Traumatic brain injury (TBI) affects 1.5 to 2 million individuals in the United States each year. Approximately 30% of the 300,000 severely injured survivors endure long-term disabilities, leading to costly medical and rehabilitative care. In addition to the physical impairments, TBI survivors also face a significant disturbance in cognitive function. Because memory impairment is a multifaceted phenomenon, alleviating this dysfunction may necessitate either a combination of pharmacotherapies or single pharmacologic agents that modulate various neurotransmitter systems. In this application, the investigators are investigating the latter possibility via a serotonin (5-HT-1A) receptor agonist -- a phamacotherapy paradigm used clinically to treat depression and anxiety. Both the 5-HT and acetylcholine (ACh) neurotransmitter systems are implicated in mediating cognition. 5-HT-1A receptor (5-HT-1AR) agonists are known to interact with the cholinergic system by increasing ACh release. ACh neurotransmission is chronically decreased after TBI, which may, in part, contribute to cognitive deficits. Thus, the interaction between the serotonergic and cholinergic systems via 5-HT-1AR agonists may provide an alternative and potentially beneficial therapeutic strategy after brain injury. Preliminary support for this hypothesis stems from recent work demonstrating that acute 5-HT-1AR agonism attenuates learning and memory deficits produced by controlled conical impact injury. While the mechanisms for the beneficial effect observed in this novel therapeutic approach are not known, the results have prompted a general hypothesis that 5-HT-1AR agonism attenuates TBI-induced cognitive dysfunction by increasing cholinergic neurotransmission and decreasing cholinergic cell death. The following aims are proposed to test this hypothesis:
Aim I will evaluate the potential efficacy of a delayed (24 hr after injury) and chronic (20 days) 5-HT-1AR agonist treatment paradigm on cognitive performance after experimental TBI produced by a well-established cortical impact model.
Aim 2 will assess biochemical and immunohistochemical markers of cholinergic neurotransmission after chronic 5-HT-1AR agonist treatments. The results from these novel studies will demonstrate for the first time the effects of chronic treatments with a 5-HT-1AR agonist on cognitive performance after TBI as it relates to a rehabilitative setting. This R03 pilot project will serve as proof of concept for the basis of a more comprehensive study of 5-HT-1AR-mediated mechanisms after TBI. The long-term goal is to develop pharmacotherapies that attenuate posttraumatic neuronal cell death and facilitate cognitive performance after human TBI.
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