1985 — 1988 |
Smith, Charles B |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Adrenergic Nerve Function After Psychotropic Drugs @ University of Michigan At Ann Arbor
The proposed project will test the following hypotheses: 1) Endogenous depression might be related to abnormal presynpatic alpha2 adrenergic receptor function in the human brain, and the status of these receptors might be reflected by alpha2 adrenoreceptors on blood platelet membranes. 2) Antidepressant drugs and electroconvulsive therapy both might act by altering the function of alpha2 adrenoreceptors upon noradrenergic neurons in the brain. 3) Changes in platelet alpha2 receptor function during therapy will provide a valuable biomonitor of the therapeutic efficacy of antidepressant drug therapy. Changes in the number and/or affinity of alpha2 adrenergic receptors on human blood platelet membranes will be determined in depressed patients before, during and after treatment, in normal subjects and in patients with other psychiatric and non-psychiatric diagnoses. The specific binding of 3H-clonidine and 3H-yohimbine to platelet membranes will be used to assess alpha2 adrenoreceptor function. Diagnostic subtyping of depressed patients will be based on the Research Diagnostic Criteria as well as a variety of other diagnostic tests and procedures which include the Dexamethasone Suppression Test and sleep EEG parameters. In animal studies, functional changes in the regulation of noradrenergic neuronal activity by alpha2 adrenergic receptors caused by antidepressant drugs and procedures will be determined by the use of two different preparations: 1) superfused rat brain slices and 2) isolated rat left atrial strips. The release of norepinephrine during electrical stimulation of neurons in these preparations will be determined by measuring a) changes in the responses of the isolated muscle preparation, b) the efflux of endogenous neurotransmitter measured by a combination of high pressure liquid chromatography and electrochemical detection, c) the release of 3H-norepienphrine after incubating the tissues with 3H-dihydroxyphenylalanine and d) the release of dopamine beta hydroxylase, an enzyme which is released with norephinephrine but which is not taken back up into the neuron. Changes in the function fo postsynaptic alpha2 adrenergic receptors will be measured by the use of isolated strips of rat tail artery. The rat tail artery is a tissue rich in alpha2 adrenergic receptors. Functional changes in noradrenergic neurons will be correlated with changes in the binding of 3H-clonidine, 3H-yohimbine and other radiolabeled ligands to neuronal membranes isolated from various areas of the rat brain and to neuronal membranes isolated from the muscle preparations.
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1 |
1988 — 1991 |
Smith, Charles B |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Psychomotor Stimulants and Adrenergic Nerve Function @ University of Michigan At Ann Arbor
Presynaptic receptors are thought to be important in the regulation of transmitter release from a variety of neurons. The alpha2 adrenergic receptor is located upon noradrenergic, serotonergic, dopaminergic and cholinergic neurons and, when stimulated, inhibits neurotransmitter release. The proposed project is based upon the following hypotheses: 1) presynaptic alpha2 adrenergic receptors on noradrenergic neurons in the central nervous system are important sites for the pharmacological actions of psychotropic drugs, especially those psychomotor stimulants such as cocaine and the amphetamines which are known to release catecholamines from neurons and block neurotransmitter reuptake; 2) long-term administration of such drugs causes changes in presynaptic receptor number, affinity and/or function which differ from those produced by short-term drug administration, and those changes in alpha2 adrenergic receptor function after long-term psychomotor stimulant drug administration reflect those which occur in drug- dependent individuals; 3) psychomotor stimulants which produce dependence modify alpha2 adrenergic receptor function at specific cellular sites (e.g. alpha adrenergic receptors located upon nerve endings vs those located on cell bodies), upon specific types of neurons (e.g. noradenergic vs cholinergic neurons) and at specific sites in the brain (e.g. hippocampus vs brainstem). Receptor-ligand binding studies will be performed in order to determine whether the number and/or affinities of various adrenergic receptors change after either short- or long-term psychomotor stimulant drug administration. Functional changes in presynaptic alpha2 adrenergic receptors located upon noradrenergic neurons will be determined in three different preparations: 1) superfused, electrically stimulated rat brain slices 2) the isolated rat vas deferens preparation and 3) isolated rat left atrial strips. The release of neurotransmitter during electrical stimulation of neurons in these preparations will be determined by measuring one or more of the following parameters: a) the release of 3H-norepinephrine after incubating the tissues with 3H-norepinephrine or its precursor, 3H- dihydroxyphenylalanine, b) the efflux of endogenous neurotransmitter by a combination of high pressure liquid chromatography and electrochemical detection, c) the release of dopamine beta-hydroxylase, an enzyme which is released with norepinephrine but which is not taken back up into the neuron or d) changes in the responses of the isolated muscle preparations.
