experience were more likely to complete an application and obtain investigational agents for their patients., Conclusion: Identified perceived and actual barriers to compassionate use application submission suggest pediatric oncologists may benefit from educational resources and support to ensure children with cancer equal access to investigational agents and care., (© 2018 Wiley Periodicals, Inc.) more...
- Published
- 2019
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13. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients.
- Author
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Yaeger R, Cercek A, O'Reilly EM, Reidy DL, Kemeny N, Wolinsky T, Capanu M, Gollub MJ, Rosen N, Berger MF, Lacouture ME, Vakiani E, and Saltz LB
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colorectal Neoplasms genetics, Disease-Free Survival, Female, Humans, Male, Middle Aged, Panitumumab, Proto-Oncogene Proteins B-raf genetics, Signal Transduction drug effects, Treatment Outcome, Vemurafenib, Young Adult, Antibodies, Monoclonal therapeutic use, Colorectal Neoplasms drug therapy, ErbB Receptors antagonists & inhibitors, Indoles therapeutic use, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Sulfonamides therapeutic use
- Abstract
Purpose: BRAF-mutant metastatic colorectal cancer (mCRC) forms an aggressive subset of colorectal cancer with minimal response to selective RAF inhibitors. Preclinical data show that reactivation of EGFR signaling occurs in colorectal tumor cells treated with RAF inhibitors and that the addition of an EGFR inhibitor enhances antitumor activity. These data suggest that combined therapy with RAF and EGFR inhibitors could be an effective strategy for treating BRAF V600E mCRC., Experimental Design: We undertook a pilot trial to assess the response rate and safety of the BRAF inhibitor vemurafenib combined with anti-EGFR antibody panitumumab in patients with BRAF-mutant mCRC. Patients received standard approved doses of panitumumab and vemurafenib., Results: Fifteen patients were treated. Performance status was Eastern Cooperative Oncology Group (ECOG) 0 in 4 patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and 8 (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Treatment was well tolerated, with less cutaneous toxicity than would be expected with either agent, and no cases of keratoacanthomas/squamous cell carcinomas. Tumor regressions were seen in 10 of 12 evaluable patients with partial responses in 2 patients (100% and 64% regression lasting 40 and 24 weeks, respectively), and stable disease lasting over 6 months in 2 patients., Conclusions: Combined RAF and EGFR inhibition is well tolerated, with less cutaneous toxicity than would be expected with either agent, and results in modest clinical activity in this highly aggressive and chemoresistant subset of CRC., (©2015 American Association for Cancer Research.) more...
- Published
- 2015
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14. Differential behavioral profiling of stimulant substances in the rat using the LABORAS™ system.
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Castagné V, Wolinsky T, Quinn L, and Virley D
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- Animals, Automation, Benzhydryl Compounds pharmacology, Cocaine pharmacology, Dextroamphetamine pharmacology, Dizocilpine Maleate pharmacology, Drinking Behavior drug effects, Drug Evaluation, Preclinical statistics & numerical data, Feeding Behavior drug effects, Grooming drug effects, Ketamine pharmacology, Male, Modafinil, Motor Activity drug effects, Nicotine pharmacology, Rats, Rats, Wistar, Behavior, Animal drug effects, Central Nervous System Stimulants pharmacology, Drug Evaluation, Preclinical methods, Psychotropic Drugs pharmacology
- Abstract
Preclinical testing requires rapid and reliable evaluation of the main in vivo effects of novel test substances usually in rodents. Nevertheless, the techniques primarily used up to now involve either automated measurement of motor activity or direct observation of behavioral effects by extensively trained investigators. The advantages of these approaches are respectively high-throughput and comprehensive behavioral assessment. Nevertheless, motor activity is only one aspect of animal behavior and it cannot predict the full neurobehavioral profile of a substance, whereas direct observation is time-consuming. There is thus a need for novel approaches that combine the advantages of both automatic detection and comprehensive behavioral analysis. In the present study, we used the LABORAS™ system to analyze motor and non-motor behavior in rats administered various stimulant substances with or without known psychotomimetic properties or abuse liability (amphetamine, cocaine dizocilpine (MK-801), ketamine, modafinil and nicotine). The data show that LABORAS™ clearly detects the stimulating effects on motor behaviors of amphetamine, cocaine, dizocilpine and ketamine in a dose- and time-dependent manner. Differential effects of these test substances on non-motor behaviors, such as grooming, eating and drinking could also be detected. Nicotine displayed only slight stimulating effects on locomotion, whereas modafinil was virtually without effect on the behaviors evaluated by the system. These data with different stimulant substances suggest that LABORAS™ presents an advantage over classical methods performing automated measurements restricted to locomotion. Furthermore, the procedure is considerably more rapid than behavioral observation procedures. Characterization of the behavioral profile of test substances using LABORAS™ should therefore accelerate preclinical studies. In addition, the multi-faceted parameters measured by LABORAS™ permit a more detailed comparison of the behavioral profiles of novel substances with standard reference substances, thereby providing important indicators for orienting further substance evaluation and supporting drug development., (Copyright © 2012 Elsevier Inc. All rights reserved.) more...
