The goals of this project are to describe in detail how aging: (a) alters the response of central cholinergic pathways to injury and (b) affects the therapeutic effectiveness of anticholinergic treatment following traumatic brain injury (TBI) in the rat. Previous research, using behavioral, turnover, and binding techniques, has demonstrated the involvement of the cholinergic system in both transient unconsciousness and long-term neurological deficits associated with TBI. Treatment with the muscarinic antagonist scopolamine, but not methylscopolamine or mecamylamine, attenuates many of the deficits observed following TBI in young mature rats. Aging has been shown to be arcompanied byalterations in the cholinergic system that result in an enhanced responsivity to cholinergic agonists and decreased reactions anticholinergic agents. It is hypothesized that aging is associated with an increased vulnerability to TBI because of these alterations. In addition, it is predicted that anticholinergic treatment following TBI will be less effective in reducing neurological deficits in older animals. The behavioral and cholinergic responses to TBI will be compared in young mature (3 month-old) and aged rats (20 month-old), and the effectiveness of anticholinergic treatment will be compared in these two age groups. Experiments will use a rat model of fluid percussion brain injury. Immediate neurological outcome will be evaluated by measuring the duration of the suppression a number of reflexes, including pinna, corneal, paw and tail flexion, righting, head support, escape, and spontaneous locomotion. Long-term neurological outcome will be assessed using beam balance, beam walking, and 8-arm radial maze performance. The role of the cholinergic system will be evaluated by regional turnover and binding assays. Acetylcholine turnover will be quantitated in specific brain regions by a mass fragmentographic technique that measures the relative incorporation of deuterium label from infused phosphorylcholine percursor into choline and acetylcholine. Muscarinic receptor binding will be characterized by scintillation and autoradiographic binding studies on slide-mounted brain tissue using tritiated-quinuclidinyl benzilate as the ligand. Our long- term objective is to develop an understanding of the processes that result in the aged animals' greater vulnerability to TBI and, based on this increased understanding, to develop efficacious therapies that are best suited to the aged population.
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