Abnormal agonist-receptor interactions by acetylcholine and excitatory amino acids may mediate long-term neurological deficits following mild and moderate levels of traumatic brain injury (TBI). These interactions on involve muscarinic and N-methyl-D-asparte (NMDA) receptors. We hypothesize that TBI may produce widespread, excessive release of acetylcholine and excitatory amino acids which bind to their respective receptors, thereby increasing excitatory influences on neurons already subjected to mechanical stresses. Abnormal excitation could disturb brain information flow pathways resulting in changes in cell function (possibly related to excessive intracellular levels have measurable behavioral effects. Behavioral experiments have shown that TBI in the rat produces long-term term motor and memory deficits. Blockade of muscarinic cholinergic or NMDA receptors can reduce long-term motor deficits, and combined doses of both receptor blockers can reduce cell death following secondary ischemic insult. Preliminary data indicate TBI results in decreased binding to muscarinic and NMDA receptors in the hippocampus, possibly in response to increased extracellular levels of agonists following injury. Proposed research would include tissue slice and autoradiographic studies of mus-carinic and excitatory amino acid receptor binding in the rat hippocampus. Studies of receptor binding would be systematically compared to studies of the effects of TBI on long- term behavioral deficits including performance in a spatial memory task subserved by a restricted (hippocampal) neural substrate. We will also perform quantitative autoradiographic assessments of regional cerebral blood flow and examine the effects of systemic administration of muscarinic and NMDA receptor antagonists on each of these measures. Proposed research would supplement data from clinical studies of anticholinergic treatment of human head injury.

Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Stiefel, Michael F; Marmarou, Anthony (2002) Cation dysfunction associated with cerebral ischemia followed by reperfusion: a comparison of microdialysis and ion-selective electrode methods. J Neurosurg 97:97-103
Yamamoto, M; Marmarou, C R; Stiefel, M F et al. (1999) Neuroprotective effect of hypothermia on neuronal injury in diffuse traumatic brain injury coupled with hypoxia and hypotension. J Neurotrauma 16:487-500
Barzo, P; Marmarou, A; Fatouros, P et al. (1997) MRI diffusion-weighted spectroscopy of reversible and irreversible ischemic injury following closed head injury. Acta Neurochir Suppl 70:115-8
Marmarou, A; Barzo, P; Fatouros, P et al. (1997) Traumatic brain swelling in head injured patients: brain edema or vascular engorgement? Acta Neurochir Suppl 70:68-70

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