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- 2012
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15. How good are current approaches to nonclinical evaluation of abuse and dependence?
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Moser P, Wolinsky T, Duxon M, and Porsolt RD
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- Animals, Behavior, Addictive diagnosis, Behavior, Addictive psychology, Drug Evaluation, Preclinical methods, Drug Evaluation, Preclinical standards, Drug Evaluation, Preclinical trends, Humans, Predictive Value of Tests, Self Administration, Species Specificity, Substance Withdrawal Syndrome diagnosis, Substance Withdrawal Syndrome psychology, Telemetry methods, Telemetry standards, Telemetry trends, Models, Animal, Substance-Related Disorders diagnosis, Substance-Related Disorders psychology
- Abstract
Nonclinical assessment of drug abuse and dependence is the subject of several recent regulatory guidelines, which are generally aligned on the methods to be employed. The most direct approach to assessing reinforcing properties of a drug is the self-administration procedure whereby animals can initiate intravenous injections of the test substance, something they readily do with prototypic drugs of abuse. Complications arise because there is no standardized procedure for evaluating substances with differing potencies, reinforcement properties, or pharmacokinetics. Moreover, the choice of training substance, species, and procedural parameters can radically affect the outcome. Apart from the lower cost of rats, primates present several advantages for self-administration studies with similarity to human pharmacokinetics in particular. The most powerful method for assessing similarities between a test substance and a prototypic drug of abuse is the drug discrimination procedure. In contrast to self-administration, drug discrimination is pharmacologically very specific, often reflecting functional activity at receptor level. Dependence is assessed by the occurrence of withdrawal effects on drug discontinuation. Although conceptually simple, interpretation can be complicated by factors such as duration and frequency of administration and observations as well as the choice of end points. Telemetry allows continuous observation of multiple parameters during withdrawal, thereby increasing sensitivity. Presently available tools identify all substances known to cause abuse or dependence, with little risk of false-positives. It remains unclear, however, how predictive these models are with entirely novel substances. Nonetheless, drug abuse/dependence is an area of safety pharmacology where the predictive value of animal models is remarkably high. more...
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- 2011
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16. Current approaches and issues in non-clinical evaluation of abuse and dependence.
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Moser P, Wolinsky T, Castagné V, and Duxon M
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- Animals, Dose-Response Relationship, Drug, Humans, Models, Animal, Primates, Rats, Self Administration, Substance Withdrawal Syndrome etiology, Substance-Related Disorders etiology, Drug Evaluation, Preclinical methods, Illicit Drugs pharmacology
- Abstract
Preclinical assessment of drug abuse and dependence has been the subject of several recent regulatory guidelines. Both the European and US authorities recommend a tiered approach and are generally aligned on the methods which should be used. The first tier simply compares the pharmacology of the novel substance to known drugs of abuse. The second tier aims to identify abuse and dependence liability more directly. The most direct approach to assessing reinforcing properties is the i.v. self-administration procedure. Unfortunately there is no standardized procedure for evaluating substances with differing potencies, reinforcement properties or pharmacokinetics (PK). Indeed, the choice of training substance, species and procedural parameters can radically affect the outcome. Apart from the lower cost of the rat, the primate presents several advantages for self-administration studies (potentially greater similarity to humans in behavioral effects, active doses and PK). Although it does not measure abuse liability directly, drug discrimination is a powerful method for assessing the similarity of a test substance to a known drug of abuse. In this procedure an animal uses the interoceptive effects of the substance as the discriminative stimulus to determine which of two responses to make. For certain classes of substance, such as hallucinogens acting via the 5-HT(2A) receptor, discrimination is the only procedure currently able to identify them. Drug dependence is assessed by the occurrence of withdrawal effects on drug discontinuation. Although conceptually simple, many factors (duration and frequency of drug treatment, dose/exposure levels, duration of observation after discontinuation) can complicate interpretation. Telemetry may represent a novel approach which allows continuous observation of somatic and behavioral parameters during drug withdrawal thereby increasing sensitivity. Presently available tools can identify essentially all substances known to cause abuse or dependence with little risk of false positives. It remains unclear how effective these models will be with entirely novel substances. Nonetheless, drug abuse/dependence is an area of safety pharmacology where the predictive value of animal models remains very high., (Copyright © 2010 Elsevier Inc. All rights reserved.) more...
