Our goal is to develop a pharmacological treatment regimen for conclusive head injury. Specifically, we will investigate the role of cholinergic neurons in specific brain areas in neurological deficits following fluid percussion injury in the rat. It is postulated that increases in cholinergic activity in certain brain areas immediately following head injury may lead to acute and longer lasting neurologic deficits. The mechanisms of acute and longer lasting neurological deficits may be very different; some of the more chronic deficits may reflect decreased cholinergic activity in some brain regions at the later times. Changes in cholinergic neurochemistry will be correlated with selected neurological deficits at various times following head injury. As previous experience has shown that scopolamine pretreatment reduces the neurological deficits following head injury, the actions of scopolamine will be measured at selected times following injury. Experiments will be performed to determine if there is a restricted time period in which scopolamine must be administered to reduce persistent neurological deficits. Specific manipulations of central cholinergic neurons will be used to confirm the mechanism of action of scopolamine on neurological outcome. Central cholinergic tone will be enhanced or decreased by intracerebral injection of diisopropylfluorophosphate (DFP) or hemicholium-3, respectively. Acute neurological testing will include measuring simple reflexes (pinna, corneal and startle reflexes) and postural and nociceptive somatomotor function (righting and escape responses, muscle tone, locomotor activity, and paw and tail flexion reflexes). Chronic neurological deficits will be assessed by measuring ability to to balance on a beam and a learned avoidance task requiring coordinated movement (beam-walking). Central cholinergic activity will be assessed by quantitating acetylcholine turnover in tissue punches of specific brain regions by a mass fragmentographic technique that measures the relative incorporation of deuterium label from infused phosphorylcholine precursor into choline and acetylcholine. Acetylcholine turnover will be measured in the following areas: dorsomedial pontine tegmentum, laterodorsal pontine tegmentum/parabrachial nucleus, mammillary and posterior nuclei of the hypothalamus, interpenducular nucleus, amygdala, anteroventral nucleus of the thalamus, hippocampus, corpus striatum, prefrontal cortex and parietal cortex.
