95 results on '"Warnick JE"'
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2. Specification of variables predictive of victories in the sport of boxing: II. further characterization of previous success.
- Author
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Warnick JE and Warnick K
- Published
- 2009
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- View/download PDF
3. Zebrafish models of autism spectrum disorder.
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Meshalkina DA, N Kizlyk M, V Kysil E, Collier AD, Echevarria DJ, Abreu MS, Barcellos LJG, Song C, Warnick JE, Kyzar EJ, and Kalueff AV
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- Animals, Autism Spectrum Disorder chemically induced, Autism Spectrum Disorder physiopathology, Behavior, Animal, Disease Models, Animal, Humans, Social Behavior, Autism Spectrum Disorder genetics, Autism Spectrum Disorder psychology, Zebrafish genetics
- Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by motor, social and cognitive deficits that develop early during childhood. The pathogenesis of ASD is not well characterized and involves a multifaceted interaction between genetic, neurobiological and environmental factors. Animal (experimental) models possess evolutionarily conserved behaviors and molecular pathways that are highly relevant for studying ASD. The zebrafish (Danio rerio) is a relatively new animal model with promise for understanding the pathogenesis of complex brain disorders and discovering novel treatments. As a highly social and genetically tractable organism, zebrafish have recently been applied to model a variety of deficits relevant to ASD. Here, we discuss the developing utility of zebrafish models of ASD, as well as current behavioral, toxicological and genetic models of ASD, and future directions of research in this field., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2018
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4. Adult zebrafish in CNS disease modeling: a tank that's half-full, not half-empty, and still filling.
- Author
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Meshalkina DA, Kysil EV, Warnick JE, Demin KA, and Kalueff AV
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- Animals, Humans, Central Nervous System Diseases etiology, Central Nervous System Diseases pathology, Central Nervous System Diseases physiopathology, Disease Models, Animal, Zebrafish
- Abstract
The zebrafish (Danio rerio) is increasingly used in a broad array of biomedical studies, from cancer research to drug screening. Zebrafish also represent an emerging model organism for studying complex brain diseases. The number of zebrafish neuroscience studies is exponentially growing, significantly outpacing those conducted with rodents or other model organisms. Yet, there is still a substantial amount of resistance in adopting zebrafish as a first-choice model system. Studies of the repertoire of zebrafish neural and behavioral functions continue to reveal new opportunities for understanding the pathobiology of various CNS deficits. Although some of these models are well established in zebrafish, including models for anxiety, depression, and addiction, others are less recognized, for example, models of autism and obsessive-compulsive states. However, mounting data indicate that a wide spectrum of CNS diseases can be modeled in adult zebrafish. Here, we summarize recent findings using zebrafish CNS assays, discuss model limitations and the existing challenges, as well as outline future directions of research in this field.
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- 2017
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5. Zebrafish models in neuropsychopharmacology and CNS drug discovery.
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Khan KM, Collier AD, Meshalkina DA, Kysil EV, Khatsko SL, Kolesnikova T, Morzherin YY, Warnick JE, Kalueff AV, and Echevarria DJ
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- Animals, Central Nervous System Agents chemical synthesis, Central Nervous System Agents chemistry, Drug Evaluation, Preclinical, Small Molecule Libraries chemical synthesis, Small Molecule Libraries chemistry, Zebrafish, Central Nervous System Agents therapeutic use, Central Nervous System Diseases drug therapy, Disease Models, Animal, Drug Discovery, Small Molecule Libraries therapeutic use
- Abstract
Despite the high prevalence of neuropsychiatric disorders, their aetiology and molecular mechanisms remain poorly understood. The zebrafish (Danio rerio) is increasingly utilized as a powerful animal model in neuropharmacology research and in vivo drug screening. Collectively, this makes zebrafish a useful tool for drug discovery and the identification of disordered molecular pathways. Here, we discuss zebrafish models of selected human neuropsychiatric disorders and drug-induced phenotypes. As well as covering a broad range of brain disorders (from anxiety and psychoses to neurodegeneration), we also summarize recent developments in zebrafish genetics and small molecule screening, which markedly enhance the disease modelling and the discovery of novel drug targets., (© 2017 The British Pharmacological Society.)
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- 2017
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6. The failure of anxiolytic therapies in early clinical trials: what needs to be done.
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Stewart AM, Nguyen M, Poudel MK, Warnick JE, Echevarria DJ, Beaton EA, Song C, and Kalueff AV
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- Animals, Anti-Anxiety Agents adverse effects, Anxiety Disorders drug therapy, Anxiety Disorders physiopathology, Clinical Trials as Topic methods, Drug Evaluation, Preclinical methods, Humans, Anti-Anxiety Agents therapeutic use, Drug Design
- Abstract
Introduction: Anxiety spectrum disorders (ASDs) are highly prevalent psychiatric illnesses that affect millions of people worldwide. Strongly associated with stress, common ASDs include generalized anxiety disorder, panic, social anxiety, phobias and drug-abuse-related anxiety. In addition to ASDs, several other prevalent psychiatric illnesses represent trauma/stressor-related disorders, such as post-traumatic stress disorder and acute stress disorder. Anxiolytic drugs, commonly prescribed to treat ASDs and trauma/stressor-related disorders, form a highly heterogenous group, modulating multiple neurotransmitters and physiological mechanisms. However, overt individual differences in efficacy and the potential for serious side-effects (including addiction and drug interaction) indicate a need for further drug development. Yet, over the past 50 years, there has been relatively little progress in the development of novel anxiolytic medications, especially when promising candidate drugs often fail in early clinical trials., Areas Covered: Herein, the authors present recommendations of the Task Force on Anxiolytic Drugs of the International Stress and Behavior Society on how to improve anxiolytic drug discovery. These recommendations cover a wide spectrum of aspects, ranging from methodological improvements to conceptual insights and innovation., Expert Opinion: In order to improve the success of anxiolytic drugs in early clinical trials, the goals of preclinical trials may need to be adjusted from a clinical perspective and better synchronized with those of clinical studies. Indeed, it is important to realize that the strategic goals and approaches must be similar if we want to have a smoother transition between phases.
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- 2015
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7. PROMISE: Maryland's Alliance for Graduate Education and the Professoriate enhances recruitment and retention of underrepresented minority graduate students.
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Tull RG, Rutledge JC, Carter FD, and Warnick JE
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- Career Choice, Cooperative Behavior, Education, Female, Humans, Interdisciplinary Communication, Male, Maryland, Mentors, Schools, Medical organization & administration, Cultural Diversity, Education, Graduate organization & administration, Faculty, Medical organization & administration, Minority Groups education, School Admission Criteria, Science education
- Abstract
PROMISE: Maryland's Alliance for Graduate Education and the Professoriate (AGEP), sponsored by the National Science Foundation, is a consortium that is designed to increase the numbers of underrepresented minority (URM) PhDs in science, technology, engineering, and mathematics fields who will pursue academic careers. A strength of PROMISE is its alliance infrastructure that connects URM graduate students on different campuses through centralized programming for the three research universities in Maryland: the University of Maryland Baltimore County (the lead institution in the alliance), the University of Maryland College Park, and the University of Maryland Baltimore (UMB). PROMISE initiatives cover graduate student recruitment, retention, community building, PhD completion, and transition to careers.Although it is not a fellowship, PROMISE offers professional development and skill-building programs that provide academic and personal support for URM students on all three campuses. PROMISE on UMB's campus includes the School of Medicine, which sponsors tricampus programs that promote health and wellness to accompany traditional professional development programs. PROMISE uniquely and atypically includes a medical school within its alliance. The PROMISE programs serve as interventions that reduce isolation and facilitate degree completion among diverse students on each campus. This article describes details of the PROMISE AGEP and presents suggestions for replicating professional development programs for URMs in biomedical, MD/master's, and MD/PhD programs on other campuses.
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- 2012
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8. Antidepressant efficacy screening of novel targets in the chick anxiety-depression model.
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Sufka KJ, Warnick JE, Pulaski CN, Slauson SR, Kim YB, and Rimoldi JM
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- Animals, Antidepressive Agents therapeutic use, Clinical Trials as Topic, Dose-Response Relationship, Drug, Male, Vocalization, Animal drug effects, Antidepressive Agents pharmacology, Anxiety drug therapy, Chickens, Depression drug therapy, Disease Models, Animal, Drug Evaluation, Preclinical methods
- Abstract
The chick anxiety-depression model is a hybrid simulation, which may prove useful as an early preclinical dual pharmacological screen for novel therapeutics. Separate dose-response studies were conducted with seven test compounds that have screened positive for antidepressant effects in rodent depression models and included prasterone (5.0-40.0 mg/kg), memantine (2.5-20.0 mg/kg), ketamine (1.0-10.0 mg/kg), mifepristone (50.0-400.0 mg/kg), DOV216,303 (5.0-20.0 mg/kg), CGP36742 (2.5-15.0 mg/kg), and antalarmin (1.0-30.0 mg/kg). Chicks aged 4-6 days posthatch received test compounds intramuscularly 15 min before social separation, in which distress vocalization rates were recorded. High rates of vocalization in the first phase (0-5 min) of social separation seem to model an anxiety-like state and lower rates of vocalization in the second phase (30-60 min) seem to model a depression-like state. Prasterone, memantine, ketamine, and DOV216,303 attenuated and CPG36742 enhanced the pattern of vocalizations in the first phase. Prasterone, ketamine, mifepristone, DOV216,303, and CPG36742 attenuated and memantine and antalarmin enhanced the pattern of vocalizations in the second phase. This pattern of drug effects parallels what clinical data exist, and highlights two important characteristics of this dual-screening assay. For the compounds tested, this chick model identified phase II and III clinical failures (e.g. memantine and antalarmin) and has the potential to reveal possible contraindications of compounds (i.e. CPG36742) in cases where anxiety symptoms are concomitant with a depressive episode.
