Improved medical means of reducing CSF production would be of major benefit to patients with increased intracranial pressure (ICP). Such patients include those with acute head trauma, intracranial hemorrhage, some tumors, and malfunctioning CSF shunts. Trauma is the fourth leading cause of death, and up to 70% of these deaths are due to the head injury. Fatal head injury is associated with increased ICP, usually within the first 3-5 days. Drugs capable of reducing ICP, by reducing CSF production, might save some of these lives. The goal of this project is to develop further our understanding of the neural control of the production of cerebrospinal fluid (CSF) by the choroid plexus. It is currently known that sympathetic tone inhibits secretion of CSF. Preliminary data from our laboratory suggest that neuroleptics, or antipsychotic drugs, also cause a decrease in the net production of CSF. It is hypothesized that he receptors responsible for mediating this effect are localized to the choroid plexus and/or the sympathetic ganglia. We will study both of the receptors labeled by 3H-SCH-23390 and 3H-mesulergine. One of these is the 5-HT1c receptor, but it is not yet clear what subtype of receptor the second one is. Many drugs have high affinity for both receptors. Pharmacological characterization of the latter receptor will be carried out using receptor and second messenger assays. The major effort will be to study modulation of CSF production by agonists and antagonists at these receptors. Rats will be treated acutely with which the cisterna magna is cannulated will be compared with the isotope dilution method. Rats treated with superior cervical ganglionectomy will be studied to determine whether some drugs act by modulating sympathetic tone. To determine the chronic efficacy of drugs which decrease CSF production, rats will be treated with such drugs via implanted minipumps and tested to determine whether tolerance has developed to an acute administration of the drug. Evidence of crosstolerance to CSF- modulating effects will be sought in rats treated chronically with neuroleptics and challenged acutely with another agent, such as a glucocorticoid. To evaluate the possibility that drugs which reduce CSF production act by reducing blood flow to the choroid plexus, the 14C- iodoantipyrine technique will be used to measure regional blood flow both before and after drug administration. It is planned that promising animal studies will be followed up by clinical study proposals.
