Ontogeny of glutamate receptors mediated morphine tolerance and withdrawal in rats.
Item
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Title
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Ontogeny of glutamate receptors mediated morphine tolerance and withdrawal in rats.
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Identifier
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AAI3047281
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identifier
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3047281
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Creator
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Zhu, Hongbo.
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Contributor
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Adviser: Gordon A. Barr
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Date
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2002
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Language
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English
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Publisher
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City University of New York.
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Subject
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Psychology, Psychobiology | Biology, Neuroscience | Health Sciences, Pharmacology
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Abstract
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There is an increasing interest in the study and treatment of opiate tolerance and withdrawal in human infants. Glutamate receptors, especially NMDA receptors, are suggested to play key roles in the processes of opiate tolerance and withdrawal. Numerous studies in the past decade indicate that NMDA receptor antagonists inhibit opiate tolerance and withdrawal. Accumulating data also show that AMPA receptor antagonists and group II mGluR agonists attenuate opiate tolerance and withdrawal. However, most existing data are derived from adult animal models. All glutamate receptor types undergo dramatic developmental changes during early life. Thus, the author hypothesizes that the pharmacological effects on opiate tolerance and withdrawal of NMDA receptor antagonists, AMPA receptor antagonists and mGluR agonists in the developing organism may not be comparable to those in the adult. A combination of in vivo and in vitro assays were used in the present thesis to test the effect of treatment of agents acting on the NMDA, AMPA and group II mGluR on opiate tolerance and withdrawal in rats of 1--7, 8--14, and 15--21 days of age, which are the critical periods when various glutamate receptor subunits experience differential change. NMDA receptor antagonists were found to be not effective in blocking either morphine tolerance or withdrawal in the 7-day-old rat, partially effective in the 14-day-old, and fully effective in the 21-day-old. There is a transition period around the second postnatal week for NMDA receptor antagonists to be effective in suppressing opiate tolerance and withdrawal. In contrast, the AMPA receptor antagonist and the group II mGluR agonist do not show such age effects, and were effective in attenuating opiate tolerance or withdrawal at all ages tested. These data demonstrate that age is a significant factor determining the effectiveness of NMDA receptor antagonists in suppressing morphine tolerance and withdrawal. The author concludes that NMDA receptor antagonists should not be used in human infant for the treatment of opiate tolerance and withdrawal. In contrast, AMPA receptors and mGluRs may prove to be good targets for the modulation of opiate tolerance and withdrawal at all ages.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