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- 2009
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9. Modelling the anxiety-depression continuum in chicks.
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Warnick JE, Huang CJ, Acevedo EO, and Sufka KJ
- Subjects
- Animals, Animals, Newborn, Anti-Anxiety Agents pharmacology, Antidepressive Agents pharmacology, Chickens, Chlordiazepoxide pharmacology, Clonidine pharmacology, Disease Models, Animal, Dose-Response Relationship, Drug, Fluoxetine pharmacology, Imipramine pharmacology, Interleukin-6 blood, Maprotiline pharmacology, Social Isolation psychology, Stress, Psychological drug therapy, Stress, Psychological psychology, Anxiety drug therapy, Anxiety psychology, Depression drug therapy, Depression psychology
- Abstract
The clinical syndromes of anxiety and depression are now thought to exist along a temporal continuum and this construct has been modelled in a preclinical setting in chicks separated from conspecifics. This research sought to further the validity of the chick anxiety-depression continuum model. Dose-response studies using two classes of anxiolytics (chlordiazepoxide: 2.5, 5.0, 10.0, 15.0 mg/kg, and clonidine: 0.1, 0.15, 0.2, 0.25 mg/kg) and three classes of antidepressants (imipramine: 1.0, 3.0, 10.0, 15.0 mg/kg, maprotoline: 2.5, 5.0, 10.0, 20.0 mg/kg and fluoxetine: 1.0, 5.0, 10.0, 20.0 mg/kg) showed an ability to detect anxiolytic activity of chlordiazepoxide, clonidine, imipramine and maprotoline in the anxiety-like phase of the model and to detect antidepressant effects of imipramine, maprotoline and fluoxetine in the depression-like phase of the model. In addition, blood plasma interleukin-6, a biomarker of stress, was found to be elevated in response to social-separation stress. Collectively, these findings further characterize the model as a simulation of the anxiety-depression continuum and begin to establish the paradigm as a high-utility adjuvant to rodent screening assays for putative anxiolytic and antidepressant compounds.
- Published
- 2009
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10. Sex differences in working memory.
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Harness A, Jacot L, Scherf S, White A, and Warnick JE
- Subjects
- Female, Humans, Male, Neuropsychological Tests, Sex Factors, Space Perception, Visual Perception, Vocabulary, Memory, Short-Term
- Abstract
In two separate studies, sex differences in modal-specific elements of working memory were investigated by utilizing words and pictures as stimuli. Groups of men and women performed a free-recall task of words or pictures in which 20 items were presented concurrently and the number of correct items recalled was measured. Following stimulus presentation, half of the participants were presented a verbal-based distraction task. On the verbal working-memory task, performance of men and women was not significantly different in the no-distraction condition. However, in the distraction condition, women's recall was significantly lower than their performance in the no-distraction condition and men's performance in the distraction condition. These findings are consistent with previous research and point to sex differences in cognitive ability putatively resulting from functional neuroanatomical dissimilarities. On the visual working-memory task, women showed significantly greater recall than men. These findings are inconsistent with previous research and underscore the need for further research.
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- 2008
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11. Propranolol and its potential inhibition of positive post-traumatic growth.
- Author
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Warnick JE
- Subjects
- Adaptation, Psychological drug effects, Humans, Stress Disorders, Post-Traumatic prevention & control, Adrenergic beta-Antagonists therapeutic use, Bioethical Issues, Propranolol therapeutic use, Stress Disorders, Post-Traumatic psychology
- Published
- 2007
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12. Modeling the anxiety-depression continuum hypothesis in domestic fowl chicks.
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Sufka KJ, Feltenstein MW, Warnick JE, Acevedo EO, Webb HE, and Cartwright CM
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- Animals, Animals, Newborn, Anti-Anxiety Agents pharmacology, Antidepressive Agents, Tricyclic pharmacology, Chlordiazepoxide pharmacology, Corticosterone blood, Imipramine pharmacology, Male, Social Isolation psychology, Stress, Psychological blood, Stress, Psychological drug therapy, Stress, Psychological psychology, Vocalization, Animal drug effects, Anxiety blood, Anxiety drug therapy, Anxiety psychology, Chickens, Depression blood, Depression drug therapy, Depression psychology, Disease Models, Animal
- Abstract
Anxiety and depression are currently classified as separate clinical syndromes despite considerable similarities in their symptoms, pathophysiological substrates and response to treatment interventions. An alternative hypothesis views anxiety and depression along a temporal continuum, a construct that the current research attempts to model in a preclinical setting. In experiment 1, socially raised domestic fowl chicks separated from conspecifics demonstrated a pattern of distress vocalizations that sequentially models anxiety-like and depressive-like states. In addition, administration of the benzodiazepine anxiolytic chlordiazepoxide and the tricyclic antidepressant imipramine provided pharmacological validation for the model in that they were capable of dissociating the anxiety-like and depressive-like states. In experiment 2, corticosterone levels were quantified across the isolation test session to provide convergent validity to the model. These findings fit well with the human clinical literature on the anxiety-depression continuum perspective, and suggest the consideration of a nosology that emphasizes the inter-relatedness of these clinical states rather than their boundaries.
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- 2006
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13. Modeling anxiety-like states: pharmacological characterization of the chick separation stress paradigm.
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Warnick JE, Wicks RT, and Sufka KJ
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- Animals, Anxiety Disorders drug therapy, Anxiety, Separation drug therapy, Disease Models, Animal, Male, Models, Psychological, Panic Disorder psychology, Stress, Psychological drug therapy, Vocalization, Animal drug effects, Anti-Anxiety Agents pharmacology, Anxiety Disorders psychology, Anxiety, Separation psychology, Chickens physiology, Stress, Psychological psychology
- Abstract
While previous research has sought to validate the chick separation stress paradigm as an anxiolytic screening assay, it is unknown whether the paradigm better models a nonspecific anxiety-like state or something similar to panic disorder or generalized anxiety disorder. To characterize the anxiety model pharmacologically, cockerels were administered drug probes that were either: (1) only effective for treating panic disorder (phenelzine 3.125-25.0 mg/kg), (2) effective for treating both panic disorder and generalized anxiety disorder (alprazolam 0.065-0.5 mg/kg; clonidine 0.1-0.25 mg/kg; imipramine 1.0-15.0 mg/kg), (3) only effective for treating generalized anxiety disorder (buspirone 2.5-10.0 mg/kg; trazodone 0.1-3.0 mg/kg) or (4) capable of exacerbating symptoms of panic disorder in humans (yohimbine 0.1-3.0 mg/kg). At 7 days after hatch, chicks received either vehicle or drug probe intramuscularly 15 min prior to social separation under a mirror (low-stress) or no-mirror (high-stress) condition for a 180-s observation period. Dependent measures were distress vocalizations to index separation stress and sleep-onset latency to index sedation. Phenelzine, alprazolam, imipramine and clonidine were able to attenuate distress vocalizations (at doses without significant sedation) whereas buspirone and trazodone did not. Paradoxically, yohimbine modestly attenuated distress vocalizations. These results suggest that the chick separation stress paradigm better models panic disorder than generalized anxiety disorder as an anxiolytic screen.
- Published
- 2006
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14. Antinociceptive profile of salvinorin A, a structurally unique kappa opioid receptor agonist.
- Author
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McCurdy CR, Sufka KJ, Smith GH, Warnick JE, and Nieto MJ
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- Acetic Acid antagonists & inhibitors, Acetic Acid toxicity, Animals, Diterpenes, Clerodane, Dose-Response Relationship, Drug, Hot Temperature, Male, Mice, Muscle Contraction drug effects, Naltrexone analogs & derivatives, Naltrexone pharmacology, Nociceptors drug effects, Pain Measurement drug effects, Plant Leaves chemistry, Reaction Time drug effects, Analgesics, Diterpenes pharmacology, Psychotropic Drugs pharmacology, Receptors, Opioid, kappa agonists
- Abstract
Salvinorin A, is a structurally unique, non-nitrogenous, kappa opioid receptor (KOP) agonist. Given the role of KOPs in analgesic processes, we set out to determine whether salvinorin A has antinociceptive activity in thermal and chemo-nociceptive assays. The tail-flick assay was employed to investigate 1) salvinorin A's (0.5, 1.0, 2.0, and 4.0 mg/kg) dose-response and time-course (10, 20, and 30 min) effects in a thermal nociceptive assay, and 2) the ability for the KOP antagonist norBNI (10.0 mg/kg) to prevent salvinorin A antinociception. The hotplate assay was utilized as a second thermal nociceptive measure to test salvinorin A's dose-response effects. The acetic acid abdominal constriction assay was used to study salvinorin A's dose-response and time-course (over 30 min) effects in a chemo-nociceptive assay. Together, these studies revealed that salvinorin A produces a dose-dependent antinociception that peaked at 10 min post-injection but rapidly returned to baseline. Additionally, pretreatment with the KOP antagonist norbinaltorphimine (norBNI) reversed salvinorin A-induced antinociception. These findings demonstrate that salvinorin A produces a KOP mediated antinociceptive effect with a short duration of action.
