42 results on '"Doze VA"'
Search Results
2. Virtually the Same? Evaluating the Effectiveness of Remote Undergraduate Research Experiences.
- Author
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Hess RA, Erickson OA, Cole RB, Isaacs JM, Alvarez-Clare S, Arnold J, Augustus-Wallace A, Ayoob JC, Berkowitz A, Branchaw J, Burgio KR, Cannon CH, Ceballos RM, Cohen CS, Coller H, Disney J, Doze VA, Eggers MJ, Ferguson EL, Gray JJ, Greenberg JT, Hoffmann A, Jensen-Ryan D, Kao RM, Keene AC, Kowalko JE, Lopez SA, Mathis C, Minkara M, Murren CJ, Ondrechen MJ, Ordoñez P, Osano A, Padilla-Crespo E, Palchoudhury S, Qin H, Ramírez-Lugo J, Reithel J, Shaw CA, Smith A, Smith RJ, Tsien F, and Dolan EL
- Subjects
- Humans, Pandemics, Students, COVID-19
- Abstract
In-person undergraduate research experiences (UREs) promote students' integration into careers in life science research. In 2020, the COVID-19 pandemic prompted institutions hosting summer URE programs to offer them remotely, raising questions about whether undergraduates who participate in remote research can experience scientific integration and whether they might perceive doing research less favorably (i.e., not beneficial or too costly). To address these questions, we examined indicators of scientific integration and perceptions of the benefits and costs of doing research among students who participated in remote life science URE programs in Summer 2020. We found that students experienced gains in scientific self-efficacy pre- to post-URE, similar to results reported for in-person UREs. We also found that students experienced gains in scientific identity, graduate and career intentions, and perceptions of the benefits of doing research only if they started their remote UREs at lower levels on these variables. Collectively, students did not change in their perceptions of the costs of doing research despite the challenges of working remotely. Yet students who started with low cost perceptions increased in these perceptions. These findings indicate that remote UREs can support students' self-efficacy development, but may otherwise be limited in their potential to promote scientific integration.
- Published
- 2023
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3. Pharmacological characterization of the α 2A -adrenergic receptor inhibiting rat hippocampal CA3 epileptiform activity: comparison of ligand efficacy and potency.
- Author
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Biggane JP, Xu K, Goldenstein BL, Davis KL, Luger EJ, Davis BA, Jurgens CWD, Perez DM, Porter JE, and Doze VA
- Subjects
- Animals, Rats, Epinephrine pharmacology, Ligands, Receptors, Adrenergic, In Vitro Techniques, Adrenergic alpha-Agonists pharmacology, Norepinephrine pharmacology, CA3 Region, Hippocampal physiopathology, Seizures drug therapy
- Abstract
The mechanism underlying the antiepileptic actions of norepinephrine (NE) is unclear with conflicting results. Our objectives are to conclusively delineate the specific adrenergic receptor (AR) involved in attenuating hippocampal CA3 epileptiform activity and assess compounds for lead drug development. We utilized the picrotoxin model of seizure generation in rat brain slices using electrophysiological recordings. Epinephrine (EPI) reduced epileptiform burst frequency in a concentration-dependent manner. To identify the specific receptor involved in this response, the equilibrium dissociation constants were determined for a panel of ligands and compared with established binding values for α
1 , α2 , and other receptor subtypes. Correlation and slope of unity were found for the α2A -AR, but not other receptors. Effects of different chemical classes of α-AR agonists at inhibiting epileptiform activity by potency (pEC50 ) and relative efficacy (RE) were determined. Compared with NE (pEC50 , 6.20; RE, 100%), dexmedetomidine, an imidazoline (pEC50 , 8.59; RE, 67.1%), and guanabenz, a guanidine (pEC50 , 7.94; RE, 37.9%), exhibited the highest potency (pEC50 ). In contrast, the catecholamines, EPI (pEC50 , 6.95; RE, 120%) and α-methyl-NE (pEC50 , 6.38; RE, 116%) were the most efficacious. These findings confirm that CA3 epileptiform activity is mediated solely by α2A -ARs without activation of other receptor systems. These findings suggest a pharmacotherapeutic target for treating epilepsy and highlight the need for selective and efficacious α2A -AR agonists that can cross the blood-brain barrier.- Published
- 2022
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4. "How Do We Do This at a Distance?!" A Descriptive Study of Remote Undergraduate Research Programs during COVID-19.
- Author
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Erickson OA, Cole RB, Isaacs JM, Alvarez-Clare S, Arnold J, Augustus-Wallace A, Ayoob JC, Berkowitz A, Branchaw J, Burgio KR, Cannon CH, Ceballos RM, Cohen CS, Coller H, Disney J, Doze VA, Eggers MJ, Farina S, Ferguson EL, Gray JJ, Greenberg JT, Hoffmann A, Jensen-Ryan D, Kao RM, Keene AC, Kowalko JE, Lopez SA, Mathis C, Minkara M, Murren CJ, Ondrechen MJ, Ordoñez P, Osano A, Padilla-Crespo E, Palchoudhury S, Qin H, Ramírez-Lugo J, Reithel J, Shaw CA, Smith A, Smith R, Summers AP, Tsien F, and Dolan EL
- Subjects
- Humans, Pandemics, SARS-CoV-2, Students, Systemic Racism, United States, COVID-19
- Abstract
The COVID-19 pandemic shut down undergraduate research programs across the United States. A group of 23 colleges, universities, and research institutes hosted remote undergraduate research programs in the life sciences during Summer 2020. Given the unprecedented offering of remote programs, we carried out a study to describe and evaluate them. Using structured templates, we documented how programs were designed and implemented, including who participated. Through focus groups and surveys, we identified programmatic strengths and shortcomings as well as recommendations for improvements from students' perspectives. Strengths included the quality of mentorship, opportunities for learning and professional development, and a feeling of connection with a larger community. Weaknesses included limited cohort building, challenges with insufficient structure, and issues with technology. Although all programs had one or more activities related to diversity, equity, inclusion, and justice, these topics were largely absent from student reports even though programs coincided with a peak in national consciousness about racial inequities and structural racism. Our results provide evidence for designing remote Research Experiences for Undergraduates (REUs) that are experienced favorably by students. Our results also indicate that remote REUs are sufficiently positive to further investigate their affordances and constraints, including the potential to scale up offerings, with minimal concern about disenfranchising students.
- Published
- 2022
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5. Postbaccalaureate terminal degree and career choices of students who performed undergraduate research.
- Author
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Sens DA, Bobylev M, Cisek KL, Garrett SH, Somji S, Sens MA, and Doze VA
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- Humans, Minority Groups, Students, Universities, Biomedical Research, Career Choice
- Abstract
This study analyzed terminal degree and career choices of students who performed undergraduate research. In one analysis, the study compared terminal degree and career choices between a course-based undergraduate research experience (CURE) and traditional non-course-based undergraduate research experiences at one primarily undergraduate institution (PUI). Students who pursued postbaccalaureate programs chose terminal degrees at levels exceeding 75%, with no significant difference between a CURE experience and a traditional research experience. Analysis of terminal degree and career choices at four PUIs providing traditional research experiences showed a marked difference in the number of students pursuing terminal degrees. Two PUIs showed rates > 75%, whereas students at the other two PUIs pursued terminal degrees <50% of the time. The majority of students not pursuing terminal degrees chose M.S. degrees in education and healthcare. An analysis was also performed among students participating in traditional summer undergraduate research on a research-intensive university (RIU) campus with a medical school. Students were accepted from two programs, an NIH IDeA Network of Biomedical Research Excellence (INBRE) program recruiting students from the RIU and an NSF Research Experiences for Undergraduates (REU) program recruiting undergraduates from rural PUIs and minority-serving institutions, particularly tribal colleges. Analysis showed that >70% of the students who pursued postbaccalaureate programs chose terminal degrees. INBRE undergraduates displayed a marked preference for the M.D. degree (73.9% vs. 17.4%), whereas the REU students chose the Ph.D. degree (75.0% vs. 22.9%). American Indian students were also analyzed separately for career choice and showed an equal preference for the M.D. and Ph.D. degrees when pursuing postbaccalaureate education. Overall, the results provide evidence that undergraduate student research stimulates student careers in areas needed by the nation's citizen stakeholders.
- Published
- 2021
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6. STEERing an IDeA in Undergraduate Research at a Rural Research Intensive University.
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Sens DA, Cisek KL, Garrett SH, Somji S, Dunlevy JR, Sens MA, Conway P, and Doze VA
- Abstract
This study documents outcomes, including student career choices, of the North Dakota Institutional Development Award Networks of Biomedical Research Excellence program that provides 10-week, summer undergraduate research experiences at the University of North Dakota School of Medicine and Health Sciences. Program evaluation initiated in 2008 and, to date, 335 students have completed the program. Of the 335, 214 students have successfully completed their bachelor's degree, 102 are still undergraduates, and 19 either did not complete a bachelor's degree or were lost to follow-up. The program was able to track 200 of the 214 students for education and career choices following graduation. Of these 200, 76% continued in postgraduate health-related education; 34.0% and 20.5% are enrolled in or have completed MD or PhD programs, respectively. Other postbaccalaureate pursuits included careers in pharmacy, optometry, dentistry, public health, physical therapy, nurse practitioner, and physician's assistant, accounting for an additional 21.5%. Most students electing to stop formal education at the bachelor's degree also entered fields related to health care or science, technology, engineering, and mathematics (19.5%), with only a small number of the 200 students tracked going into service or industries which lacked an association with the health-care workforce (4.5%). These student outcomes support the concept that participation in summer undergraduate research boosts efforts to populate the pipeline of future researchers and health professionals. It is also an indication that future researchers and health professionals will be able to communicate the value of research in their professional and social associations. The report also discusses best practices and issues in summer undergraduate research for students originating from rural environments., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2017
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7. An IDeA for enhancing undergraduate research at rural primarily undergraduate institutions.