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- 2011
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17. Pharmacological characterization of a novel positive modulator at alpha 4 beta 3 delta-containing extrasynaptic GABA(A) receptors.
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Hoestgaard-Jensen K, Dalby NO, Wolinsky TD, Murphey C, Jones KA, Rottländer M, Frederiksen K, Watson WP, Jensen K, and Ebert B
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- Animals, Dose-Response Relationship, Drug, Fear drug effects, Fear physiology, Fear psychology, Female, GABA Modulators chemistry, Humans, Male, Protein Isoforms metabolism, Rats, Rats, Sprague-Dawley, Rats, Wistar, Xenopus laevis, gamma-Aminobutyric Acid biosynthesis, GABA Modulators pharmacology, Protein Subunits metabolism, Receptors, GABA-A metabolism, Synapses drug effects, Synapses metabolism
- Abstract
The in vitro and in vivo pharmacological effects of [2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504), which is a close analogue of retigabine, have been investigated. AA29504 induced a rightward shift of the activation threshold at cloned KCNQ2, 2/3 and 4 channels expressed in Xenopus oocytes, with a potency 3-4fold lower than retigabine. AA29504 (1 muM) had no agonist activity when tested at alpha(1)beta(3)gamma(2s) or alpha(4)beta(3)delta GABA(A) receptors expressed in Xenopus oocytes, but left-shifted the EC(50) for GABA and gaboxadol (THIP) at both receptors. The maximum GABA response at alpha(1)beta(3)gamma(2s) receptors was unchanged by AA29504 (1 muM), but increased 3-fold at alpha(4)beta(3)delta receptors. In slices prepared from the prefrontal cortex of adult rats AA29504 had no effect alone on the average IPSC or the tonic current in layer II/III pyramidal neurons, but potentiated the effect of gaboxadol on both phasic and tonic currents. Thus, the effects of gaboxadol could be positively modulated by AA29504. Systemic administration of AA29504 at doses relevant for modulating GABA transmission produced anxiolytic effects and reduced motor coordination consistent with activity at GABA(A) receptors. We conclude that AA29504 exerts a major action via alpha(4)beta(3)delta-containing GABA(A) receptors, which will be important for interpreting its effect in vivo., (Copyright 2009. Published by Elsevier Ltd.) more...
- Published
- 2010
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18. Diabetes alters mu and kappa opioid binding in rat brain regions: comparison with effects of food restriction.
- Author
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Wolinsky TD, Abrahamsen GC, and Carr KD
- Subjects
- Animals, Autoradiography, Benzomorphans metabolism, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Enkephalins metabolism, Male, Rats, Rats, Sprague-Dawley, Tissue Distribution, Brain metabolism, Diabetes Mellitus, Experimental metabolism, Food Deprivation physiology, Receptors, Opioid, kappa metabolism, Receptors, Opioid, mu metabolism
- Abstract
Diabetic rats display changes in opioid pharmacology and brain regional levels of opioid peptides and prodynorphin mRNA. Previous investigations of opioid receptor binding, carried out in whole-brain homogenates, have, however, failed to detect changes. In the present study, quantitative autoradiography was used to measure mu and kappa opioid receptor binding in discrete brain regions of streptozotocin-treated diabetic rats. Measurement was limited to regions that previously displayed opioid binding changes in chronically food-restricted rats, since our primary aim is to identify brain mechanisms that mediate adaptive responses to persistent metabolic need and adipose depletion. Diabetics displayed strong trends or statistically significant changes which matched seven of the thirteen binding changes observed in food-restricted rats. In no case did diabetics display changes in the opposite direction. The two statistically significant changes common to food-restricted and diabetic rats are increased kappa binding in the medial preoptic area and decreased mu binding in the lateral habenula. The possible functional significance of these changes is discussed. more...