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- 2006
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15. Opioid receptor function in social attachment in young domestic fowl.
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Warnick JE, McCurdy CR, and Sufka KJ
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- Analgesics, Opioid pharmacology, Analysis of Variance, Animals, Animals, Newborn, Chickens, Dose-Response Relationship, Drug, Narcotic Antagonists pharmacology, Receptors, Opioid agonists, Vocalization, Animal drug effects, Behavior, Animal drug effects, Receptors, Opioid physiology, Social Behavior
- Abstract
Opioid systems are implicated in social attachment processes. This research sought to determine the functional contribution of each opioid receptor in modulating social attachment/separation distress. Following ICV administration of opiate probes, 7-day-old cockerels were isolated from conspecifics for a 3 min test period under either a mirror or no-mirror condition. Vocalizations served as the measure of separation-stress. Opioid receptor probes included: the mu agonist DAMGO (0.02, 0.19, 1.95 nmol), the mu antagonist CTOP (0.009, 0.09, 0.9 nmol), the delta agonist SNC80 (0.3, 1.0, 3.0 micromol), the delta antagonist naltrindole (0.2, 2.2, 22.2 nmol), the kappa agonist U50, 488 (1, 30, 100 nmol), the kappa antagonist norBNI (1.3, 13.6, 136.1 nmol), the NOP agonist N/OFQ (0.01, 0.1, 1.0 nmol), and the NOP antagonist UFP-101 (0.1, 1.0, 10.0 nmol). DAMGO attenuated separation distress vocalizations. No other drug probe enhanced or attenuated distress vocalizations. Further, the non-selective opiate antagonist naloxone (0.3, 8.3, 27.5 nmol) did not exacerbate distress vocalizations. These results suggest that only the mu receptor modulates social attachment in young domestic fowl.
- Published
- 2005
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16. Anti-inflammatory and anti-hyperalgesic effects of sesquiterpene lactones from Magnolia and Bear's foot.
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Feltenstein MW, Schühly W, Warnick JE, Fischer NH, and Sufka KJ
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- Analgesics, Non-Narcotic chemistry, Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Carrageenan, Indomethacin pharmacology, Inflammation drug therapy, Inflammation etiology, Lactones chemistry, Lactones isolation & purification, Lactones pharmacology, Male, Molecular Structure, Rats, Rats, Sprague-Dawley, Sesquiterpenes chemistry, Analgesics, Non-Narcotic isolation & purification, Analgesics, Non-Narcotic pharmacology, Anti-Inflammatory Agents, Non-Steroidal isolation & purification, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Asteraceae chemistry, Magnolia chemistry, Sesquiterpenes isolation & purification, Sesquiterpenes pharmacology
- Abstract
Sesquiterpene lactones possess a variety of biological activities, including anti-inflammatory activity. Two plants native to the southeastern United States, Magnolia grandiflora (L.) and Smallanthus uvedalius (L.) [syn Polymnia uvedalius (L.)], are novel sources of the sesquiterpene lactones parthenolide and enhydrin, respectively. In this study, the anti-inflammatory and anti-hyperalgesic effects of these isolated lactones from these two plant sources were evaluated in the rat carrageenan inflammation model. Rats received ip injections of either vehicle (propylene glycol), indomethacin (5 mg/kg), 11,13-dihydroparthenolide (20 mg/kg), parthenolide (5 or 20 mg/kg) or enhydrin (5 or 20 mg/kg). A 100-microl injection of 2.0% carrageenan was made into the plantar surface of the right hindpaw. Paw withdrawal latencies and paw volumes in both inflamed and non-inflamed paws were recorded at four test intervals: pre-inflammation baseline (0 time point), and 1, 2 and 4 h post-carrageenan injection. Vehicle-treated animals exhibited a significant time-dependent hyperalgesic and edema response that was greatest at the 4-h test interval. Indomethacin significantly blocked the hyperalgesic response and modestly attenuated the edema response. Parthenolide (20 mg/kg) and enhydrin (20 mg/kg) significantly blocked the hyperalgesic response and significantly attenuated the edema response; 11,13-dihydroparthenolide did not affect either inflammation or hyperalgesia. These findings suggest that parthenolide and enhydrin from these plant sources may be useful in the treatment of inflammatory pain.
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- 2004
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17. High-performance liquid chromatographic determination of xanthohumol in rat plasma, urine, and fecal samples.
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Avula B, Ganzera M, Warnick JE, Feltenstein MW, Sufka KJ, and Khan IA
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- Animals, Biological Availability, Flavonoids, Male, Propiophenones administration & dosage, Propiophenones blood, Propiophenones urine, Rats, Rats, Wistar, Chromatography, High Pressure Liquid methods, Feces chemistry, Propiophenones pharmacokinetics
- Abstract
Xanthohumol (XN) is the major prenylated flavonoid in hop plants and as such a constituent of beer. Pharmacological studies have shown that XN possesses marked antioxidant and antiproliferative effects. In order to study the resorption and metabolism of this compound, reversed-phase high-performance liquid chromatography is used for the determination of XN in rat plasma, urine, and feces. In session one, rats receive either oral or intravenous (iv) administration (20 mg/kg body weight) of XN. In session two, rats receive oral administration of 50, 100, 200, 400, and 500 mg/kg body weight XN for bioavailability studies at various dose levels. Plasma, urine, and feces are collected at varying time points and assayed for their XN content. Plasma levels of XN fell rapidly within 60 min after iv administration; no XN is detected in plasma after oral administration in either session. XN and its metabolites are excreted mainly in feces within 24 h of administration. The method is a reliable tool for performing studies of XN in different biological material.
- Published
- 2004
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18. The chick separation stress paradigm: a validation study.
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Feltenstein MW, Warnick JE, Guth AN, and Sufka KJ
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- Animals, Anxiety chemically induced, Drug Evaluation, Preclinical, False Positive Reactions, Male, Sleep drug effects, Vocalization, Animal drug effects, Anti-Anxiety Agents pharmacology, Anxiety, Separation drug therapy, Chickens physiology, Stress, Psychological drug therapy
- Abstract
To expand the generalizability of the chick separation stress paradigm as a high-throughput anxiolytic screen, six positive drug probes (doses in mg/kg: meprobamate 15-120, pentobarbital 2.5-20.0, chlordiazepoxide 2.5-15.0, buspirone 2.5-10.0, imipramine 1-15, and clonidine 0.10-0.25) and five negative drug probes (amphetamine 0.5-4.0, scopolamine 0.2-1.6, caffeine 5-20, chlorpromazine 1-30, and haloperidol 0.03-1.00) were evaluated in the test. Seven-day-old chicks received intramuscular injections of either vehicle or drug probe 15 min prior to tests in either a mirror (low-stress) or a no-mirror (high-stress) condition for a 3-min observation period. The dependent measures were distress vocalizations to index separation stress and sleep onset latency to index sedation. All positive drug probes attenuated distress vocalizations in a dose-dependent manner, except buspirone. All positive drug probes affected sleep onset latency in a dose-dependent manner, except buspirone and imipramine. In all cases, the anxiolytic-like effect of positive drug probes was greater than its sedative effect. None of the negative drug probes affected either distress vocalizations or sleep onset latency, except for the highest dose of amphetamine, which caused pronounced stereotypy. These findings demonstrate that this anxiolytic screen is sensitive to a wide range of positive pharmacological probes and insensitive to a wide range of negative pharmacological probes.
- Published
- 2004
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19. Practice and incentive motivation in recognition of inverted faces.
- Author
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Haggbloom SJ and Warnick JE
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- Adult, Female, Humans, Face, Motivation, Practice, Psychological, Recognition, Psychology
- Abstract
In each of three experiments, participants received successive daily practice sessions on the task of recognizing inverted faces. In all practice sessions, an initial study series of 25 inverted faces was followed immediately by a test series of 17 pairs of inverted faces. Each test pair comprised a face from the study series and a new face. Completely new sets of faces were used in each session. Recognition of inverted faces did not improve across sessions in Exp. 1 but did improve in Exps. 2 and 3. Unlike Exp. 1, Exps. 2 and 3 employed an explicit incentive for improved performance. These results show that sufficiently motivated participants can become quite proficient at recognizing inverted faces. Implications of the results for the role of expertise at recognition in producing the inversion effect are discussed.