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Sens DA, Cisek KL, Conway P, and Doze VA
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- Biomedical Research education, Career Choice, Faculty statistics & numerical data, Humans, North Dakota, Rural Population, Science statistics & numerical data, Science trends, Students statistics & numerical data, Biomedical Research standards, Science education
- Abstract
This study documents the efforts of the North Dakota (ND) IDeA Networks of Biomedical Research Excellence (INBRE) program to assist in the development of undergraduate research programs at four state-supported primarily undergraduate institutions (PUIs) in ND. The study was initiated in the 2004-2005 academic year and continues to the present. The study shows that gaining initial institutional support for undergraduate research was assisted by providing salary support for faculty involved in undergraduate research. Once research was ongoing, each institution evolved their own unique plan for the use of support from the ND INBRE. Undergraduate student researchers have prepared, presented, and defended their research results on 188 unique posters since initiation of the program, with many posters being presented at more than one meeting. PUI faculty have authored 35 peer-reviewed manuscripts. Evaluation has shown that over 95% of the undergraduate students performing research matriculated with their bachelor's degree. Career choices of 77.2% of these graduates was determined, and 37% pursued a career in the health professions. Of the students not pursuing a post-baccalaureate degree, 81.2% chose careers directly linked to science. The study reinforces the concept that undergraduate research can be performed directly on the PUI campus and be of value in preparing the next generation of health professionals in research, service, and teaching., (Copyright © 2017 the American Physiological Society.)
- Published
- 2017
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8. Norepinephrine controls astroglial responsiveness to local circuit activity.
- Author
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Paukert M, Agarwal A, Cha J, Doze VA, Kang JU, and Bergles DE
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- Animals, Mice, Mice, Transgenic, Visual Cortex metabolism, Action Potentials physiology, Astrocytes metabolism, Nerve Net metabolism, Norepinephrine metabolism, Photic Stimulation methods
- Abstract
Astrocytes perform crucial supportive functions, including neurotransmitter clearance, ion buffering, and metabolite delivery. They can also influence blood flow and neuronal activity by releasing gliotransmitters in response to intracellular Ca(2+) transients. However, little is known about how astrocytes are engaged during different behaviors in vivo. Here we demonstrate that norepinephrine primes astrocytes to detect changes in cortical network activity. We show in mice that locomotion triggers simultaneous activation of astrocyte networks in multiple brain regions. This global stimulation of astrocytes was inhibited by alpha-adrenoceptor antagonists and abolished by depletion of norepinephrine from the brain. Although astrocytes in visual cortex of awake mice were rarely engaged when neurons were activated by light stimulation alone, pairing norepinephrine release with light stimulation markedly enhanced astrocyte Ca(2+) signaling. Our findings indicate that norepinephrine shifts the gain of astrocyte networks according to behavioral state, enabling astrocytes to respond to local changes in neuronal activity., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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9. Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence.
- Author
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Collette KM, Zhou XD, Amoth HM, Lyons MJ, Papay RS, Sens DA, Perez DM, and Doze VA
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- Animals, Female, Follow-Up Studies, Male, Mice, Mice, Transgenic, Neoplasms, Experimental epidemiology, Signal Transduction, Time Factors, Aging, Gene Expression Regulation, Neoplastic, Longevity physiology, Neoplasms, Experimental metabolism, Receptors, Adrenergic, alpha-1 metabolism
- Abstract
The α1-adrenergic receptor (α1AR) subtypes, α1AAR and α1BAR, have differential effects in the heart and central nervous system. Long-term stimulation of the α1AAR subtype prolongs lifespan and provides cardio- and neuro-protective effects. We examined the lifespan of constitutively active mutant (CAM)-α1BAR mice and the incidence of cancer in mice expressing the CAM form of either the α1AAR (CAM-α1AAR mice) or α1BAR. CAM-α1BAR mice have a significantly shortened lifespan when compared with wild-type (WT) animals; however, the effect was sex dependent. Female CAM-α1BAR mice lived significantly shorter lives, while the median lifespan of male CAM-α1BAR mice was not different when compared with that of WT animals. There was no difference in the incidence of cancer in either sex of CAM-α1BAR mice. The incidence of cancer was significantly decreased in CAM-α1AAR mice when compared with that in WT, and no sex-dependent effects were observed. Further study is warranted on cancer incidence after activation of each α1AR subtype and the effect of sex on lifespan following activation of the α1BAR. The implications of a decrease in cancer incidence following long-term α1AAR stimulation could lead to improved treatments for cancer.
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- 2014
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10. GPCRs in stem cell function.
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Doze VA and Perez DM
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- Animals, Humans, Neoplastic Stem Cells metabolism, Receptors, G-Protein-Coupled metabolism, Stem Cells metabolism
- Abstract
Many tissues of the body cannot only repair themselves, but also self-renew, a property mainly due to stem cells and the various mechanisms that regulate their behavior. Stem cell biology is a relatively new field. While advances are slowly being realized, stem cells possess huge potential to ameliorate disease and counteract the aging process, causing its speculation as the next panacea. Amidst public pressure to advance rapidly to clinical trials, there is a need to understand the biology of stem cells and to support basic research programs. Without a proper comprehension of how cells and tissues are maintained during the adult life span, clinical trials are bound to fail. This review will cover the basic biology of stem cells, the various types of stem cells, their potential function, and the advantages and disadvantages to their use in medicine. We will next cover the role of G protein-coupled receptors in the regulation of stem cells and their potential in future clinical applications., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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11. G-protein-coupled receptors in adult neurogenesis.
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Doze VA and Perez DM
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- Adult, Adult Stem Cells drug effects, Adult Stem Cells pathology, Animals, Cellular Senescence physiology, Humans, Neural Stem Cells drug effects, Neural Stem Cells pathology, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases pathology, Neurodegenerative Diseases therapy, Neurogenesis drug effects, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Signal Transduction, Stem Cell Transplantation, Adult Stem Cells metabolism, Neural Stem Cells metabolism, Neurogenesis physiology, Receptors, G-Protein-Coupled physiology
- Abstract
The importance of adult neurogenesis has only recently been accepted, resulting in a completely new field of investigation within stem cell biology. The regulation and functional significance of adult neurogenesis is currently an area of highly active research. G-protein-coupled receptors (GPCRs) have emerged as potential modulators of adult neurogenesis. GPCRs represent a class of proteins with significant clinical importance, because approximately 30% of all modern therapeutic treatments target these receptors. GPCRs bind to a large class of neurotransmitters and neuromodulators such as norepinephrine, dopamine, and serotonin. Besides their typical role in cellular communication, GPCRs are expressed on adult neural stem cells and their progenitors that relay specific signals to regulate the neurogenic process. This review summarizes the field of adult neurogenesis and its methods and specifies the roles of various GPCRs and their signal transduction pathways that are involved in the regulation of adult neural stem cells and their progenitors. Current evidence supporting adult neurogenesis as a model for self-repair in neuropathologic conditions, adult neural stem cell therapeutic strategies, and potential avenues for GPCR-based therapeutics are also discussed.
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- 2012
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12. Long-term α1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity.
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Doze VA, Papay RS, Goldenstein BL, Gupta MK, Collette KM, Nelson BW, Lyons MJ, Davis BA, Luger EJ, Wood SG, Haselton JR, Simpson PC, and Perez DM
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- Affect drug effects, Animals, Cognition drug effects, Female, Hippocampus drug effects, Hippocampus metabolism, Long-Term Potentiation drug effects, Long-Term Potentiation physiology, Longevity drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, Mice, Transgenic, Neuronal Plasticity drug effects, Organ Culture Techniques, Receptors, Adrenergic, alpha-1 physiology, Synapses drug effects, Synapses physiology, Adrenergic alpha-1 Receptor Agonists pharmacology, Affect physiology, Cognition physiology, Longevity physiology, Neuronal Plasticity physiology, Receptors, Adrenergic, alpha-1 metabolism
- Abstract
The role of α(1)-adrenergic receptors (α(1)ARs) in cognition and mood is controversial, probably as a result of past use of nonselective agents. α(1A)AR activation was recently shown to increase neurogenesis, which is linked to cognition and mood. We studied the effects of long-term α(1A)AR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM) form of the α(1A)AR. CAM-α(1A)AR mice showed enhancements in several behavioral models of learning and memory. In contrast, mice that have the α(1A)AR gene knocked out displayed poor cognitive function. Hippocampal brain slices from CAM-α(1A)AR mice demonstrated increased basal synaptic transmission, paired-pulse facilitation, and long-term potentiation compared with wild-type (WT) mice. WT mice treated with the α(1A)AR-selective agonist cirazoline also showed enhanced cognitive functions. In addition, CAM-α(1A)AR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests compared with WT mice. Furthermore, the lifespan of CAM-α(1A)AR mice was 10% longer than that of WT mice. Our results suggest that long-term α(1A)AR stimulation improves synaptic plasticity, cognitive function, mood, and longevity. This may afford a potential therapeutic target for counteracting the decline in cognitive function and mood associated with aging and neurological disorders.
- Published
- 2011
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13. Cardiac and neuroprotection regulated by α(1)-adrenergic receptor subtypes.
- Author
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Perez DM and Doze VA
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- Animals, Humans, Protective Agents classification, Receptors, Adrenergic, alpha-1 genetics, Cytoprotection, Myocardium cytology, Neurons cytology, Protective Agents metabolism, Receptors, Adrenergic, alpha-1 classification, Receptors, Adrenergic, alpha-1 metabolism
- Abstract
Sympathetic nervous system regulation by the α(1)-adrenergic receptor (AR) subtypes (α(1A), α(1B), α(1D)) is complex, whereby chronic activity can be either detrimental or protective for both heart and brain function. This review will summarize the evidence that this dual regulation can be mediated through the different α(1)-AR subtypes in the context of cardiac hypertrophy, heart failure, apoptosis, ischemic preconditioning, neurogenesis, locomotion, neurodegeneration, cognition, neuroplasticity, depression, anxiety, epilepsy, and mental illness.
