The objective is to develop a treatment to promote functional recovery after traumatic brain injury (TBI). Several research areas have promising developments for the treatment of stroke, but TBI has received less attention. Using a rat TBI model, we will investigate two approaches for enhancing functional recovery: drugs affecting catecholamines (CA) and excitatory amino acid (EAA) receptor antagonists. After TBI, administration of drugs evoking CA release, such as amphetamine (AMPH), promote functional recovery only when combined with experience (EXP). This enhanced recovery may result from a CA alleviation of a diaschisis. This hypothesis will be tested by correlating measures of monoamine (MA) and metabolite levels using in vivo microdialysis and high performance liquid chromatography (HPLC). Monitoring MA changes during behavioral assessment will indicate MA changes related to recovery rather than time after injury. Also, measures of local cerebral glucose utilization (LCGU) and cytochrome oxidase histochemistry (CYOH) will be taken when animals show marked functional recovery. LCGU and CYOH measures will also be used in experiments designed to distinguish structures uniquely altered by AMPH/EXP from changes due to AMPH or EXP. The second experiments will determine if excitatory amino acids (EAA) receptor antagonists administered after TBI influence recovery of function. Two effects of EAA receptor antagonists are predicted depending on time of administration after TBI; early treatment will protect against TBI by reducing excitotoxicity; later treatment after TBI will slow functional recovery by blocking mechanisms involved in plasticity required for alleviation of symptoms. The effects of these drugs on the extent of cortical necrosis at the trauma site and secondary neuronal death will also be investigated. Administration of drugs increasing release of norepinephrine and selective alphal adrenergic receptor agonists reduce secondary neuronal death in this TBI model. A reduction of cell death in other trauma models has been reported using EAA receptor antagonists but whether these effects are similar is unknown. To begin to study this question a comparison of these drugs from these two classes will be conducted in our TBI model to determine if similar areas of neuronal sparing are produced. These studies will utilize two histological methods to reveal injured neurons, acid- fucshhin and the recently developed silver stain of Vandenpol. Finally, behavioral measures of learning and memory deficits will be investigated in this model of TBI, since data indicate neuronal dysfunction in brain areas involved in these processes. The results of these experiments will also provide a basis for evaluating potential therapies which may alleviate some of the deficits of the 300,000 Americans permanently disabled by trauma every year.
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