- Published
- 2003
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20. Corticosterone response in the chick separation-stress paradigm.
- Author
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Feltenstein MW, Lambdin LC, Webb HE, Warnick JE, Khan SI, Khan IA, Acevedo EO, and Sufka KJ
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- Animals, Anti-Anxiety Agents therapeutic use, Chickens, Chlordiazepoxide therapeutic use, Male, Statistics as Topic, Anti-Anxiety Agents pharmacology, Chlordiazepoxide pharmacology, Corticosterone blood, Social Isolation psychology, Stress, Psychological drug therapy, Stress, Psychological metabolism, Stress, Psychological psychology, Vocalization, Animal drug effects
- Abstract
Corticosterone response to separation stress and its sensitivity to the anxiolytic, chlordiazepoxide (CDP), were examined in 7-day-old domestic fowl (Gallus gallus). Saline or CDP (8.0 mg/kg) was injected intramuscularly 30 min before tests. Chicks were placed in isolation either with or without mirrors for a 15-min observation period, in which distress vocalizations were recorded. After testing, chicks were euthanized and blood was collected for the corticosterone assay. Chicks tested in the No-Mirror condition displayed an increase in vocalizations that was attenuated by CDP. Similarly, corticosterone levels were highest in chicks tested in the No-Mirror condition; however, CDP only modestly attenuated corticosterone levels. The present findings demonstrate that corticosterone levels parallel the behavioral marker of distress vocalizations in this paradigm, but this biological marker may be less sensitive than the behavioral marker to benzodiazepine anxiolytic manipulations.
- Published
- 2003
- Full Text
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21. Analogs of thyrotropin-releasing hormone in potentiating the spinal monosynaptic reflex in vitro.
- Author
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Deshpande SB and Warnick JE
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- Animals, In Vitro Techniques, Pyrrolidonecarboxylic Acid analogs & derivatives, Rats, Spinal Cord physiology, Structure-Activity Relationship, Thiazolidines, Thyrotropin-Releasing Hormone analogs & derivatives, Reflex, Monosynaptic drug effects, Spinal Cord drug effects, Thyrotropin-Releasing Hormone pharmacology
- Abstract
The efficacy of thyrotropin-releasing hormone (TRH) and its analogs to potentiate the spinal monosynaptic reflex was studied in isolated cords. The analogs examined were L-pyro-2-aminoadipyl-histidyl-thizolidine-4-carboxyamide (MK-771); pyroglutamyl-histidyl-prolineamide (TRH); pyroglutamyl-L-histidyl-3,3'-dimethyl-prolineamide (RX77368); (3-methyl-His2)TRH(methyl-TRH); gamma-buturolactone-gamma-carbonyl-histidyl-prolineamide citrate (DN-1417); pyroglutamyl-histidyl-proline (TRH-free acid); and histidyl-proline-diketopiperazine (cyclo(His-Pro)). The TRH analogs potentiated the monosynaptic reflex in a dose-dependent manner and the maximal potentiation occurred at about 1 microM. TRH-free acid potentiated the monosynaptic reflex but the maximal potentiation occurred at 100 times the TRH concentration. Cyclo(His-Pro) was totally ineffective. The concentration required to potentiate the monosynaptic reflex by 50% of the maximal response (EC50) was taken as an index for comparing various analogs in relation to TRH. The EC50 values of the analogs did not differ significantly from each other. However, the ratio of the mean value of an analog to that of TRH was of the following order: MK-771 (N- and C-terminally altered) > or = TRH > or = DN-1417 (N-terminal) > or = methyl-TRH > or = RX77368 (C-terminal) >>> TRH-free acid. Cyclo(His-Pro) was ineffective.
- Published
- 1994
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22. Assessment of spinal cord trauma using evoked potentials in a rat model of decompression sickness.
- Author
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Marzella L and Warnick JE
- Subjects
- Action Potentials, Anesthetics pharmacology, Animals, Chloral Hydrate pharmacology, Decompression Sickness complications, H-Reflex, Hindlimb innervation, Male, Rats, Rats, Sprague-Dawley, Reaction Time, Sciatic Nerve physiopathology, Spinal Cord Injuries etiology, Decompression Sickness physiopathology, Disease Models, Animal, Evoked Potentials, Spinal Cord Injuries physiopathology
- Abstract
A rapid quantitative technique for assessing spinal cord trauma in a rat model of decompression sickness is described. Evoked potentials are measured from the lower limbs of rats before and after dives with compressed air in a hyperbaric chamber. Under chloral hydrate anesthesia, the sciatic nerve is stimulated at the sciatic notch with needle electrodes and platinum/iridium electrodes are used to record the action potentials from the plantar muscles. Analysis showed that the sensory reflex response was markedly depressed in the rats soon after diving and did not recover for up to 5 days. The motor response was similarly affected although to a lesser degree. The latency of the reflex response also became prolonged after 3 days. The significant and complex pattern of neurological dysfunction shown by this electrophysiologic technique validates the use of the rat model for the study of spinal cord decompression sickness. This technique should aid studies aimed at testing new therapies for this disease.
- Published
- 1994
- Full Text
- View/download PDF
23. Thyrotropin-releasing hormone reverses the supersensitively depressed monosynaptic transmission by serotonin in 5,7-dihydroxytryptamine-treated neonatal rats in vitro.
- Author
-
Deshpande SB and Warnick JE
- Subjects
- Animals, Animals, Newborn, Indoles pharmacology, Methysergide pharmacology, Rats, Rats, Wistar, Reflex, Monosynaptic drug effects, Serotonin Antagonists pharmacology, Spinal Cord cytology, Spinal Cord drug effects, Tropisetron, 5,7-Dihydroxytryptamine pharmacology, Serotonin pharmacology, Synapses drug effects, Synaptic Transmission drug effects, Thyrotropin-Releasing Hormone pharmacology
- Abstract
The interaction of serotonin and thyrotropin-releasing hormone (TRH) on monosynaptic reflex (MSR) in isolated neonatal spinal cords was examined. Superfusion of serotonin (1-30 microM) in untreated cords, depressed the MSR in a dose-dependent manner. The depression was about 25% at 10 microM of serotonin, in either control or vehicle-treated groups. While for the same concentration of serotonin, the depression was 97 +/- 2.1% of the control in cords from 5,7 dihydroxytryptamine (5,7-DHT)-treated animals. The inhibition of the reflex seen in cords obtained from 5,7-DHT-treated animals could not be reversed by washing with normal physiological solution (> 60 min) or in presence of serotonin antagonists. TRH (0.03-1.0 microM) reversed the depression in a concentration-dependent manner and complete reversal could be seen with 1 microM of TRH. These observations indicate that, serotonin and TRH act dissimilarly on the spinal synaptic transmission though they are known to coexist in the descending bulbospinal tracts.
- Published
- 1994
- Full Text
- View/download PDF
24. Thyrotropin releasing hormone-induced potentiation of spinal monosynaptic reflex in rats in vitro.
- Author
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Deshpande SB and Warnick JE
- Subjects
- Animals, Animals, Newborn, In Vitro Techniques, Male, Rats, Receptors, Serotonin drug effects, Spinal Cord drug effects, Reflex, Monosynaptic drug effects, Thyrotropin-Releasing Hormone pharmacology
- Abstract
Superfusion of thyrotropin-releasing hormone (TRH) in neonatal rat spinal cord in vitro produced dose (0.01-1.00 microM) dependent potentiation of monosynaptic reflex (MSR) which was maximum (44% of control) at 1 microM of TRH. But no ventral root depolarization was observed with TRH (1 microM) although potassium concentration out side ([K+]0) when increased produced a depolarization at the magnitude of 0.2 mV/mM of [K+]0. TRH-induced potentiation of MSR was not altered in spinal cords, obtained from the animals pretreated with 5,7-dihydroxytryptamine or 6-hydroxydopamine. Neither serotonin antagonists (spiperone, ketanserin, cyproheptadine or 3-troponyl-indole-3-carboxylate) nor adrenergic antagonists (phentolamine or haloperidol) could attenuate TRH-induced potentiation. Inhibition of MSR observed in the spinal cord elicited by stimulating the adjacent dorsal root was unaffected by TRH. The results suggest that, TRH potentiates MSR by directly acting on the motoneurons, without involving presynaptic serotonergic or catecholaminergic neuronal systems or the disinhibition of pre- or post-synaptic inhibition in the spinal cord.