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- 2011
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14. alpha(1A)- and alpha(1B)-adrenergic receptors differentially modulate antidepressant-like behavior in the mouse.
- Author
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Doze VA, Handel EM, Jensen KA, Darsie B, Luger EJ, Haselton JR, Talbot JN, and Rorabaugh BR
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- Adrenergic alpha-Agonists pharmacology, Animals, Behavior, Animal drug effects, Behavior, Animal physiology, Brain drug effects, Brain physiopathology, Depressive Disorder drug therapy, Depressive Disorder physiopathology, Disease Models, Animal, Female, Imidazoles pharmacology, Male, Maze Learning drug effects, Maze Learning physiology, Mice, Mice, Inbred CBA, Neuropsychological Tests, Prazosin pharmacology, Receptors, Adrenergic, alpha-1 drug effects, Stress, Psychological complications, Stress, Psychological metabolism, Stress, Psychological physiopathology, Antidepressive Agents pharmacology, Brain metabolism, Catecholamines metabolism, Depressive Disorder metabolism, Receptors, Adrenergic, alpha-1 metabolism
- Abstract
Tricyclic antidepressant (TCA) drugs are used for the treatment of chronic depression, obsessive-compulsive disorder (OCD), and anxiety-related disorders. Chronic use of TCA drugs increases the expression of alpha(1)-adrenergic receptors (alpha(1)-ARs). Yet, it is unclear whether increased alpha(1)-AR expression contributes to the antidepressant effects of these drugs or if this effect is unrelated to their therapeutic benefit. In this study, mice expressing constitutively active mutant alpha(1A)-ARs (CAM alpha(1A)-AR) or CAM alpha(1B)-ARs were used to examine the effects of alpha(1A)- and alpha(1B)-AR signaling on rodent behavioral models of depression, OCD, and anxiety. CAM alpha(1A)-AR mice, but not CAM alpha(1B)-AR mice, exhibited antidepressant-like behavior in the tail suspension test and forced swim test. This behavior was reversed by prazosin, a selective alpha(1)-AR inverse agonist, and mimicked by chronically treating wild type mice with cirazoline, an alpha(1A)-AR agonist. Marble burying behavior, commonly used to model OCD in rodents, was significantly decreased in CAM alpha(1A)-AR mice but not in CAM alpha(1B)-AR mice. In contrast, no significant differences in anxiety-related behavior were observed between wild type, CAM alpha(1A)-AR, and CAM alpha(1B)-AR animals in the elevated plus maze and light/dark box. This is the first study to demonstrate that alpha(1A)- and alpha(1B)-ARs differentially modulate antidepressant-like behavior in the mouse. These data suggest that alpha(1A)-ARs may be a useful therapeutic target for the treatment of depression.
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- 2009
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15. alpha1-Adrenergic receptors regulate neurogenesis and gliogenesis.
- Author
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Gupta MK, Papay RS, Jurgens CW, Gaivin RJ, Shi T, Doze VA, and Perez DM
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- Adrenergic alpha-1 Receptor Agonists, Animals, Animals, Newborn, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Biomarkers metabolism, Cell Differentiation genetics, Cell Differentiation physiology, Cell Movement genetics, Cell Movement physiology, Green Fluorescent Proteins metabolism, Imidazoles pharmacology, Immunohistochemistry, Interneurons cytology, Interneurons metabolism, Mice, Mice, Transgenic, Neurons cytology, Neurons drug effects, Phosphatidylinositol 3-Kinases metabolism, Receptors, Adrenergic, alpha-1 genetics, Spheroids, Cellular metabolism, Neurogenesis, Neuroglia metabolism, Neurons metabolism, Receptors, Adrenergic, alpha-1 metabolism
- Abstract
The understanding of the function of alpha(1)-adrenergic receptors in the brain has been limited due to a lack of specific ligands and antibodies. We circumvented this problem by using transgenic mice engineered to overexpress either wild-type receptor tagged with enhanced green fluorescent protein or constitutively active mutant alpha(1)-adrenergic receptor subtypes in tissues in which they are normally expressed. We identified intriguing alpha(1A)-adrenergic receptor subtype-expressing cells with a migratory morphology in the adult subventricular zone that coexpressed markers of neural stem cell and/or progenitors. Incorporation of 5-bromo-2-deoxyuridine in vivo increased in neurogenic areas in adult alpha(1A)-adrenergic receptor transgenic mice or normal mice given the alpha(1A)-adrenergic receptor-selective agonist, cirazoline. Neonatal neurospheres isolated from normal mice expressed a mixture of alpha(1)-adrenergic receptor subtypes, and stimulation of these receptors resulted in increased expression of the alpha(1B)-adrenergic receptor subtype, proneural basic helix-loop-helix transcription factors, and the differentiation and migration of neuronal progenitors for catecholaminergic neurons and interneurons. alpha(1)-Adrenergic receptor stimulation increased the apoptosis of astrocytes and regulated survival of neonatal neurons through phosphatidylinositol 3-kinase signaling. However, in adult normal neurospheres, alpha(1)-adrenergic receptor stimulation increased the expression of glial markers at the expense of neuronal differentiation. In vivo, S100-positive glial and betaIII tubulin neuronal progenitors colocalized with either alpha(1)-adrenergic receptor subtype in the olfactory bulb. Our results indicate that alpha(1)-adrenergic receptors can regulate both neurogenesis and gliogenesis that may be developmentally dependent. Our findings may lead to new therapies to treat neurodegenerative diseases.
- Published
- 2009
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16. Regulator of G protein signaling protein suppression of Galphao protein-mediated alpha2A adrenergic receptor inhibition of mouse hippocampal CA3 epileptiform activity.
- Author
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Goldenstein BL, Nelson BW, Xu K, Luger EJ, Pribula JA, Wald JM, O'Shea LA, Weinshenker D, Charbeneau RA, Huang X, Neubig RR, and Doze VA
- Subjects
- Adrenergic alpha-2 Receptor Antagonists, Animals, Epinephrine pharmacology, Female, Hippocampus physiology, Imidazoles pharmacology, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Norepinephrine pharmacology, Oxymetazoline pharmacology, Pertussis Toxin pharmacology, GTP-Binding Protein alpha Subunits, Gi-Go physiology, Hippocampus drug effects, RGS Proteins physiology, Receptors, Adrenergic, alpha-2 physiology
- Abstract
Activation of G protein-coupled alpha(2) adrenergic receptors (ARs) inhibits epileptiform activity in the hippocampal CA3 region. The specific mechanism underlying this action is unclear. This study investigated which subtype(s) of alpha(2)ARs and G proteins (Galpha(o) or Galpha(i)) are involved in this response using recordings of mouse hippocampal CA3 epileptiform bursts. Application of epinephrine (EPI) or norepinephrine (NE) reduced the frequency of bursts in a concentration-dependent manner: (-)EPI > (-)NE >>> (+)NE. To identify the alpha(2)AR subtype involved, equilibrium dissociation constants (pK(b)) were determined for the selective alphaAR antagonists atipamezole (8.79), rauwolscine (7.75), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride (WB-4101; 6.87), and prazosin (5.71). Calculated pK(b) values correlated best with affinities determined previously for the mouse alpha(2A)AR subtype (r = 0.98, slope = 1.07). Furthermore, the inhibitory effects of EPI were lost in hippocampal slices from alpha(2A)AR-but not alpha(2C)AR-knockout mice. Pretreatment with pertussis toxin also reduced the EPI-mediated inhibition of epileptiform bursts. Finally, using knock-in mice with point mutations that disrupt regulator of G protein signaling (RGS) binding to Galpha subunits to enhance signaling by that G protein, the EPI-mediated inhibition of bursts was significantly more potent in slices from RGS-insensitive Galpha(o)(G184S) heterozygous (Galpha(o)+/GS) mice compared with either Galpha(i2)(G184S) heterozygous (Galpha(i2)+/GS) or control mice (EC(50) = 2.5 versus 19 and 23 nM, respectively). Together, these findings indicate that the inhibitory effect of EPI on hippocampal CA3 epileptiform activity uses an alpha(2A)AR/Galpha(o) protein-mediated pathway under strong inhibitory control by RGS proteins. This suggests a possible role for RGS inhibitors or selective alpha(2A)AR agonists as a novel antiepileptic drug therapy.
- Published
- 2009
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17. Noradrenergic depression of neuronal excitability in the entorhinal cortex via activation of TREK-2 K+ channels.
- Author
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Xiao Z, Deng PY, Rojanathammanee L, Yang C, Grisanti L, Permpoonputtana K, Weinshenker D, Doze VA, Porter JE, and Lei S
- Subjects
- Animals, Cells, Cultured, Cyclic AMP-Dependent Protein Kinases metabolism, Entorhinal Cortex physiology, GTP-Binding Protein alpha Subunits, Gi-Go metabolism, Humans, Mice, Mice, Knockout, Patch-Clamp Techniques, Potassium Channels, Tandem Pore Domain genetics, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, alpha-2 genetics, Receptors, Adrenergic, alpha-2 metabolism, Signal Transduction physiology, Action Potentials drug effects, Action Potentials physiology, Entorhinal Cortex cytology, Neurons drug effects, Neurons physiology, Norepinephrine pharmacology, Potassium Channels, Tandem Pore Domain metabolism
- Abstract
The entorhinal cortex is closely associated with the consolidation and recall of memories, Alzheimer disease, schizophrenia, and temporal lobe epilepsy. Norepinephrine is a neurotransmitter that plays a significant role in these physiological functions and neurological diseases. Whereas the entorhinal cortex receives profuse noradrenergic innervations from the locus coeruleus of the pons and expresses high densities of adrenergic receptors, the function of norepinephrine in the entorhinal cortex is still elusive. Accordingly, we examined the effects of norepinephrine on neuronal excitability in the entorhinal cortex and explored the underlying cellular and molecular mechanisms. Application of norepinephrine-generated hyperpolarization and decreased the excitability of the neurons in the superficial layers with no effects on neuronal excitability in the deep layers of the entorhinal cortex. Norepinephrine-induced hyperpolarization was mediated by alpha(2A) adrenergic receptors and required the functions of Galpha(i) proteins, adenylyl cyclase, and protein kinase A. Norepinephrine-mediated depression on neuronal excitability was mediated by activation of TREK-2, a type of two-pore domain K(+) channel, and mutation of the protein kinase A phosphorylation site on TREK-2 channels annulled the effects of norepinephrine. Our results indicate a novel action mode in which norepinephrine depresses neuronal excitability in the entorhinal cortex by disinhibiting protein kinase A-mediated tonic inhibition of TREK-2 channels.