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- 1996
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19. Chronic food restriction alters mu and kappa opioid receptor binding in the parabrachial nucleus of the rat: a quantitative autoradiographic study.
- Author
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Wolinsky TD, Carr KD, Hiller JM, and Simon EJ
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- Analysis of Variance, Animals, Autoradiography, Densitometry, Image Processing, Computer-Assisted, Male, Radioligand Assay, Rats, Rats, Sprague-Dawley, Time Factors, Food Deprivation physiology, Pons metabolism, Receptors, Opioid, kappa metabolism, Receptors, Opioid, mu metabolism
- Abstract
Using quantitative autoradiography, it was previously observed that chronic food restriction alters mu and kappa receptor binding in several regions of the rat forebrain. The present autoradiographic study was designed to investigate whether food restriction affects regional mu and kappa binding in the brainstem. [3H]DAGO (mu) and-mu/delta blocked [3H]BMZ (kappa) binding were analyzed in 21 brainstem regions. A significant decrease in mu binding was observed in the external lateral and external medial subnuclei of the parabrachial nucleus while a significant increase in kappa binding was observed in the external lateral subnucleus. The possible functional significance of these changes is discussed. more...
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- 1996
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20. Functional reconstitution of a highly purified mu-opioid receptor protein with purified G proteins in liposomes.
- Author
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Fan LQ, Gioannini TL, Wolinsky T, Hiller JM, and Simon EJ
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- Animals, Brain metabolism, Cattle, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Enkephalins metabolism, Enkephalins pharmacology, GTP Phosphohydrolases metabolism, Naloxone pharmacology, Narcotics pharmacology, Receptors, Opioid, mu agonists, Receptors, Opioid, mu isolation & purification, GTP-Binding Proteins metabolism, Liposomes metabolism, Receptors, Opioid, mu metabolism
- Abstract
A mu-opioid receptor protein (mu-ORP) purified to homogeneity from bovine striatal membranes has been functionally reconstituted in liposomes with highly purified heterotrimeric guanine nucleotide regulatory proteins (G proteins). A mixture of bovine brain G proteins, predominantly GoA, was used for most of the experiments, but some experiments were performed with individual pure G proteins, GoA, GoB, Gi1, and Gi2. Low Km GTPase was stimulated up to 150% by mu-opioid receptor agonists when both mu-ORP and a G protein (either the brain G protein mixture or a single heterotrimeric G protein) were present in the liposomes. Stimulation by a selective mu-agonist was concentration dependent and was reversed by the antagonist (-)-naloxone, but not by its inactive enantiomer, (+)-naloxone. The mu selectivity of mu-ORP was demonstrated by the inability of delta and kappa agonists to stimulate GTPase in this system. High-affinity mu-agonist binding was also restored by reconstitution with the brain G protein mixture and with each of the four pure Gi and G(o) proteins studied. The binding of mu agonists is sensitive to inhibition by GTP gamma S and by sodium. more...
- Published
- 1995
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21. Regulation of feeding by multiple opioid receptors in cingulate cortex; follow-up to an in vivo autoradiographic study.
- Author
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Carr KD and Wolinsky TD
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- Animals, Autoradiography, Electric Stimulation, Hippocampus anatomy & histology, Hypothalamic Area, Lateral physiology, Male, Microinjections, Narcotic Antagonists administration & dosage, Narcotic Antagonists pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Opioid drug effects, Feeding Behavior physiology, Hippocampus physiology, Receptors, Opioid physiology
- Abstract
A previous in vivo autoradiographic study demonstrated reduced 3H-diprenorphine binding in anterior cingulate cortex of rats that were injected (i.v.) with the radiolabeled opiate during lateral hypothalamic stimulation-induced feeding (SIF). This suggests that an opioid peptide is released in cingulate cortex during feeding and excludes binding of the tracer. The aim of the present study was to determine whether opioid activity in cingulate cortex contributes to the expression of SIF. Agonists and antagonists for multiple opioid receptors were microinjected into cingulate cortex and effects on stimulation frequency threshold for SIF were determined. Although the universal opioid antagonist naloxone (20.0 micrograms) increased threshold, high doses of selective antagonists for mu, delta, and kappa receptors--D-Tic-CTAP, natrindole and norbinaltorphimine, respectively--had no effect. The unique efficacy of naloxone may be due to this lipophilic compound's rapid diffusion throughout an extensive volume of anterior cingulate tissue. While high doses of the kappa agonist U50,488 and the delta agonist DPDPE had no effect, the mu agonist, DAGO (1.0 microgram), decreased the SIF threshold. Moreover, the threshold-lowering effect of DAGO was blocked by pretreatment with the irreversible mu antagonist beta-FNA. These results suggest that mu opioid activity in cingulate cortex can facilitate SIF but that under basal conditions endogenous opioid activity in this brain region makes only a small positive contribution, if any, to the expression of SIF. more...