- Published
- 1993
25. Biphasic action of sarin on monosynaptic reflex in the neonatal rat spinal cord in vitro.
- Author
-
Warnick JE, Deshpande SB, Yang QZ, and Das Gupta S
- Subjects
- Animals, Atropine pharmacology, Electric Stimulation, Female, In Vitro Techniques, Nicotinic Antagonists, Parasympatholytics pharmacology, Pregnancy, Rats, Rats, Wistar, Sarin antagonists & inhibitors, Spinal Cord physiology, gamma-Aminobutyric Acid physiology, Animals, Newborn physiology, Reflex, Monosynaptic drug effects, Sarin pharmacology, Spinal Cord drug effects
- Abstract
The action of sarin, an organophosphorus (OP) compound, was examined in vitro for its effects on the spinal monosynaptic reflex (MSR) in neonatal rats. The effects of sarin were biphasic, i.e. facilitation at lower concentrations (2-20 nM) followed by depression of the MSR at concentrations above 30 nM. Facilitation of MSR was maximal (150% of control) at 20 nM sarin. The depression of MSR was maximal (70% of control) at 200 nM sarin, with half maximal inhibition occurring at 90 nM sarin. Atropine (200-500 nM) effectively reversed the depression caused by sarin, while pretreatment with low concentrations of atropine (10 nM) completely blocked the depression otherwise observed with sarin. Benactyzine was also effective in preventing sarin-induced depression, while pirenzepine was less effective. The nicotinic blocking agents tubocurarine and mecamylamine were, however, ineffective in preventing or reversing sarin-induced depression. The facilitation of MSR seen with lower concentrations (2-20 nM) correlated well with the blockade of late phase inhibition (between 30 and 50 ms conditioning-test interval) elicited in spinal cord by stimulating the adjacent dorsal root at various condition-test intervals, which has been shown elsewhere to be sensitive to bicuculline (Deshpande and Warnick 1988). Thus it is speculated that sarin at lower concentrations blocks GABA transmission, producing facilitation, and at higher concentrations activates the muscarinic receptors producing depression of MSR. The beneficial action of pretreatment with antimuscarinic agents may be attributed to the protection of the muscarinic receptors.
- Published
- 1993
- Full Text
- View/download PDF
26. Interaction of thyrotropin-releasing hormone and methysergide on the monosynaptic reflex in isolated mammalian spinal cord.
- Author
-
Deshpande SB and Warnick JE
- Subjects
- 5,7-Dihydroxytryptamine pharmacology, Animals, Animals, Newborn, Cyproheptadine pharmacology, Drug Interactions, In Vitro Techniques, Indoles pharmacology, Ketanserin pharmacology, Male, Rats, Rats, Inbred Strains, Serotonin Antagonists pharmacology, Spinal Cord drug effects, Spiperone pharmacology, Synapses drug effects, Tropisetron, Methysergide pharmacology, Reflex drug effects, Spinal Cord physiology, Synapses physiology, Thyrotropin-Releasing Hormone pharmacology
- Abstract
The interaction between thyrotropin-releasing hormone (TRH) and methysergide (MeSG) on reflex activity was examined in spinal cords from neonatal rats. MeSG depressed the monosynaptic reflex (MSR) by nearly 90% at 0.03 microM but had no effect on the dorsal root reflex at 0.003-3.0 microM. Neither spiperone, ketanserin, cyproheptadine nor ICS 205-930 (3-tropanyl-indole-3-carboxylate) depressed the MSR nor did they affect the potentiation elicited by TRH. TRH reversed the depression of the MSR by MeSG in a concentration-dependent manner without affecting the dorsal root reflex. MeSG-induced depression of the MSR was also reversed by 3,4-diaminopyridine which simultaneously increased the magnitude and duration of both reflexes. It appears that neither MeSG-induced depression nor TRH-induced potentiation of the MSR involves the spinal serotonergic system or blockade of K+ channels.
- Published
- 1990
- Full Text
- View/download PDF
27. Selective depression of the segmental polysynaptic reflex by phencyclidine and its analogs in the rat in vitro: interaction with N-methyl-D-aspartate receptors.
- Author
-
Ohno Y and Warnick JE
- Subjects
- 2-Amino-5-phosphonovalerate pharmacology, Amino Acids pharmacology, Animals, Aspartic Acid analogs & derivatives, Aspartic Acid antagonists & inhibitors, Binding Sites, Haloperidol pharmacology, In Vitro Techniques, Magnesium pharmacology, Male, Methiothepin pharmacology, N-Methylaspartate, Phencyclidine analogs & derivatives, Rats, Rats, Inbred Strains, Receptors, N-Methyl-D-Aspartate, Receptors, Neurotransmitter physiology, Spinal Cord physiology, Phencyclidine pharmacology, Receptors, Neurotransmitter drug effects, Reflex drug effects, Spinal Cord drug effects
- Abstract
The differential sensitivity of monosynaptic and polysynaptic reflexes to phencyclidine (PCP) and its analogs was examined in a Mg+(+)-free physiological solution using an in vitro spinal cord preparation of neonatal rats. Whereas the monosynaptic reflex was relatively resistant to N-methyl-D-aspartate antagonists [Mg++, 2-amino-5-phosphonovalerate (APV) and 2-amino-7-phosphonoheptanoate (AP7)], the polysynaptic reflex was markedly reduced in a concentration-dependent manner. The magnitude of the monosynaptic reflex only decreased 20 to 30% at concentrations of Mg++ (1.3 mM), APV (10 microM) and AP (10 microM), which completely depressed the polysynaptic reflex. PCP and its analogs also selectively depressed the polysynaptic reflex in a concentration-dependent manner and had relative potencies consistent with those for the PCP receptor [i.e., 1-(1-m-amino-phenylcyclohexyl)piperidine = MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate] greater than 1-[1-(2-thienyl)cyclohexyl]piperidine greater than or equal to PCP much greater than (+)-N-allylnormetazocine much greater than 1-(1-m-nitrophenylcyclohexyl)piperidine. The latter compounds depressed the monosynaptic reflex to the same extent as Mg++, APV and AP7 at concentrations which completely depressed the polysynaptic reflex. Furthermore, the depression of the reflexes by PCP was unaffected by haloperidol and methiothepin precluding the involvement of sigma and serotonin receptors in PCP-induced depression of the polysynaptic reflex. Our results suggest that PCP and its analogs selectively depressed the polysynaptic reflex through PCP receptors associated with the N-methyl-D-aspartate receptor complex.
- Published
- 1990
28. Characterization of the electrogenic sodium channel from rat brain membranes using neurotoxin-dependent 22Na uptake.
- Author
-
Matthews JC, Warnick JE, Albuquerque EX, and Eldefrawi ME
- Subjects
- Action Potentials drug effects, Animals, Batrachotoxins pharmacology, Diterpenes pharmacology, Female, Male, Membranes metabolism, Rats, Saxitoxin pharmacology, Tetrodotoxin pharmacology, Veratridine pharmacology, Brain metabolism, Ion Channels metabolism, Muscles physiology, Sodium metabolism, Toxins, Biological pharmacology
- Abstract
The sodium channel was studied in osmotically-sensitive membrane preparations from rat brain and in innervated and chronically denervated rat soleus and extensor digitorum longus muscles. These experiments were undertaken in order to define a set of parameters for sodium channel function at the subcellular level to be used as a measure of retention of channel integrity upon subsequent isolation of the channel. Various neurotoxins and drugs were employed to control the permeability of the brain membranes to 22Na and the sodium-conductance properties of the muscles. Batrachotoxin (ED50 = 0.2 micrometer), veratridine (ED50 = 1 micrometer), or grayanotoxin I (ED50 = 30 micrometers) stimulated 22Na uptake in brain membranes is inhibited in an apparently uncompetitive manner by the sodium channel blocking agents tetrodotoxin and saxitoxin in a simple competitive manner by Ca2+ and in a partial or allosteric competitive manner by lidocaine and procaine. This 22Na uptake assay, which can be equated to a measure of equilibrium toxin binding, shows dependence on the concentration of the membranes and is sensitive to pH, temperature, ionic strength, and the ionic composition of the media. Parallel biophysical studies on sodium channels in rat muscle show that the properties of the sodium channel are similarly affected by these agents.
- Published
- 1981
- Full Text
- View/download PDF
29. Site of action of phencyclidine. IV. Interaction of phencyclidine and its analogues on ionic channels of the electrically excitable membrane and nicotinic receptor: implications for behavioral effects.
- Author
-
Aguayo LG, Warnick JE, Maayani S, Glick SD, Weinstein H, and Albuquerque EX
- Subjects
- Animals, Electrophysiology, In Vitro Techniques, Membranes drug effects, Muscle Contraction drug effects, Potassium metabolism, Rana pipiens, Behavior, Animal drug effects, Ion Channels drug effects, Muscles drug effects, Phencyclidine analogs & derivatives, Phencyclidine pharmacology, Receptors, Cholinergic drug effects, Receptors, Nicotinic drug effects
- Published
- 1982
30. Interaction of reversible and irreversible cholinesterase inhibitors on the monosynaptic reflex in neonatal rats.
- Author
-
Das Gupta S, Bass KN, and Warnick JE
- Subjects
- Animals, Atropine pharmacology, Dose-Response Relationship, Drug, Female, In Vitro Techniques, Male, Pregnancy, Rats, Rats, Inbred Strains, Sarin toxicity, Spinal Cord drug effects, Spinal Cord enzymology, Spinal Cord physiology, Cholinesterase Inhibitors toxicity, Physostigmine pharmacology, Pyridostigmine Bromide pharmacology, Reflex, Monosynaptic drug effects
- Abstract
The ability of physostigmine (PHY) and pyridostigmine (PYR) to protect against the segmental synaptic depression caused by sarin was examined in isolated spinal cords from neonatal rats. The monosynaptic reflex was unaffected at concentrations up to 0.1 microM PHY or 0.3 microM PYR but raising the concentrations of either drug produced a concentration-dependent depression of the monosynaptic reflex which could be completely antagonized by atropine. The monosynaptic reflex was depressed by 50% at 0.45 microM PHY and 2 microM PYR with maximal depression occurring at 1 microM PHY (to about 10% of control) and 10 microM PYR (to about 35% of control). Pretreating the cords with 0.1 microM PHY and PYR for 30 min failed to protect against the depressant effects of sarin even though they inhibited total cholinesterase (ChE) by 27 and 21%, respectively. Both PHY and PYR depressed total ChE activity of the spinal cord in a concentration-dependent manner with 50% inhibition of ChE occurring at 0.8 microM. These results suggest that the carbamates affect segmental transmission by activation of a muscarinic receptor, that protective carbamylation of ChE is ineffective against organophosphorus-induced segmental depression, and that inhibition of ChE is unrelated to both carbamate- and organophosphorus-induced depression of the monosynaptic reflex.