- Published
- 2009
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18. Alpha-1A adrenergic receptor activation increases inhibitory tone in CA1 hippocampus.
- Author
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Hillman KL, Lei S, Doze VA, and Porter JE
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Adrenergic alpha-Agonists pharmacology, Adrenergic alpha-Antagonists pharmacology, Animals, Animals, Newborn, Dose-Response Relationship, Drug, Evoked Potentials drug effects, Evoked Potentials physiology, GABA Antagonists pharmacology, Hippocampus drug effects, In Vitro Techniques, Inhibitory Postsynaptic Potentials drug effects, Male, Neural Inhibition drug effects, Neurons drug effects, Organophosphorus Compounds pharmacology, Patch-Clamp Techniques, Phenylephrine pharmacology, Picrotoxin pharmacology, Piperazines pharmacology, Rats, Rats, Sprague-Dawley, Sodium Channel Blockers pharmacology, Somatostatin pharmacology, Tetrodotoxin pharmacology, Time Factors, Hippocampus cytology, Hippocampus physiology, Neural Inhibition physiology, Neurons physiology, Receptors, Adrenergic, alpha-1 metabolism
- Abstract
The endogenous catecholamine norepinephrine (NE) exhibits anti-epileptic properties, however it is not well understood which adrenergic receptor (AR) mediates this effect. The aim of this study was to investigate alpha(1)-adrenergic receptor activation in region CA1 of the hippocampus, a subcortical structure often implicated in temporal lobe epilepsies. Using cell-attached and whole-cell recordings in rat hippocampal slices, we confirmed that selective alpha(1)-AR activation increases action potential firing in a subpopulation of CA1 interneurons. We found that this response is mediated via the alpha(1A)-AR subtype, initiated by sodium influx, and appears independent of second messenger signaling. In CA1 pyramidal cells, alpha(1A)-AR activation decreases activity due to increased pre-synaptic GABA and somatostatin release. Examination of post-synaptic receptor involvement revealed that while GABA(A) receptors mediate the majority of alpha(1A)-adrenergic effects on CA1 pyramidal cells, significant contributions are also made by GABA(B) and somatostatin receptors. Finally, to test whether alpha(1A)-AR activation could have potential therapeutic implications, we performed AR agonist challenges using two in vitro epileptiform models. When GABA(A) receptors were available, alpha(1A)-AR activation significantly decreased epileptiform bursting in CA1. Together, our findings directly link stimulation of the alpha(1A)-AR subtype to release of GABA and somatostatin at the single cell level and suggest that alpha(1A)-AR activation may represent one mechanism by which NE exerts anti-epileptic effects within the hippocampus.
- Published
- 2009
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19. Alpha1A-adrenergic receptors are functionally expressed by a subpopulation of cornu ammonis 1 interneurons in rat hippocampus.
- Author
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Hillman KL, Doze VA, and Porter JE
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Adrenergic alpha-1 Receptor Agonists, Adrenergic alpha-1 Receptor Antagonists, Adrenergic alpha-Agonists pharmacology, Adrenergic alpha-Antagonists pharmacology, Animals, Clonidine pharmacology, Dioxanes pharmacology, Dose-Response Relationship, Drug, Electrophysiology, Hippocampus drug effects, In Vitro Techniques, Interneurons drug effects, Isoproterenol pharmacology, Phenylephrine pharmacology, Piperazines pharmacology, Prazosin analogs & derivatives, Prazosin pharmacology, Rats, Rats, Sprague-Dawley, Hippocampus physiology, Interneurons physiology, Receptors, Adrenergic, alpha-1 physiology
- Abstract
The importance of adrenergic receptors (ARs) in the hippocampus has generally focused on betaARs; however, interest is growing in hippocampal alphaARs given their purported neuroprotective role. We have previously reported alpha(1)AR transcripts in a subpopulation of cornu ammonis 1 (CA1) interneurons. The goal of this study was to identify the specific alpha(1)AR subtype (alpha(1A), alpha(1B), alpha(1D)) functionally expressed by these cells. Using cell-attached recordings to measure action potential frequency changes, concentration-response curves for the selective alpha(1)AR agonist phenylephrine (PE) were generated in the presence of competitive subtype-selective alpha(1)AR antagonists. Schild regression analysis was then used to estimate equilibrium dissociation constants (K(b)) for each receptor antagonist in our system. The selective alpha(1A)AR antagonists, 5-methylurapidil and WB-4101 [2-[(2,6-dimethoxyphenoxyethyl)aminomethyl]-1,4-benzodioxane hydrochloride], produced consecutive rightward shifts in the concentration-response curve for PE when used at discriminating, nanomolar concentrations. Calculated K(b) values for 5-methylurapidil (10 nM) and WB-4101 (5 nM) correlate to previously published affinity values for these antagonists at the alpha(1A)AR. The selective alpha(1B)AR antagonist L-765,314 [(2S)-4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinecarboxylic acid], as well as the selective alpha(1D)AR antagonist BMY7378 [8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride], produced significant rightward shifts in the concentration-response curve for PE only when used at nondistinguishing, micromolar concentrations. Calculated K(b) values for L-765,314 (794 nM) and BMY7378 (316 nM) do not agree with affinity values for these antagonists at the alpha(1B) or alpha(1D)AR, respectively. Rather, these K(b) values more closely match equilibrium dissociation constants estimated for these compounds when used to identify alpha(1A)AR subtypes. Together, our results provide strong evidence to support functional expression of alpha(1A)ARs in a subpopulation of CA1 interneurons.
- Published
- 2007
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20. Alpha2A adrenergic receptor activation inhibits epileptiform activity in the rat hippocampal CA3 region.
- Author
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Jurgens CW, Hammad HM, Lichter JA, Boese SJ, Nelson BW, Goldenstein BL, Davis KL, Xu K, Hillman KL, Porter JE, and Doze VA
- Subjects
- Adrenergic Agents administration & dosage, Adrenergic Agonists pharmacology, Animals, Catecholamines pharmacology, Epinephrine pharmacology, Female, Hippocampus pathology, Hippocampus physiopathology, Male, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, alpha-2 drug effects, Adrenergic Agonists therapeutic use, Epilepsy prevention & control, Hippocampus drug effects, Receptors, Adrenergic, alpha-2 metabolism
- Abstract
Norepinephrine has potent antiepileptic properties, the pharmacology of which is unclear. Under conditions in which GABAergic inhibition is blocked, norepinephrine reduces hippocampal cornu ammonis 3 (CA3) epileptiform activity through alpha(2) adrenergic receptor (AR) activation on pyramidal cells. In this study, we investigated which alpha(2)AR subtype(s) mediates this effect. First, alpha(2)AR genomic expression patterns of 25 rat CA3 pyramidal cells were determined using real-time single-cell reverse transcription-polymerase chain reaction, demonstrating that 12 cells expressed alpha(2A)AR transcript; 3 of the 12 cells additionally expressed mRNA for alpha(2C)AR subtype and no cells possessing alpha(2B)AR mRNA. Hippocampal CA3 epileptiform activity was then examined using field potential recordings in brain slices. The selective alphaAR agonist 6-fluoronorepinephrine caused a reduction of CA3 epileptiform activity, as measured by decreased frequency of spontaneous epileptiform bursts. In the presence of betaAR blockade, concentration-response curves for AR agonists suggest that an alpha(2)AR mediates this response, as the rank order of potency was 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK-14304) >or= epinephrine >6-fluoronorepinephrine > norepinephrine >>> phenylephrine. Finally, equilibrium dissociation constants (K(b)) of selective alphaAR antagonists were functionally determined to confirm the specific alpha(2)AR subtype inhibiting CA3 epileptiform activity. Apparent K(b) values calculated for atipamezole (1.7 nM), MK-912 (4.8 nM), BRL-44408 (15 nM), yohimbine (63 nM), ARC-239 (540 nM), prazosin (4900 nM), and terazosin (5000 nM) correlated best with affinities previously determined for the alpha(2A)AR subtype (r = 0.99, slope = 1.0). These results suggest that, under conditions of impaired GABAergic inhibition, activation of alpha(2A)ARs is primarily responsible for the antiepileptic actions of norepinephrine in the rat hippocampal CA3 region.
- Published
- 2007
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21. Localization of the mouse alpha1A-adrenergic receptor (AR) in the brain: alpha1AAR is expressed in neurons, GABAergic interneurons, and NG2 oligodendrocyte progenitors.