- Published
- 1994
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22. Norbinaltorphimine blocks the feeding but not the reinforcing effect of lateral hypothalamic electrical stimulation.
- Author
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Carr KD, Papadouka V, and Wolinsky TD
- Subjects
- Animals, Electric Stimulation, Injections, Intraventricular, Male, Naltrexone pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Opioid, kappa drug effects, Feeding Behavior drug effects, Hypothalamic Area, Lateral physiology, Naltrexone analogs & derivatives, Reward, Self Stimulation physiology
- Abstract
The role of central kappa opioid receptors in the regulation of feeding and reward was evaluated using electrical brain stimulation paradigms in combination with the selective kappa antagonist, norbinaltorphimine (nor-BNI). Lateral ventricular injection of 10.0 and 50.0 nmol doses of nor-BNI increased the lateral hypothalamic stimulation frequency threshold for eliciting feeding behavior but had no effect on threshold for self-stimulation in the absence of food. This result is identical to those previously reported for naloxone and antibodies to dynorphin A and suggests that opioid activity is associated with feeding behavior rather than the eliciting brain stimulation. A further similarity between naloxone, dynorphin antiserum, and nor-BNI is their preferential effect on feeding threshold values obtained later, rather than initially, in a post-injection test session. This pattern of threshold elevation is shown to differ from that of the appetite suppressants, amphetamine and phenylpropanolamine, which elevate threshold uniformly throughout a post-injection test. The signature pattern of threshold elevation produced by opioid antagonism is consistent with the hypothesis that opioid activity is involved in the maintenance rather than the initiation of feeding. Specifically, it is hypothesized that a dynorphin A/kappa receptor mechanism is triggered by food taste and sustains feeding behavior by facilitating incentive reward. more...
- Published
- 1993
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23. The effects of electroconvulsive shock on dopamine-1 and dopamine-2 receptor ligand binding activity in MPTP-treated mice.
- Author
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Sershen H, Wolinsky T, Douyon R, Hashim A, Wiener HL, Lajtha A, Coons EE, and Serby M
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- Animals, Ligands, Mice, Mice, Inbred BALB C, Parkinson Disease, Secondary chemically induced, Parkinson Disease, Secondary physiopathology, Receptors, Dopamine D1 drug effects, Receptors, Dopamine D1 metabolism, Receptors, Dopamine D2 drug effects, Receptors, Dopamine D2 metabolism, Dopamine Agents toxicity, Electroshock, MPTP Poisoning, Parkinson Disease, Secondary metabolism, Receptors, Dopamine D1 physiology, Receptors, Dopamine D2 physiology
- Abstract
To explore the possible therapeutic use of electric convulsive treatment in Parkinson's disease (PD), the authors examined the biochemical effects of electroconvulsive shock (ECS) on dopaminergic systems in a rodent model of PD, induced with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP increased dopamine turnover, as indicated by an increase in the ratio of the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid to dopamine. [3H]Spiperone binding to the D2 site increased after lesioning of striatal dopamine terminals. With ECS alone, no changes were found in monoamine levels, brain monoamine oxidase activity, or the D2-labeled sites measured 24 hours after the last treatment. [3H]SCH-23390 binding to the D1 site increased after ECS. In MPTP-treated mice, ECS also increased [3H]SCH-23390 binding to the D1 site, whereas [3H]spiperone binding to the D2 site was unchanged compared to control or to only ECS-treated animals, and decreased compared to the MPTP-treated group that did not receive ECS. ECS appears to selectively modify both the D1 and D2 sites when given after MPTP, increasing the binding of a D1 radioligand and decreasing the binding of a D2 radioligand. more...
- Published
- 1991
- Full Text
- View/download PDF
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