- Published
- 1989
- Full Text
- View/download PDF
31. Discriminant effects of behaviorally active and inactive analogs of phencyclidine on membrane electrical excitability.
- Author
-
Aguayo LG, Weinstein H, Maayani S, Glick SD, Warnick JE, and Albuquerque EX
- Subjects
- Action Potentials drug effects, Animals, Astacoidea, Calcium metabolism, Calcium Channel Blockers pharmacology, Electric Conductivity, Ion Channels drug effects, Muscles drug effects, Phencyclidine pharmacology, Potassium metabolism, Rana pipiens, Behavior, Animal drug effects, Membrane Potentials drug effects, Phencyclidine analogs & derivatives
- Abstract
The discriminant effects of several behaviorally active and inactive analogs of phencyclidine [PCP; 1-(phenylcyclohexyl) piperidine] and the actions of PCP and three Ca-channel antagonists were examined on electrical excitability in frog and crayfish skeletal muscles. In frog sartorius muscle, 1-[1-(2-thienylcyclohexyl)piperidine (TCP; 100 microM), a behaviorally active analog of PCP, increased action potential duration nearly 9-fold, blocked delayed rectification and at 0.5 to 1 microM also increased the quantal release of transmitter. A partial blockade of delayed rectification and slight prolongation of the action potential occurred with 1-(p-fluorophenylcyclohexyl)piperidine (p-F-PCP; 100 microM), which possesses about 25% of the behavioral activity of PCP. Of the remaining p-phenyl- substituted analogs which never exhibited more than 10% of the behavioral potency of PCP, only 1-(1-p-nitrophenylcyclohexyl)piperidine (p-NO2-PCP; 100 microM) produced a frequency-dependent prolongation of the action potential but, like the p-methoxy-, p-chloro- and p-methyl- analog, it did not block delayed rectification. The order of potencies of these analogs in blocking delayed rectification, prolonging the muscle action potential and in affecting alternation impairment and response rate depression is therefore: PCP much greater than TCP greater than p-F-PCP much greater than p-CH3-PCP = p-CH3O-PCP = p-Cl-PCP = p-NO2-PCP. Like PCP and its behaviorally active analogs, verapamil (50 microM) and bepridil (50 microM), two Ca-channel blockers, also blocked delayed rectification in frog sartorius muscles whereas nifedipine (50 microM), another Ca-channel blocker, did not.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1984
32. Kinetics of interaction of batrachotoxin and tetrodotoxin on rat diaphragm muscle.
- Author
-
Albuquerque EX, Brookes N, Onur R, and Warnick JE
- Subjects
- Animals, Drug Interactions, In Vitro Techniques, Kinetics, Lidocaine pharmacology, Male, Membrane Potentials drug effects, Motor Endplate drug effects, Procaine pharmacology, Rats, Muscles drug effects, Tetrodotoxin pharmacology, Toxins, Biological pharmacology
- Published
- 1976
33. Differentiation of the open and closed states of the ionic channels of nicotinic acetylcholine receptors by tricyclic antidepressants.
- Author
-
Schofield GG, Witkop B, Warnick JE, and Albuquerque EX
- Subjects
- Amitriptyline pharmacology, Animals, Kinetics, Membrane Potentials drug effects, Nortriptyline pharmacology, Rana pipiens, Antidepressive Agents, Tricyclic pharmacology, Ion Channels drug effects, Neuromuscular Junction drug effects, Receptors, Cholinergic drug effects, Receptors, Nicotinic drug effects
- Abstract
The actions of two clinically important dibenzocycloheptane antidepressant drugs, amitriptyline and nortriptyline, were studied on ionic channels of nicotinic acetylcholine (AcCho) receptors at the neuromuscular junction of frog skeletal muscle. Amitriptyline (5-10 microM) and nortriptyline (1-2 microM), like imipramine (5-10 microM), did not react with the nicotinic AcCho receptor but caused a voltage- and time-dependent decrease in the peak amplitude of the endplate current (epc). The time constant of epc decay, however, retained its voltage sensitivity. The voltage- and time-dependent effect of amitriptyline was nonlinear with regard to the current/voltage (I/V) relationship. Nortriptyline also had a more pronounced voltage- and time-dependent effect evidenced by a hysteresis loop in the I/V relationship of the epc was eliminated by the use of 50-msec stepwise changes of the membrane potential. The nonlinearity and hysteresis were due to a time-dependent phenomenon and did not involve previous AcCho receptor activation. The rate constant of the voltage- and time-dependent decrease in epc amplitude was sensitive to the membrane electric field and varied linearly with the membrane potential. Iontophoretically elicited epcs were much more depressed by both drugs than were spontaneous miniature epcs. There was no effect on the time constant of miniature epc decay, single-channel lifetime, or conductance. Thus (as we have pointed out in our histrionicotoxin studies) the primary site of action of these agents presumably is the activated but nonconducting species of the ionic channel of the nicotinic AcCho receptor. These agents, particularly nortriptyline, point to several different binding sites of the ionic channel and are suitable tools for the separation of the effects on peak current amplitude from its time constant of decay.
- Published
- 1981
- Full Text
- View/download PDF
34. The roles of disuse and loss of neurotrophic function in denervation atrophy of skeletal muscle.
- Author
-
Guth L, Kemerer VF, Samaras TA, Warnick JE, and Albuquerque EX
- Subjects
- Acetylcholine pharmacology, Acetylcholinesterase metabolism, Animals, Diaphragm physiology, Female, Membrane Potentials, Muscles enzymology, Phrenic Nerve physiology, Rats, Receptors, Cholinergic physiology, Spinal Cord physiology, Muscle Contraction drug effects, Muscle Denervation
- Published
- 1981
- Full Text
- View/download PDF
35. Segmental synaptic depression caused by diisopropylphosphorofluoridate and sarin is reversed by thyrotropin-releasing hormone in the neonatal rat spinal cord.
- Author
-
Das Gupta S, Deshpande SB, and Warnick JE
- Subjects
- Animals, Animals, Newborn, Atropine pharmacology, Cholinesterases analysis, Rats, Rats, Inbred Strains, Receptors, Neurotransmitter drug effects, Receptors, Thyrotropin-Releasing Hormone, Spinal Cord physiology, Isoflurophate toxicity, Organophosphorus Compounds toxicity, Reflex, Monosynaptic drug effects, Sarin toxicity, Spinal Cord drug effects, Thyrotropin-Releasing Hormone pharmacology
- Abstract
The organophosphorus compounds diisopropylphosphorofluoridate (DFP) and isopropylmethylphosphonofluoridate (sarin) depressed the monosynaptic reflex (MSR) in spinal cords from 7- to 9-day-old male rats. The concentrations of DFP and sarin which depressed the MSR by nearly 50% were 100 microM and 100 nM, respectively. Simultaneous superfusion of the cords with thyrotropin-releasing hormone (TRH) with either DFP or sarin resulted in a reversal of the depression. The depression caused by DFP was reversed to 95% of control by 100 nM TRH whereas similar reversal of sarin-induced depression required a 10-fold greater concentration of TRH. The potentiating effect of TRH was not affected by atropine even at a high concentration (1 microM) although atropine easily reversed organophosphorus-induced depression of the MSR. It appears that reversal of organophosphorus-induced depression by TRH might occur through a noncholinergic, TRH-sensitive receptor mechanism and may be unrelated to acetylcholinesterase activity. This action represents a possible utility of TRH as an adjunct in organophosphorus toxicity.
- Published
- 1988
- Full Text
- View/download PDF
36. The mechanism and site of action of ketamine on skeletal muscle.
- Author
-
Maleque MA, Warnick JE, and Albuquerque EX
- Subjects
- Acetylcholine pharmacology, Action Potentials drug effects, Animals, Female, In Vitro Techniques, Membrane Potentials drug effects, Motor Endplate drug effects, Muscle Contraction drug effects, Rana pipiens, Rats, Rats, Inbred Strains, Receptors, Cholinergic drug effects, Ketamine pharmacology, Muscles drug effects
- Published
- 1981
37. Prevention of phencyclidine-induced depression of the segmental reflex by L-3,4-dihydroxyphenylalanine in the rat spinal cord in vitro.