- Author
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Papay R, Gaivin R, Jha A, McCune DF, McGrath JC, Rodrigo MC, Simpson PC, Doze VA, and Perez DM
- Subjects
- Adrenergic alpha-1 Receptor Agonists, Animals, Brain metabolism, Cell Differentiation physiology, Gene Expression physiology, Green Fluorescent Proteins metabolism, Immunohistochemistry methods, In Vitro Techniques, Membrane Potentials drug effects, Membrane Potentials physiology, Mice, Mice, Transgenic, Neurons classification, Neurons drug effects, Norepinephrine analogs & derivatives, Norepinephrine pharmacology, Patch-Clamp Techniques methods, Radioligand Assay methods, Receptors, Adrenergic, alpha-1 deficiency, beta-Galactosidase metabolism, Antigens metabolism, Brain cytology, Neurons physiology, Oligodendroglia metabolism, Proteoglycans metabolism, Receptors, Adrenergic, alpha-1 metabolism, Stem Cells, gamma-Aminobutyric Acid metabolism
- Abstract
alpha(1)-Adrenergic receptors (ARs) are not well defined in the central nervous system. The particular cell types and areas that express these receptors are uncertain because of the lack of high avidity antibodies and selective ligands. We have developed transgenic mice that either systemically overexpress the human alpha(1A)-AR subtype fused with the enhanced green fluorescent protein (EGFP) or express the EGFP protein alone under the control of the mouse alpha(1A)-AR promoter. We confirm our transgenic model against the alpha(1A)-AR knockout mouse, which expresses the LacZ gene in place of the coding region for the alpha(1A)-AR. By using these models, we have now determined cellular localization of the alpha(1A)-AR in the brain, at the protein level. The alpha(1A)-AR or the EGFP protein is expressed prominently in neuronal cells in the cerebral cortex, hippocampus, hypothalamus, midbrain, pontine olivary nuclei, trigeminal nuclei, cerebellum, and spinal cord. The types of neurons were diverse, and the alpha(1A)-AR colocalized with markers for glutamic acid decarboxylase (GAD), gamma-aminobutyric acid (GABA), and N-methyl-D-aspartate (NMDA) receptors. Recordings from alpha(1A)-AR EGFP-expressing cells in the stratum oriens of the hippocampal CA1 region confirmed that these cells were interneurons. We could not detect expression of the alpha(1A)-AR in mature astrocytes, oligodendrocytes, or cerebral blood vessels, but we could detect the alpha(1A)-AR in oligodendrocyte progenitors. We conclude that the alpha(1A)-AR is abundant in the brain, expressed in various types of neurons, and may regulate the function of oligodendrocyte progenitors, interneurons, GABA, and NMDA receptor containing neurons., (Copyright 2006 Wiley-Liss, Inc.)
- Published
- 2006
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22. Adrenergic receptor characterization of CA1 hippocampal neurons using real time single cell RT-PCR.
- Author
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Hillman KL, Knudson CA, Carr PA, Doze VA, and Porter JE
- Subjects
- Animals, Blotting, Northern methods, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases genetics, Calcium-Calmodulin-Dependent Protein Kinases metabolism, Glutamate Decarboxylase genetics, Glutamate Decarboxylase metabolism, Immunohistochemistry methods, Isoenzymes genetics, Isoenzymes metabolism, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic classification, Receptors, Adrenergic genetics, Reverse Transcriptase Polymerase Chain Reaction methods, Somatostatin metabolism, Gene Expression Regulation physiology, Hippocampus cytology, Neurons metabolism, Receptors, Adrenergic metabolism
- Abstract
The CA1 region of the rat hippocampus exhibits both alpha and beta adrenergic receptor (AR) responses, however, the specific AR subtypes involved and the neuronal expression patterns for these receptors are not well understood. We have employed single cell real time RT-PCR in conjunction with cell-specific immunohistochemical markers to determine the AR expression patterns for hippocampal neurons located in CA1, a region often implicated in learning and memory processes. Cytoplasmic samples were taken from 55 individual cells located in stratum oriens, pyramidale, or radiatum and reverse transcribed. All successfully amplified pyramidal neuron samples (n = 17) expressed mRNA for the beta2AR, with four cells additionally expressing mRNA for the beta1AR subtype. Positive interneurons from stratum oriens (n = 10) and stratum radiatum (n = 8) expressed mRNA for the alpha1A and/or alpha(1B)AR (n = 9/18) only when coexpressing transcripts for somatostatin. Interneurons containing neuropeptide Y or cholecystokinin (n = 9/18) were not positive for any of the nine AR subtypes, suggesting that CA1 interneuron AR expression is limited to a subset of somatostatin-positive cells. These findings suggest that only a select number of AR subtypes are transcriptionally expressed in CA1 and that these receptors are selective to specific neuronal cell types.
- Published
- 2005
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23. Functional characterization of the beta-adrenergic receptor subtypes expressed by CA1 pyramidal cells in the rat hippocampus.
- Author
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Hillman KL, Doze VA, and Porter JE
- Subjects
- Action Potentials drug effects, Adrenergic beta-Agonists pharmacology, Adrenergic beta-Antagonists pharmacology, Animals, Electrophysiology, Gene Expression Regulation drug effects, Gene Expression Regulation physiology, Hippocampus drug effects, Isoproterenol pharmacology, Male, RNA, Messenger biosynthesis, RNA, Messenger genetics, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, beta classification, Receptors, Adrenergic, beta drug effects, Receptors, Adrenergic, beta-2 drug effects, Receptors, Adrenergic, beta-2 physiology, Reverse Transcriptase Polymerase Chain Reaction, Hippocampus cytology, Pyramidal Cells drug effects, Receptors, Adrenergic, beta biosynthesis
- Abstract
Recent studies have demonstrated that activation of the beta-adrenergic receptor (AR) using the selective beta-AR agonist isoproterenol (ISO) facilitates pyramidal cell long-term potentiation in the cornu ammonis 1 (CA1) region of the rat hippocampus. We have previously analyzed beta-AR genomic expression patterns of 17 CA1 pyramidal cells using single cell reverse transcription-polymerase chain reaction, demonstrating that all samples expressed the beta2-AR transcript, with four of the 17 cells additionally expressing mRNA for the beta1-AR subtype. However, it has not been determined which beta-AR subtypes are functionally expressed in CA1 for these same pyramidal neurons. Using cell-attached recordings, we tested the ability of ISO to increase pyramidal cell action potential (AP) frequency in the presence of subtype-selective beta-AR antagonists. ICI-118,551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol] and butoxamine [alpha-[1-(t-butylamino)ethyl]-2,5-dimethoxybenzyl alcohol) hydrochloride], agents that selectively block the beta2-AR, produced significant parallel rightward shifts in the concentration-response curves for ISO. From these curves, apparent equilibrium dissociation constant (K(b)) values of 0.3 nM for ICI-118,551 and 355 nM for butoxamine were calculated using Schild regression analysis. Conversely, effective concentrations of the selective beta1-AR antagonists CGP 20712A [(+/-)-2-hydroxy-5-[2-([2-hydroxy-3-(4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenoxy)propyl]amino)ethoxy]-benzamide methanesulfonate] and atenolol [4-[2'-hydroxy-3'-(isopropyl-amino)propoxy]phenylacetamide] did not significantly affect the pyramidal cell response to ISO. However, at higher concentrations, atenolol significantly decreased the potency for ISO-mediated AP frequencies. From these curves, an apparent atenolol K(b) value of 3162 nM was calculated. This pharmacological profile for subtype-selective beta-AR antagonists indicates that beta2-AR activation is mediating the increased AP frequency. Knowledge of functional AR expression in CA1 pyramidal neurons will aid future long-term potentiation studies by allowing selective manipulation of specific beta-AR subtypes.
- Published
- 2005
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24. Beta1 adrenergic receptor-mediated enhancement of hippocampal CA3 network activity.
- Author
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Jurgens CW, Rau KE, Knudson CA, King JD, Carr PA, Porter JE, and Doze VA
- Subjects
- Adrenergic beta-1 Receptor Agonists, Adrenergic beta-1 Receptor Antagonists, Adrenergic beta-2 Receptor Agonists, Adrenergic beta-Agonists pharmacology, Adrenergic beta-Antagonists pharmacology, Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases metabolism, Catecholamines pharmacology, Catecholamines physiology, Electrophysiology, Immunohistochemistry, Indicators and Reagents, Isoproterenol pharmacology, Patch-Clamp Techniques, Pyramidal Cells physiology, Rats, Rats, Sprague-Dawley, Regression Analysis, Synaptic Transmission drug effects, Hippocampus drug effects, Nerve Net drug effects, Receptors, Adrenergic, beta-1 metabolism
- Abstract
Norepinephrine is an endogenous neurotransmitter distributed throughout the mammalian brain. In higher cortical structures such as the hippocampus, norepinephrine, via beta adrenergic receptor (AR) activation, has been shown to reinforce the cognitive processes of attention and memory. In this study, we investigated the effect of beta1AR activation on hippocampal cornu ammonis 3 (CA3) network activity. AR expression was first determined using immunocytochemistry with antibodies against beta1ARs, which were found to be exceptionally dense in hippocampal CA3 pyramidal neurons. CA3 network activity was then examined in vitro using field potential recordings in rat brain slices. The selective betaAR agonist isoproterenol caused an enhancement of hippocampal CA3 network activity, as measured by an increase in frequency of spontaneous burst discharges recorded in the CA3 region. In the presence of alphaAR blockade, concentration-response curves for isoproterenol, norepinephrine, and epinephrine suggested that a beta1AR was involved in this response, and the rank order of potency was isoproterenol > norepinephrine = epinephrine. Finally, equilibrium dissociation constants (pK(b)) of subtype-selective betaAR antagonists were functionally determined to characterize the AR subtype modulating hippocampal CA3 activity. The selective beta1AR antagonists atenolol and metoprolol blocked isoproterenol-induced enhancement, with apparent K(b) values of 85 +/- 36 and 3.9 +/- 1.7 nM, respectively. In contrast, the selective beta2AR antagonists ICI-118,551 and butoxamine inhibited isoproterenol-mediated enhancement with apparent low affinities (K(b) of 222 +/- 61 and 9268 +/- 512 nM, respectively). Together, this pharmacological profile of subtype-selective betaAR antagonists indicates that in this model, beta1AR activation is responsible for the enhanced hippocampal CA3 network activity initiated by isoproterenol.
- Published
- 2005
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25. Adrenergic receptor modulation of hippocampal CA3 network activity.
