This proposal utilizes four genetically related, inbred rat strains to study the neurochemical correlates of hypertension and hyperactivity. Two of the strains are the widely used Spontaneously Hypertensive Rat (SHR) and normotensive controls, Wistar-Kyoto (WKY) rats, from which SHRs were derived. Since SHRs are hyperactive in behavior as well as hypertensive in blood pressure, we separated the two traits by genetic means, starting from a mating of SHRs with WKYs. By selected, successive brother/sister matings we produced two new strains: WK-HAs that are hyperactive but not hypertensive, and WK-HTs that are hypertensive but not hyperactive. Since SHRs have both traits and WKYs have neither, we now have four genetically related inbred strains that express hypertension and/or hyperactivity in all possible combinations. They provide us with a unique resource for studying the biological basis of both these conditions, and they greatly improve the validity of comparisons made using SHRs with WKYs as the only controls. The experiments that are planned using these four strains will focus on the biogenic amines (catecholamines and serotonin) and neuropeptide transmitter systems of the central nervous system (CNS), as these are thought to be involved in both hypertension and hyperactivity. These experiments include immunocytochemistry to search for changes in levels of peptides in areas of the CNS that regulate blood pressure and locomotor activity. Experiments on the high affinity uptake of amines will assess functional alterations in monoamergic transmission in the brain. In situ hybridization studies will look for changes in rates of synthesis of peptide transmitters from altered levels of mRNA in selected brain regions. Longitudinal studies of blood pressure and activity will be carried out as these have not yet been done in our new strains. Behavioral tests designed to test for attentional deficit, aggression and hyperactivity will be used to assess the usefulness of WK-HAs as an animal model of hyperactive disorder in children, known as Attentional Deficit Disorder with Hyperactivity, or ADD-H. The new WK-HT strain is similarly to be assessed as a potentially more useful model of genetic hypertension than the SHR, as it lacks the hyperactivity of the SHR. More importantly, we propose that all four strains be used in order to seek more meaningful correlations of biological changes with hypertension or hyperactivity than has previously been possible using SHRs and WKYs alone in the comparison.
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