- Author
-
Carp JS, Ohno Y, and Warnick JE
- Subjects
- Animals, Chlorpromazine pharmacology, Electric Stimulation, Female, Haloperidol pharmacology, Hydroxydopamines pharmacology, In Vitro Techniques, Male, Oxidopamine, Phentolamine pharmacology, Rats, Rats, Inbred Strains, Spinal Cord physiology, Dihydroxyphenylalanine pharmacology, Phencyclidine pharmacology, Reflex drug effects, Spinal Cord drug effects
- Abstract
The interaction between phencyclidine (PCP) and the catecholamine precursor L-3,4-dihydroxyphenylalanine (DOPA) was studied in the isolated spinal cord from neonatal rats. PCP decreased the magnitude of the dorsal-ventral reflex and enhanced frequency-dependent depression of the reflex in a concentration-dependent manner. Although DOPA and DL-threo-3,4-dihydroxyphenylserine (a direct precursor for norepinephrine) had no effect on the reflex by themselves, DOPA, but not DL-threo-3,4-dihydroxyphenylserine prevented the depression of the reflex response by PCP in a concentration-dependent manner. Inhibition of aromatic-L-amino-acid decarboxylase (EC 4.1.1.2A) by m-hydroxybenzylhydrazine markedly attenuated the action of DOPA in preventing the depression caused by PCP. The dopamine receptor antagonists haloperidol and chlorpromazine blocked the action of DOPA, but the alpha and beta adrenergic receptor antagonists phentolamine and timolol, respectively, did not. In addition, prior treatment of neonatal rats with 6-hydroxydopamine diminished the ability of DOPA to prevent the depressant effect of PCP whereas partially attenuating the depressant effect of PCP alone. These results suggest that DOPA attenuated PCP-induced depression of spinal cord transmission through its conversion to dopamine rather than norepinephrine.
- Published
- 1989
38. Interactions of phencyclidine with ion channels of nerve and muscle: behavioral implications.
- Author
-
Albuquerque EX, Aguayo LG, Warnick JE, Ickowicz RK, and Blaustein MP
- Subjects
- Action Potentials drug effects, Animals, Humans, Ion Channels drug effects, Muscles drug effects, Phencyclidine analogs & derivatives, Ranidae, Receptors, Nicotinic drug effects, Synapses drug effects, Behavior drug effects, Ion Channels physiology, Motor Endplate physiology, Muscles physiology, Neuromuscular Junction physiology, Phencyclidine pharmacology, Synapses physiology
- Abstract
Phencyclidine (1-(1-phenylcyclohexyl)piperidine [PCP]), a behaviorally active analogue (1-(1-m-aminophenylcyclohexyl)piperidine [m-amino-PCP]), and two behaviorally inactive analogues (1-(1-m-nitrophenylcyclohexyl)piperidine and 1-piperidinocyclohexanecarbonitrile) block neuromuscular transmission, depress the amplitude and rate of rise of directly elicited action potentials in frog sartorius muscle, and cause voltage- and concentration-dependent decreases of the peak end-plate current amplitude. This implies that all four compounds block the ion channel of the acetylcholine (ACh) receptors. Only PCP and m-amino-PCP prolong the action potential, block delayed rectification, potentiate muscle twitch, increase quantal content of end-plate potentials, and block K+-induced 86Rb+ efflux from rat brain synaptosomes. PCP also possesses central and peripheral antimuscarinic activity but is much less potent than 3-quinuclidinyl benzilate (QNB). Atropine, scopolamine, and QNB require much higher concentrations to induce behavioral alterations than to block muscarinic receptors. Thus PCP and some of its behaviorally active and inactive derivatives share two common effects, blockade of the nicotinic ACh receptor-ion channel complex and blockade of central and peripheral muscarinic receptors. The feature that apparently separates behaviorally active from inactive derivatives of PCP is their ability to block K+ conductance (gK) and thereby potentiate muscle twitch and increase the release of transmitters from central and peripheral synapses. The similarity between PCP-induced behavioral alterations and primary schizophrenia in humans raises the possibility of involvement of an altered gK in the human disease.
- Published
- 1983
39. The pharmacology of batrachotoxin. VII. Structure-activity relationships and the effects of pH.
- Author
-
Warnick JE, Albuquerque EX, Onur R, Jansson SE, Daly J, Tokuyama T, and Witkop B
- Subjects
- Animals, Batrachotoxins toxicity, Caffeine pharmacology, Diaphragm drug effects, Hydrogen-Ion Concentration, In Vitro Techniques, Lethal Dose 50, Male, Membrane Potentials drug effects, Muscle Contraction drug effects, Neuromuscular Junction drug effects, Phrenic Nerve drug effects, Potassium Chloride pharmacology, Rats, Structure-Activity Relationship, Synaptic Transmission drug effects, Batrachotoxins pharmacology
- Abstract
The effects of the depolarizing agent, batrachotoxin (BTX), and of various analogs were studied on rat phrenic nerve-diaphragm muscle preparations at 37 degrees C. The structural modifications of BTX included: 1) replacement of the 20alpha-pyrrole-3-carboxylate moiety; 2) alterations of substituents on the pyrrole moiety; 3) clevage of the 3alpha, 9alpha-hemiketal linkage; and 4) quaternization of the tertiary nitrogen of BTX. All of the compounds except batrachotoxinin A (BTX-A), which lacks the 20alpha-substituent, depolarized the postsynaptic membrane, transiently increased the frequency of spontaneous transmitter release to 400 to 600 sec- minus 1 and finally produced blockade of the directly and indirectly elicited muscle twitches. Of the compounds tested, only BTX-A potentiated the muscle twitches. The concentration which elicits a 50% depolarization of the muscle membrane in 1 hour was determined for all the compounds except for BTX-A and for dihydrobatrachotoxin which lacks the 3alpha, 9alpha-hemiketal linkage; these two analogs never depolarized the postsynaptic membrane by more than 10 to 15%. BTX, the 20alpha-2, 4, 5-trimethylpyrrole-3-carboxylate of BTX-A and the 20alpha-ester of BTX-A with 2-ethyl-4-methylpyrrole-3-carboxylic acid (homobatrachotoxin) were the three most potent toxins with doses of 4.5, 12 and 18 times 10- minus 9 M eliciting a 50% membrane depolarization in 1 hour. The quaternary derivative of BTX, the 20alpha-4, 5-dimethylpyrrole-3-carboxylate of BTX-A and 20alpha-2,4-dimethyl-5-acetylpyrrole-3-carboxylate of BTX-A were 24-, 65- and 110-fold less potent than BTX as depolarizing agents, whereas the 20alpha-p-bromobenzoate of BTX-A was 220-fold less potent. Each of these derivatives had the ability to increase sodium permeability since the increase in spontaneous miniature end-plate potential frequency and membrane depolarization were reversed by tetrodotoxin or by reducing the external sodium concentration. BTX was found to be more effective at alkaline pH (pH 9.0), at which it exists almost entirely in the un-ionized form, than at physiological or acidic pH(6.0). The results indicate that the analogs of BTX act by a mechanism similar to that of the parent compound, but that their potency differs and certain compounds may have a more selective action on either the pre- or postsynaptic membrane. For maximal depolarizing activity, a substituted pyrrole moiety is necessary at the 20alpha-position of BTX-A and 3alpha, 9alpha-hemiketal linkage must remain intact providing rigidity for the pentacyclic steroid nucleus.
- Published
- 1975
40. Spinal cord regeneration and paraplegia.
- Author
-
Albuquerque EX, Warnick JE, and Guth L
- Subjects
- 6-Aminonicotinamide pharmacology, Animals, Axonal Transport, Batrachotoxins pharmacology, Electrophysiology, Female, Membrane Potentials, Muscles physiopathology, Rats, Spinal Cord pathology, Spinal Cord Injuries complications, Nerve Regeneration, Paraplegia etiology, Spinal Cord Injuries physiopathology
- Published
- 1980
41. Levels of batrachotoxin and lack of sensitivity to its action in poison-dart frogs (Phyllobates).
- Author
-
Daly JW, Myers CW, Warnick JE, and Albuquerque EX
- Subjects
- Age Factors, Animals, Batrachotoxins metabolism, Membrane Potentials drug effects, Motor Endplate drug effects, Synaptic Transmission drug effects, Anura physiology, Batrachotoxins pharmacology, Diterpenes pharmacology, Ion Channels drug effects, Veratridine pharmacology, Veratrine analogs & derivatives
- Abstract
Batrachotoxin is present in remarkably high amounts in the skin of Phyllobates terribilis. Levels of batrachotoxin tend to be reduced when P. terribilis is maintained in captivity, but even after being confined for up to 6 years, these frogs were still at least five times more toxic than other Phyllobates species used by natives for poisoning blowgun darts. Batrachotoxin was not detectable in F1 progeny reared to maturity in captivity. Nerve and muscle preparations from wild-caught frogs and from the nontoxic F1 frogs were both insensitive to batrachotoxin. The regulatory site controlling sodium-channel activation and permeability appears to have been minimally altered to prevent interaction with batrachotoxin, but is still sensitive to other sodium conductance activators (veratridine, grayanotoxin) to which the frogs arenot exposed naturally.