- Author
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Jurgens CW, Boese SJ, King JD, Pyle SJ, Porter JE, and Doze VA
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Adrenergic alpha-Antagonists pharmacology, Adrenergic beta-Antagonists pharmacology, Animals, Animals, Newborn, Behavior, Animal, Bicuculline, Dose-Response Relationship, Drug, Drug Interactions, Epilepsy chemically induced, Epilepsy physiopathology, GABA Antagonists pharmacology, Hippocampus drug effects, In Vitro Techniques, Nerve Net drug effects, Neural Inhibition drug effects, Neural Inhibition physiology, Norepinephrine pharmacology, Phentolamine pharmacology, Phosphinic Acids pharmacology, Pindolol pharmacology, Propanolamines pharmacology, Rats, Rats, Sprague-Dawley, Hippocampus physiopathology, Nerve Net physiopathology, Receptors, Adrenergic physiology
- Abstract
Norepinephrine (NE) has demonstrated proconvulsant and antiepileptic properties; however, the specific pharmacology of these actions has not been clearly established. To address this, we studied the effect of NE on hippocampal CA3 epileptiform activity. Frequency changes of burst discharges in response to NE were biphasic; low concentrations increased the number of bursts, while higher concentrations reduced their frequency, suggesting the involvement of multiple adrenergic receptor (AR) types. This hypothesis was confirmed when, in the presence of betaAR blockade, increasing concentrations of NE caused a monophasic decrease in epileptiform activity. Antagonists selective for alpha1 or alpha2ARs were then used to determine which alphaAR type was involved. While discriminating concentrations of the alpha1AR antagonists prazosin and terazosin had no effect, selective amounts of the alpha2AR antagonists RS79948 and RX821002 significantly reduced the potency of NE in decreasing epileptiform activity. Furthermore, this antiepileptic action of NE persisted when all GABA-mediated inhibition was blocked. This data suggests that, under conditions of impaired GABAergic inhibition, the excitatory and inhibitory effects of NE on hippocampal CA3 epileptiform activity are mediated primarily via beta and alpha2ARs, respectively. Moreover, our results imply that the antiepileptic effect of alpha2AR activation in CA3 is not dependent on the GABAergic system.
- Published
- 2005
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26. Comparison of cardiac excitation-contraction coupling in isolated ventricular myocytes between rat and mouse.
- Author
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Hintz KK, Norby FL, Duan J, Cinnamon MA, Doze VA, and Ren J
- Subjects
- Animals, Calcium metabolism, Electric Stimulation, Heart Ventricles cytology, Heart Ventricles metabolism, In Vitro Techniques, Mice, Mice, Inbred C57BL, Rats, Rats, Sprague-Dawley, Rats, Wistar, Species Specificity, Spectrometry, Fluorescence, Ventricular Function
- Abstract
Transgenic animals offer many advantages for physiological study. The mouse is the most extensively utilized mammalian model for gene modification. Isolated ventricular myocytes are pivotal for assessment of cardiac function by allowing direct cellular and environmental manipulation without interference from compensatory mechanisms that may exist in vivo. This study was designed to compare the basic excitation-contraction coupling properties of mouse and rat ventricular myocytes. Cardiac myocytes were isolated from age- and gender-matched mice (FVB and C57BL/6) and rats (Sprague-Dawley (SD) and Wistar). Mechanical and intracellular Ca2+ properties were measured with an IonOptix SoftEdge system, including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)), maximal velocity of shortening and relengthening (+/-dL/dt), and intracellular Ca2+ fura-2 fluorescence intensity and decay rate (tau). Resting cell length was variable among the different species or strains. PS from FVB group was significantly higher than the SD group. TPS and TR(90) were significantly shorter in mice. +dL/dt was similar among all groups whereas -dL/dt was significantly faster in the C57BL/6 group compared to the rat groups. Resting intracellular Ca2+ was lower in mice than in rats, and Ca2+-induced Ca2+ release was variable among the four groups. Intracellular Ca2+ decay was slower in Wistar compared to all other groups. The myocytes from C57BL/6 did not respond to increases in extracellular Ca2+. Myocytes from the FVB group exhibited a lesser reduction in PS in response to elevated stimulus frequency. These data suggest that inherent differences between strains or species should be taken into consideration when comparing results from these different animal models.
- Published
- 2002
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27. Calcium channel involvement in GABAB receptor-mediated inhibition of GABA release in area CA1 of the rat hippocampus.
- Author
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Doze VA, Cohen GA, and Madison DV
- Subjects
- Action Potentials drug effects, Animals, Baclofen pharmacology, Calcium Channel Blockers pharmacology, Electrophysiology, GABA Agonists pharmacology, GABA-B Receptor Antagonists, Hippocampus cytology, In Vitro Techniques, Interneurons drug effects, Interneurons metabolism, Male, Nerve Endings drug effects, Nerve Endings metabolism, Rats, Rats, Sprague-Dawley, Synapses drug effects, Calcium Channels physiology, Hippocampus metabolism, Receptors, GABA-B physiology, Synapses metabolism, gamma-Aminobutyric Acid metabolism
- Abstract
1. Experiments were performed in rat hippocampal slices to examine the nature of GABAergic inhibition of inhibitory synaptic transmission. In these experiments the effects of the gamma-aminobutyric acid-B (GABAB) receptor agonist, baclofen, and of subtype-selective calcium channel blockers were tested with the use of intracellular recordings of evoked inhibitory postsynaptic potentials (IPSPs) and whole cell recordings of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs). 2. Baclofen inhibited evoked and spontaneous (action-potential-dependent) monosynaptic GABAA-mediated IPSPs and IPSCs but had no effect on the frequency of tetrodotoxin-resistant (action-potential-independent) miniature IPSCs recorded in CA1 pyramidal neurons. 3. Depolarizing GABAergic synaptic terminals by raising the extracellular potassium concentration caused an increase in action-potential-independent miniature IPSC frequency that could be inhibited by either baclofen or cadmium, a blocker of voltage-dependent calcium channels. In addition, under these depolarizing conditions, cadmium occluded the baclofen inhibition of miniature IPSCs. These data suggest that baclofen reduces only depolarization-induced, not quantal, GABA release and that it does so by decreasing presynaptic voltage-dependent calcium influx. 4. Experiments with subtype-selective calcium channel blockers demonstrate that the presynaptic action of baclofen was mediated through both omega-conotoxin-GVIA-sensitive and omega-agatoxin-IVA-sensitive, but not dihydropyridine-sensitive calcium channels.
- Published
- 1995
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28. Opioid inhibition of GABA release from presynaptic terminals of rat hippocampal interneurons.
- Author
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Cohen GA, Doze VA, and Madison DV
- Subjects
- Action Potentials drug effects, Animals, Electric Conductivity, Electric Stimulation, Enkephalin, Methionine pharmacology, Hippocampus cytology, Male, Molecular Sequence Data, Naloxone pharmacology, Rats, Rats, Inbred Strains, Tetrodotoxin pharmacology, Enkephalin, Methionine analogs & derivatives, Hippocampus physiology, Interneurons physiology, Synapses physiology, gamma-Aminobutyric Acid metabolism
- Abstract
Opiates and the opioid peptide enkephalin can cause indirect excitation of principal cortical neurons by reducing inhibitory synaptic transmission mediated by GABAergic interneurons. The mechanism by which opioids mediate these effects on interneurons is unknown, but enkephalin hyperpolarizes the somatic membrane potential of a variety of neurons in the brain, including hippocampal interneurons. We now report a new, more direct mechanism for the opioid-mediated reduction in synaptic inhibition. The enkephalin analog D-Ala2-Met5-enkephalinamide (DALA) decreases the frequency of miniature, action potential-independent, spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) without causing a change in their amplitude. Thus, we conclude that DALA inhibits the action potential-independent release of GABA through a direct action on interneuronal synaptic terminals. In contrast, DALA reduces the amplitude of action potential-evoked, GABA-mediated IPSCs, as well as decreases their frequency. This suggests that the opioid-mediated inhibition of non-action potential-dependent GABA release reveals a mechanism that contributes to reducing action potential-evoked GABA release, thereby decreasing synaptic inhibition.
- Published
- 1992
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29. Isoproterenol increases the phosphorylation of the synapsins and increases synaptic transmission in dentate gyrus, but not in area CA1, of the hippocampus.
- Author
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Parfitt KD, Doze VA, Madison DV, and Browning MD
- Subjects
- Animals, Autoradiography, Electric Stimulation, Hippocampus drug effects, Hippocampus metabolism, In Vitro Techniques, Kinetics, Male, Phosphates metabolism, Phosphorus Radioisotopes, Phosphorylation, Pyramidal Tracts drug effects, Rats, Rats, Sprague-Dawley, Synapses drug effects, Synapsins isolation & purification, Time Factors, Hippocampus physiology, Isoproterenol pharmacology, Pyramidal Tracts physiology, Synapses physiology, Synapsins metabolism, Synaptic Transmission drug effects
- Abstract
Previous studies have shown that either norepinephrine (NE) or isoproterenol (ISO) enhances the slope of the field excitatory postsynaptic potential (EPSP) in the dentate gyrus of the rat hippocampal formation. In contrast, NE and ISO cause no increase in excitatory transmission in area CA1 of the hippocampus. The molecular mechanism underlying this brain region-specific increase in synaptic transmission is not known. The phosphorylation of synapsin I and synapsin II, two homologous presynaptic vesicle-associated proteins, is thought to promote neurotransmitter release. The authors have observed previously NE- and ISO-enhanced phosphorylation of synapsins I and II in the dentate gyrus. The purpose of this study was to determine whether ISO-stimulated phosphorylation also occurs in the CA1, where ISO has no effect on excitatory neurotransmission. These studies were correlated with electrophysiological studies in in vitro hippocampal slices. Superfusion of slices with ISO resulted in an increase in EPSP slope in the dentate but not in area CA1. The enhanced dentate EPSP returned to baseline levels within 30 minutes of washout of the drug. Isoproterenol produced corresponding increases in the phosphorylation of the synapsins in dentate slices but had no effect on these proteins in CA1 slices. Moreover, in dentate slices exposed to a 30-minute wash following incubation with ISO, phosphorylation of the synapsins returned to control levels. This close temporal and brain regional correlation between ISO stimulation of both synapsin phosphorylation and synaptic transmission suggests that the synapsin proteins may play a role in the synaptic potentiation produced by ISO in the dentate.