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1 |
2006 — 2010 |
Smith, Charles B |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Clinical Core - Satellite
The Kentucky Clinic North Minority Satellite (KYCN) represents a renewed effort to recruit minorities, particularly African Americans, into the University of Kentucky Alzheimer's Disease Center ( UK ADC) clinical and research programs. This application integrates KYCN into a unique comprehensive model of dementia-related services and research in the local African American community. Resources of the Administration on Aging (AOA), the Kentucky Cabinet for Health Services, the Alzheimer's Association, and the UK ADC are combined in a multidisciplinary partnership. These efforts include direct minority participation in recruitment, education, administration, care delivery, dementia awareness, in-home safety assessment, and transportation services. KYCN, under the auspices of UK ADC, maintains an independent research function distinct from the service orientation of the AOA, state agencies, and the Alzheimer's Association. The success of this clinic and our research efforts in this population is based on developing trust between the UK ADC and the African American community nurtured through the provision of quality medical care, and the stable on-going presence of a local clinic staffed by well-trained, dedicated multicultural professionals. Over the last several years, we have met program goals, providing 97 initial dementia evaluations, recruiting 51 of these individuals into our longitudinal research programs, and obtaining autopsy consent in 6 of these subjects. For this proposal, the initial success of this clinic will be expanded in order to meet the following goals: (1) To provide dementia diagnoses for 30 new patients per year and to follow a cohort of 100 primarily African American patients longitudinally. (2) To collect data, reportable to NACC as a Uniform Data Set (UDS), for normal controls, MCI, AD and other non-AD dementias in a central Kentucky African American population. (3) In conjunction with the Education and Information Transfer Core, to educate the African American community about AD and other dementias, the importance of early diagnosis and treatment, and participation in dementia research. (4) To increase participation by African Americans in AD research with prearranged autopsy, including the BRAINS and Dementia Research programs.
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0.961 |
2006 — 2010 |
Smith, Charles B |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Clinical Core
The overall goal of the Clinical Core of the University of Kentucky Alzheimer's Disease Center (UK ADC) is to provide thoroughly evaluated, longitudinally followed, normal control subjects and Alzheimer's disease (AD) and other non-AD dementing disorders patients for innovative research studies at UK, other ADCs and institutions studying AD and aging. This Core will maintain a normal control population of 500 initially normal aged subjects who will be followed longitudinally to autopsy (all have prearranged autopsies). The major emphases will be on studies of normal aging and transition to preclinical AD, mild cognitive impairment (MCI), and early AD. Control participants will be evaluated annually with medical, neurologic, and neuropsychological tests to define subtle changes in cognitive and neurologic functions. A developmental study will be carried out to attempt to define the theoretical entity, preclinical AD, in this population. This Core will maintain a Dementia Research Clinic of 200 subjects with dementing disorders who will be followed longitudinally to autopsy (all have prearranged autopsies). Emphasis will be placed on recruiting MCI, early AD, and mixed dementia (AD/vascular dementia, AD/DLB, Parkinson's Disease Dementia) patients. Dementia Research Clinic patients undergo the same thorough annual evaluation as our control subjects. The detailed evaluation of control and dementia subjects provides a database for use by UK investigators associated with our Center and investigators at other ADCs and institutions. Longitudinally followed control subjects and MCI and early AD patients will provide important data about the course and progression of AD. The Clinical Core will expand and maintain a satellite clinic for African Americans, the Kentucky Clinic North Minority Satellite, in Lexington to provide longitudinal follow and broadening research opportunities for an understudied population. This Core will also obtain serum, plasma, buffy coats and CSF from normal control subjects, MCI and early AD patients for use by investigators. The Core will participate in the NIA AD neuroimaging initiative, NACC funded studies, ADCS trials, and industry sponsored drug trials. The uniform data set and the minimum data set are collected by this Core and submitted to NACC in a timely fashion by the Biostatistics and Data Management Core. The close relationship between the Clinical Core and the Neuropathology Core allows for unique clinical-pathological correlation studies on longitudinally followed subjects to better understand normal aging and transition to MCI and AD.
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0.961 |