Benzodiazepine site modulation of GABAA-induced chloride currents in young and aged basal forebrain neurons /
The purpose of this study was to characterize the pharmacological profile of compounds acting at the [GABAw]/benzodiazepine site using electrophysiological techniques. Benzodiazepine site modulation of [GABA] induced chloride currents was explored in acutely dissociated medial septum/nucleus of the...
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
1998.
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| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=732838301&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | The purpose of this study was to characterize the pharmacological profile of compounds acting at the [GABAw]/benzodiazepine site using electrophysiological techniques. Benzodiazepine site modulation of [GABA] induced chloride currents was explored in acutely dissociated medial septum/nucleus of the diagonal band (MS/OB) neurons using the whole-cell configuration of patch clamp recording. We studied the differences in [GABA]-induced current modulation between MS/OB neurons of young (1-3 months) and aged (24-26 months) male Fischer 344 rats. Benzodiazepine modulation of [GABA]-induced whole-cell currents was greater in aged neurons. Midazolam modulation of GABA concentration-response curves demonstrated two noteworthy age-related effects. First, at low GABA concentrations [(1 gM)] midazolam potentiation of [GABAA] receptor currents was greater in aged neurons. Second, at high GABA concentrations [(k10 gM)] midazolam decreased the maximum response in young neurons, while potentiating currents in aged cells. Therefore, we separated our studies into experiments with low and high GABA concentrations. We studied age-related midazolam effects at high GABA concentrations using two separate application protocols (sequential and initial) because the age-related elects of midazolam at this GABA concentration were not straightforward. We found that the depressive effects of midazolam in young neurons was dependent upon GABA concentration applied and experimental protocol used. The application of Gumazenil, a benzodiazepine antagonist, blocked all midazolam elects equally in young and aged neurons. Therefore, our data suggests compounds acting at the berlzodiazepine site may modulate [GABAA]- induced currents differently in young and age neurons. Age-related increased potentiation was found with the partial agonist bretazenil. The potentiation of GABAA currents with bretazenil showed a concentration-dependent elect in aged, but not young neurons. Further analysis showed an age-related difference in bretazenil potentiation at [lgM], but not [3gM] or [lOgM] GABA. No age-related elects were noted with either zolpidem (full BZ agonist) or [P-]CCM (inverse BZ agonist). We conclude that age-related increased benzodiazepine potentiation is not a global benzodiazepine potentiation is not a global These studies suggest that specific age-related changes occur at the [GABAA] receptor ion channel complex in MS/nDB neurons and these changes could explain, in part, age-related benzodiazepine elects seen clinically in elderly patients and experimentally in aged animals. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". |
| Physical Description: | x, 146 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilm Inc. |
| Bibliography: | Includes bibliographical references: pages 127-144. |