- Published
- 1992
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30. Synaptic localization of adrenergic disinhibition in the rat hippocampus.
- Author
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Doze VA, Cohen GA, and Madison DV
- Subjects
- Adrenergic alpha-Agonists pharmacology, Animals, Baclofen pharmacology, Enkephalin, Methionine analogs & derivatives, Enkephalin, Methionine pharmacology, Epinephrine pharmacology, Evoked Potentials drug effects, Hippocampus drug effects, In Vitro Techniques, Isoproterenol pharmacology, Male, Picrotoxin pharmacology, Pyramidal Tracts drug effects, Pyramidal Tracts physiology, Rats, Rats, Inbred Strains, Receptors, Adrenergic, alpha drug effects, Synapses drug effects, Hippocampus physiology, Norepinephrine pharmacology, Receptors, Adrenergic, alpha physiology, Synapses physiology
- Abstract
Norepinephrine is an endogenous neurotransmitter that reduces synaptic inhibition onto pyramidal neurons in the hippocampus by an action at an alpha-adrenergic receptor. The physiological mechanism of this disinhibition was previously not known, except that it occurred at a site presynaptic to the inhibited pyramidal cell. In this paper we present evidence that adrenergic disinhibition is restricted to the early phase of the evoked inhibitory postsynaptic potential in area CA1 of the hippocampus. The locus of disinhibition does not appear to reside in the interneuronal terminal, axon, or cell body. Instead, adrenergic agonists appear to reduce evoked synaptic inhibition by depressing excitatory synapses that activate the interneuron.
- Published
- 1991
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31. The alpha 2-adrenoceptor agonist dexmedetomidine increases the apparent potency of the volatile anesthetic isoflurane in rats in vivo and in hippocampal slice in vitro.
- Author
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Savola MK, MacIver MB, Doze VA, Kendig JJ, and Maze M
- Subjects
- Animals, Drug Synergism, Electric Stimulation, Evoked Potentials drug effects, Hippocampus drug effects, In Vitro Techniques, Male, Medetomidine, Rats, Rats, Inbred Strains, Adrenergic alpha-Agonists pharmacology, Hippocampus physiology, Imidazoles pharmacology, Isoflurane pharmacology
- Abstract
Alpha 2-adrenoceptor agonists such as clonidine are sedatives and enhance the effectiveness of several different kinds of anesthetics. This study was performed to quantitate the effect of dexmedetomidine, a novel alpha 2-adrenoceptor agonist, on the action of the volatile anesthetic agent isoflurane in rats in vivo. A separate set of experiments in rat hippocampal slices was designed to determine whether isoflurane and dexmedetomidine exerted similar effects on synaptic transmission in vitro and to examine the interaction between the two agents. In vivo, dexmedetomidine (100 micrograms/kg i.p.) reduced isoflurane minimum alveolar anesthetic requirement (MAC), determined by loss of response to tail pinch, by approximately 90%. In hippocampal CA1 neurons, on the other hand, there was a relatively small potentiation of the effects of isoflurane at the maximally effective dexmedetomidine concentration (1 nM). The hippocampal CA1 area, at least in the slice preparation, may thus not be representative of the CNS site(s) at which alpha 2 adrenoceptor agonists lessen anesthetic requirement in vivo.
- Published
- 1991
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32. Protein kinases and long-term potentiation.
- Author
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Meffert MK, Parfitt KD, Doze VA, Cohen GA, and Madison DV
- Subjects
- Animals, Calcium physiology, Electric Stimulation, Glutamates physiology, Glutamic Acid, Hippocampus ultrastructure, Humans, Nerve Fibers physiology, Synapses ultrastructure, Time Factors, Hippocampus physiology, Protein Kinases physiology, Synapses physiology
- Published
- 1991
- Full Text
- View/download PDF
33. Pharmacokinetic variability of midazolam infusions in critically ill patients.
- Author
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Shafer A, Doze VA, and White PF
- Subjects
- Adult, Aged, Female, Humans, Infusions, Intravenous, Kidney physiopathology, Liver physiopathology, Male, Midazolam administration & dosage, Critical Care, Midazolam pharmacokinetics
- Published
- 1990
- Full Text
- View/download PDF
34. Pertussis toxin and 4-aminopyridine differentially affect the hypnotic-anesthetic action of dexmedetomidine and pentobarbital.
- Author
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Doze VA, Chen BX, Tinklenberg JA, Segal IS, and Maze M
- Subjects
- 4-Aminopyridine administration & dosage, Animals, Dose-Response Relationship, Drug, Drug Interactions, GTP-Binding Proteins antagonists & inhibitors, Male, Medetomidine, Potassium Channels drug effects, Rats, Rats, Inbred Strains, Time Factors, Virulence Factors, Bordetella administration & dosage, 4-Aminopyridine pharmacology, Adrenergic alpha-Agonists pharmacology, Hypnotics and Sedatives pharmacology, Imidazoles pharmacology, Pentobarbital pharmacology, Pertussis Toxin, Virulence Factors, Bordetella pharmacology
- Abstract
Dexmedetomidine, a highly selective and potent agonist at alpha-2 adrenoceptors, produces a hypnotic-anesthetic action in rats. The mechanism for this response may involve an inhibitory G-protein and increased conductance through a potassium channel. To investigate this, the effects of pertussis toxin, a specific inactivator of inhibitory G-proteins, and 4-aminopyridine, a blocker of potassium channels, on the hypnotic-anesthetic response to dexmedetomidine were studied in rats. Pertussis toxin and 4-aminopyridine both decreased the hypnotic-anesthetic action of dexmedetomidine in a dose-dependent fashion. To preclude the possibility that pertussis toxin and 4-aminopyridine attenuated the hypnotic-anesthetic action of dexmedetomidine via indirect central nervous system excitation, the effects of pertussis toxin and 4-aminopyridine on the hypnotic-anesthetic action of pentobarbital also were assessed. Pentobarbital-induced hypnosis was not attenuated by either treatment. These results suggest that the receptor-effector mechanism for the hypnotic-anesthetic action of dexmedetomidine involves an inhibitory G-protein and increased conductance through a potassium channel.
- Published
- 1990
- Full Text
- View/download PDF
35. Dexmedetomidine diminishes halothane anesthetic requirements in rats through a postsynaptic alpha 2 adrenergic receptor.
- Author
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Segal IS, Vickery RG, Walton JK, Doze VA, and Maze M
- Subjects
- Animals, Benzylamines pharmacology, Brain metabolism, Dioxanes pharmacology, Idazoxan, Imidazoles antagonists & inhibitors, Male, Medetomidine, Naltrexone pharmacology, Norepinephrine metabolism, Rats, Rats, Inbred Strains, Receptors, Adrenergic, alpha drug effects, Stereoisomerism, Theophylline analogs & derivatives, Theophylline pharmacology, Halothane, Imidazoles pharmacology, Receptors, Neurotransmitter drug effects
- Abstract
The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the alpha 2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was determined before and after either dexmedetomidine (d-enantiomer) or levomedetomidine (l-enantiomer) 10, 30, and 100 micrograms/kg or vehicle ip. There was a dose-dependent decrease in MAC with the d-, but not the l-, stereoisomer. At the highest dose of dexmedetomidine (100 micrograms/kg), halothane could be discontinued for up to 30 min with no response to tail clamping. To determine whether alpha 2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10 mg/kg ip, a highly selective alpha 2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by dexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5 mg/kg ip, an opiate antagonist, or 8-phenyltheophylline, 2.5 mg/kg ip, an A1 adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whether postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine (DSP-4) or reserpine and alpha-methyl-para-tyrosine and MAC was determined before and after each dose of dexmedetomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of dexmedetomidine. The reduction of MAC by dexmedetomidine was blocked with idazoxan in the catecholamine depleted rats.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1988
- Full Text
- View/download PDF
36. Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia.
- Author
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Shafer A, Doze VA, Shafer SL, and White PF
- Subjects
- Adult, Anesthetics administration & dosage, Anesthetics pharmacology, Chromatography, High Pressure Liquid, Drug Evaluation, Half-Life, Humans, Infusions, Intravenous, Phenols administration & dosage, Phenols pharmacology, Propofol, Psychomotor Performance drug effects, Time Factors, Anesthesia, General methods, Anesthetics pharmacokinetics, Phenols pharmacokinetics
- Abstract
The pharmacokinetic and pharmacodynamic properties of propofol were studied in 50 surgical patients. Propofol was administered as a bolus dose, 2 mg/kg iv, followed by a variable-rate infusion, 0-20 mg/min, and intermittent supplemental boluses, 10-20 mg iv, as part of a general anesthetic technique that included nitrous oxide, meperidine, and muscle relaxants. For a majority of the patients (n = 30), the pharmacokinetics of propofol were best described by a two-compartment model. The propofol mean total body clearance rate was 2.09 +/- 0.65 1/min (mean +/- SD), the volume of distribution at steady state was 159 +/- 57 l, and the elimination half-life was 116 +/- 34 min. Elderly patients (patients older than 60 yr vs. those younger than 60 yr) had significantly decreased clearance rates (1.58 +/- 0.42 vs. 2.19 +/- 0.64 l/min), whereas women (vs. men) had greater clearance rates (33 +/- 8 vs. 26 +/- 7 l.kg-1.min-1) and volumes of distribution (2.50 +/- 0.81 vs. 2.05 +/- 0.65 l/kg). Patients undergoing major (intraabdominal) surgery had longer elimination half-life values (136 +/- 40 vs. 108 +/- 29 min). Patients required an average blood propofol concentration of 4.05 +/- 1.01 micrograms/ml for major surgery and 2.97 +/- 1.07 micrograms/ml for nonmajor surgery. Blood propofol concentrations at which 50% of patients (EC50) were awake and oriented after surgery were 1.07 and 0.95 microgram/ml, respectively. Psychomotor performance returned to baseline at blood propofol concentrations of 0.38-0.43 microgram/ml (EC50). This clinical study demonstrates the feasibility of performing pharmacokinetic and pharmacodynamic analyses when complex infusion and bolus regimens are used for administering iv anesthetics.