- Published
- 1980
- Full Text
- View/download PDF
42. Sea nettle (Chrysaora quinquecirrha) toxin on electrogenic and chemosensitive properties of nerve and muscle.
- Author
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Warnick JE, Weinreich D, and Burnett JW
- Subjects
- Action Potentials drug effects, Animals, Aplysia, Female, Histamine pharmacology, In Vitro Techniques, Membrane Potentials drug effects, Neuromuscular Junction drug effects, Neurotransmitter Agents metabolism, Rana pipiens, Rats, Cnidarian Venoms pharmacology, Muscles drug effects, Neurons drug effects
- Published
- 1981
- Full Text
- View/download PDF
43. Trophic functions of the neuron. 3. Mechanisms of neurotrophic interactions. The effects of vinblastine and colchicine on neural regulation of muscle.
- Author
-
Albuquerque EX, Warnick JE, Sansone FM, and Onur R
- Subjects
- Acetylcholine pharmacology, Action Potentials drug effects, Adenosine Triphosphatases metabolism, Animals, Caffeine pharmacology, Cell Membrane metabolism, Cycloheximide pharmacology, Electrophysiology, Iontophoresis, Membrane Potentials drug effects, Microtubules metabolism, Muscle Contraction, Nerve Degeneration, Neuromuscular Junction drug effects, Rats, Sarcoplasmic Reticulum metabolism, Tetrodotoxin pharmacology, Time Factors, Colchicine pharmacology, Muscles innervation, Peripheral Nerves drug effects, Vinblastine pharmacology
- Published
- 1974
- Full Text
- View/download PDF
44. Antagonism of carbamylcholine-induced depolarization by batrachotoxin and veratridine.
- Author
-
Garrison DL, Albuquerque EX, Warnick JE, Daly JW, and Witkop B
- Subjects
- Acetylcholine pharmacology, Animals, Anura, Bungarotoxins pharmacology, Female, In Vitro Techniques, Motor Endplate drug effects, Rana pipiens, Rats, Batrachotoxins pharmacology, Carbachol antagonists & inhibitors, Neuromuscular Junction drug effects, Veratridine pharmacology, Veratrine analogs & derivatives
- Published
- 1978
45. Gender-specific action of thyrotropin-releasing hormone in the mammalian spinal cord.
- Author
-
Deshpande SB, Pilotte NS, and Warnick JE
- Subjects
- Animals, Female, In Vitro Techniques, Male, Orchiectomy, Ovariectomy, Rats, Rats, Inbred Strains, Sex Factors, Spinal Cord drug effects, Synapses drug effects, Synapses physiology, Reflex drug effects, Spinal Cord physiology, Thyrotropin-Releasing Hormone pharmacology
- Abstract
Thyrotropin-releasing hormone (TRH) potentiated the monosynaptic reflex in isolated spinal cords obtained from 7- to 9-day-old rats. A concentration-dependent increase in the monosynaptic reflex was observed in spinal cords obtained from male but not from female or castrated male rats. In contrast, the magnitude of potentiation in cords from ovariectomized control female rats and in ovariectomized female rats treated with testosterone approached that seen in intact males. The results provide evidence that gender plays a prominent role in the variability of response both of humans with amyotrophic lateral sclerosis and of animal tissues to TRH. Furthermore, exposure to androgen during the neonatal period may determine the responsiveness of motoneurons to TRH. Thus the use of TRH in the treatment of amyotrophic lateral sclerosis may be more effective in males than in females.
- Published
- 1987
- Full Text
- View/download PDF
46. The pharmacology of pumiliotoxin-B. I. Interaction with calcium sites in the sarcoplasmic reticulum of skeletal muscle.
- Author
-
Albuquerque EX, Warnick JE, Maleque MA, Kauffman FC, Tamburini R, Nimit Y, and Daly JW
- Subjects
- Animals, Astacoidea, Caffeine pharmacology, Calcium-Transporting ATPases antagonists & inhibitors, Electrophysiology, Glycerol pharmacology, Muscle Contraction drug effects, Muscles physiology, Rana pipiens, Rats, Alkaloids pharmacology, Calcium pharmacology, Indolizines, Muscles drug effects, Piperidines, Sarcoplasmic Reticulum drug effects
- Published
- 1981
47. Quantal release of acetylcholine does not regulate the resting membrane potential of mammalian skeletal muscle: evidence from in vivo experiments.
- Author
-
Deshpande SS, Warnick JE, Guth L, and Albuquerque EX
- Subjects
- Animals, Female, Hindlimb innervation, Membrane Potentials, Motor Endplate physiology, Muscle Denervation, Rats, Sciatic Nerve physiology, Acetylcholine metabolism, Muscle Contraction, Muscles innervation
- Published
- 1980
- Full Text
- View/download PDF
48. Elucidation of the mechanism and site of action of quinuclidinyl benzilate (QNB) on the electrical excitability and chemosensitivity of the frog sartorius muscle.
- Author
-
Schofield GG, Warnick JE, and Albuquerque EX
- Subjects
- Animals, Evoked Potentials drug effects, Kinetics, Membrane Potentials drug effects, Motor Endplate drug effects, Muscles drug effects, Rana pipiens, Motor Endplate physiology, Muscles physiology, Neuromuscular Junction physiology, Quinuclidines pharmacology, Quinuclidinyl Benzilate pharmacology
- Abstract
The effects of the muscarinic antagonist quinuclidinyl benzilate (QNB) on transmission at the frog sartorius neuromuscular junction have been examined. QNB decreases endplate potential (EPP) amplitude without affecting miniature endplate (MEPP) frequency or resting potential. QNB also increased the latency of the EPP and the nerve terminal spike in a frequency dependent fashion, suggesting the site of action is the unmyelinated nerve terminal. Since the rate and amplitude of muscle action are potentials decreased it is likely that QNB causes a blockade of electrically excitable sodium channels; the agent also blocks ionic channels associated with nicotinic acetylcholine receptors. It is possible that these effects of QNB may explain some of the behavioral disturbances produced by its administration.
- Published
- 1981
- Full Text
- View/download PDF
49. Junctional and extrajunctional aspects of inherited muscular dystrophy in chickens: development and pharmacology.
- Author
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Warnick JE, Lebeda FJ, and Albuquerque EX
- Subjects
- Acetylcholine pharmacology, Action Potentials, Animals, Chickens, Membrane Potentials, Motor Endplate drug effects, Motor Endplate physiopathology, Muscle Denervation, Muscles drug effects, Muscles physiopathology, Neurotransmitter Agents metabolism, Penicillamine pharmacology, Posture, Species Specificity, Muscular Dystrophy, Animal physiopathology, Neuromuscular Junction physiopathology
- Published
- 1979
- Full Text
- View/download PDF
50. Aminoglycoside-induced blockade of reflex activity in the isolated spinal cord from the neonatal rat.
- Author
-
Tolliver JM and Warnick JE
- Subjects
- Animals, Calcium pharmacology, Drug Interactions, Gentamicins pharmacology, In Vitro Techniques, Magnesium pharmacology, Rats, Rats, Inbred Strains, Synapses drug effects, Aminoglycosides pharmacology, Animals, Newborn physiology, Nerve Block, Reflex drug effects, Spinal Cord drug effects
- Abstract
The subarachnoid injection of gentamicin into rats causes a transient flaccid paralysis of the hindlimbs lasting 1 to 5 hrs followed by a permanent flaccid paralysis which develops after 24 to 36 hrs. Although the early transient paralysis could be attributed to a pharmacologic blockade of central synaptic transmission, the mechanism of the blockade was not apparent. This study examines the effects of gentamicin and two other aminoglycoside antibiotics, kanamycin and neomycin, on reflex transmission in the isolated, hemisected spinal cord of the neonatal rat and the interaction with calcium. Gentamicin produced a concentration-dependent depression of reflex activity with a 50% inhibitory concentration of 1.6 mM at an external calcium concentration ([Ca2+]o) of 2.5 mM. Reducing the [Ca2+]o by half (i.e., to 1.25 mM) lowered the 50% inhibitory concentration of gentamicin to 0.22 mM. Gentamicin also increased the magnitude of homosynaptic depression of reflex activity in a manner qualitatively similar to that of decreasing [Ca2+]o. Lowering the [Ca2+]o potentiated the effect of gentamicin on homosynaptic depression. The actions of neomycin, kanamycin and magnesium on reflex transmission were nearly identical to those of gentamicin. These findings demonstrate that the early paralysis seen after subarachnoid injection of gentamicin may result from a central blockade of transmission. It is most likely that the site for blockade of reflex activity by gentamicin is presynaptic.
- Published
- 1987
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