- Published
- 1988
- Full Text
- View/download PDF
37. Effects of fluid therapy on serum glucose levels in fasted outpatients.
- Author
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Doze VA and White PF
- Subjects
- Adult, Female, Glucose metabolism, Humans, Intraoperative Period, Isotonic Solutions administration & dosage, Postoperative Period, Ringer's Lactate, Ambulatory Surgical Procedures, Blood Glucose, Fasting, Glucose administration & dosage
- Published
- 1987
- Full Text
- View/download PDF
38. Benzodiazepine antagonism does not provoke a stress response.
- Author
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White PF, Shafer A, Boyle WA 3rd, Doze VA, and Duncan S
- Subjects
- Adult, Aged, Clinical Trials as Topic, Double-Blind Method, Humans, Middle Aged, Random Allocation, Anti-Anxiety Agents antagonists & inhibitors, Flumazenil adverse effects, Midazolam antagonists & inhibitors, Stress, Physiological chemically induced
- Abstract
Acute anxiety reactions have been reported following antagonism of benzodiazepine-induced sedation. In this study, the level of sedation and anxiety was assessed in 30 patients randomly assigned to receive either saline or flumazenil (a benzodiazepine antagonist) after midazolam sedation according to a double-blind protocol. Carefully titrated doses of flumazenil, 0.8 +/- 0.2 mg (mean +/- SD), effectively reversed residual midazolam-induced sedation without producing significant changes in the patients' level of anxiety. In addition, plasma epinephrine, norepinephrine, vasopressin, and beta-endorphin concentrations were measured in a subset of patients (n = 5) from each group. The levels of these stress hormones did not acutely change following flumazenil (or saline). These results indicate that flumazenil, 0.6-1.0 mg iv, can antagonize midazolam sedation without producing acute anxiety or evidence of a stress response.
- Published
- 1989
- Full Text
- View/download PDF
39. Dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors.
- Author
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Doze VA, Chen BX, and Maze M
- Subjects
- Adrenergic alpha-Agonists antagonists & inhibitors, Adrenergic beta-Antagonists pharmacology, Animals, Dioxanes pharmacology, Idazoxan, Imidazoles antagonists & inhibitors, Injections, Intraperitoneal, Male, Medetomidine, Muscle Relaxation drug effects, Rats, Rats, Inbred Strains, Adrenergic alpha-Agonists pharmacology, Anesthetics antagonists & inhibitors, Hypnotics and Sedatives antagonists & inhibitors, Imidazoles pharmacology, Receptors, Adrenergic, alpha drug effects
- Abstract
Dexmedetomidine, a highly selective and potent alpha-2 adrenoceptor agonist, reduces halothane anesthetic requirements by over 90% in rats. The present study examined whether dexmedetomidine produces a hypnotic-anesthetic action in rats. Dexmedetomidine induced a hypnotic-anesthetic state in rats characterized by loss of righting reflex at doses greater than or equal to 0.1 mg/kg. This response was dose-dependent between 0.1 and 3 mg/kg. Alpha-2 adrenoceptor antagonists that cross the blood-brain barrier (antipamezole and idazoxan) decreased the hypnotic-anesthetic action of dexmedetomidine in a dose-dependent fashion. In contrast, the alpha-2 antagonist, L-659,066, which does not penetrate into the CNS did not affect dexmedetomidine-induced hypnosis. Antagonists for the other adrenoceptors not only failed to reduce the hypnotic-anesthetic action of dexmedetomidine but in some cases even potentiated this effect. Thus, prazosin, an alpha-1 adrenoceptor antagonist, significantly enhanced the hypnotic-anesthetic property of dexmedetomidine. Antagonists with beta-2 receptor blocking properties also enhanced dexmedetomidine-induced hypnosis. Selective beta-1 receptor antagonists did not affect the hypnotic action of dexmedetomidine. These results suggest that dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors.
- Published
- 1989
- Full Text
- View/download PDF
40. Comparison of propofol with methohexital for outpatient anesthesia.
- Author
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Doze VA, Westphal LM, and White PF
- Subjects
- Adult, Blood Pressure drug effects, Electromyography, Female, Heart Rate drug effects, Humans, Methohexital adverse effects, Phenols adverse effects, Propofol, Ambulatory Surgical Procedures, Anesthesia, Intravenous, Anesthetics adverse effects, Methohexital pharmacology, Phenols pharmacology
- Abstract
Propofol is an intravenous anesthetic currently available for clinical investigative use. The intraoperative and postoperative effects of propofol were compared to methohexital when used as an adjuvant to nitrous oxide for outpatient anesthesia. Sixty healthy young women were randomly assigned to receive either methohexital, 1.5 mg/kg intravenously (IV), or propofol, 2.5 mg/kg IV, for induction of anesthesia. Both drugs produced transient cardiovascular and respiratory depression after induction. Maintenance of anesthesia consisted of either methohexital, 6 +/- 2 mg/min, or propofol, 7 +/- 2 mg/min (mean +/- SD) by continuous infusion in combination with nitrous oxide, 70% in oxygen. Use of a propofol infusion was associated with lower blood pressures and heart rates during maintenance. Propofol was associated with fewer side effects (e.g., hiccoughing, nausea, and vomiting) intra- and postoperatively. Recovery times for awakening, orientation, and ambulation were consistently shorter with propofol. We conclude that propofol is a useful alternative to methohexital for induction and maintenance of outpatient anesthesia.
- Published
- 1986
41. Propofol-nitrous oxide versus thiopental-isoflurane-nitrous oxide for general anesthesia.
- Author
-
Doze VA, Shafer A, and White PF
- Subjects
- Adult, Anesthesia, Inhalation, Anesthesia, Intravenous, Clinical Trials as Topic, Female, Humans, Male, Middle Aged, Propofol, Random Allocation, Anesthesia, General, Anesthetics, Isoflurane, Nitrous Oxide, Phenols, Thiopental
- Abstract
One hundred and twenty patients undergoing elective operations were randomly assigned to receive anesthesia with either thiopental, 4 mg/kg-isoflurane, 0.2-3%-nitrous oxide, 60-70% (control) or propofol, 2 mg/kg-propofol infusion, 1-20 mg/min-nitrous oxide, 60-70% (propofol). Although anesthetic conditions were similar during the operation, differences were noted in the recovery characteristics. For non-major (superficial) surgical procedures, the times to awakening, responsiveness, orientation, and ambulation were significantly shorter in the propofol group (4 +/- 3, 5 +/- 4, 6 +/- 4, and 104 +/- 36 min) than in the control group (8 +/- 7, 9 +/- 7, 11 +/- 9, and 142 +/- 61 min, respectively). In addition, less nausea and vomiting (20 vs. 45%) and significantly less psychomotor impairment was noted in the non-major propofol (vs. control) group. Following major abdominal operations, recovery characteristics did not differ between propofol and control groups. Delayed emergence (greater than 20 min), significant psychometric impairment, and a high overall incidence of postoperative side effects (55-60%) were noted in both drug treatment groups. The authors conclude that propofol-nitrous oxide compares favorably to thiopental-isoflurane-nitrous oxide for maintenance of anesthesia during short outpatient procedures. However, for major abdominal operations, propofol anesthesia does not appear to offer any clinically significant advantages over a standard inhalational anesthetic technique.
- Published
- 1988
- Full Text
- View/download PDF
42. Outpatient premedication: use of midazolam and opioid analgesics.
- Author
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Shafer A, White PF, Urquhart ML, and Doze VA
- Subjects
- Adult, Double-Blind Method, Drug Combinations, Female, Humans, Intraoperative Period, Male, Randomized Controlled Trials as Topic, Ambulatory Surgical Procedures, Fentanyl, Hydromorphone analogs & derivatives, Midazolam, Oxymorphone, Preanesthetic Medication
- Abstract
The perioperative effects of administering sedative and analgesic drugs prior to outpatient surgery were evaluated. One hundred fifty adult outpatients were randomly assigned to one of six study groups according to a double-blind protocol design. Patients were given placebo (saline) or midazolam (5 mg im) 30-60 min prior to surgery, and then either placebo, oxymorphone (1 mg iv), or fentanyl (100 micrograms iv) 3-5 min prior to a standardized anesthetic technique. Preoperatively, midazolam premedication was associated with a significantly lower anxiety level (37 +/- 29 mm vs. 50 +/- 32 mm, P less than 0.05), higher sedation level (254 +/- 136 mm vs. 145 +/- 109 mm, P less than 0.01), worsening of psychomotor skill (5 +/- 5 vs. 2 +/- 2 dots missed, P less than 0.01; midazolam vs. placebo), and impaired recall abilities. In addition, use of midazolam did not prolong the discharge time. Compared to control patients, those who received fentanyl had a decreased incidence of intraoperative airway difficulties such as coughing (28% vs. 0%, P less than 0.01). Although use of opioids increased the incidence of postoperative nausea (42% vs. 18%, P less than 0.01) and vomiting (23% vs. 2%, P less than 0.01; opioid vs. no opioid), average recovery times were not affected by opioid administration. Oxymorphone use was associated with a lower incidence of pain at home compared with that following fentanyl (46% vs. 74%, P less than 0.05). Finally, preoperative administration of both midazolam and fentanyl or oxymorphone prior to a standardized methohexital-nitrous oxide anesthetic technique did not adversely affect recovery after outpatient surgery.
- Published
- 1989
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