Cholesterol reduction by dietary or pharmacologic means is recommended for all Americans despite the absence of controlled studies evaluating the biobehavioral or other health effects of this intervention. Such evaluation is warranted as a matter of general medical prudence, since the intervention is recommended for initially healthy individuals. A more specific rationale is provided by the results of numerous studies linking low or clinically reduced plasma cholesterol concentrations to significant increases in violence-related mortality (accident, suicide, homicide) and depression. In the proposed research, behavioral and neurobiologic procedures impossible to use on healthy human volunteers will be applied to cynomolgus macaques (Macaca fascicularis) to evaluate the biobehavioral sequelae of cholesterol lowering. In this experiment, we will study the behavior and neurobiologic function of 30 male and 30 female adult monkeys undergoing significant cholesterol reduction induced by both dietary and pharmacologic means. This is a within-subjects design, with all animals exposed in turn to 3 seven-month treatments: 1) a diet low in fat and cholesterol, modeled after current dietary recommendations (lofat); 2) a diet high in fat and cholesterol, modeled after typical American consumption (hifat); and 3) the hifat diet plus cholestyramine, a cholesterol-lowering drug used in many epidemiologic trials. The monkeys will be housed in social groups of five animals each for the entire experiment. Behavioral samples of social interactions will be collected routinely in each treatment period. Additional measurements will include plasma cholesterol concentration, cerebrospinal fluid 5- hydroxyindoleacetic acid concentration, and peripheral serotonergic stimulation. The applicant will investigate two major hypotheses are: 1) lowering plasma cholesterol by either the lofat diet or cholestyramine will provoke increased aggression and decreased sociability; and 2) any such behavioral changes induced by cholesterol lowering will be accompanied by reduced central serotonergic activity. In vitro autoradiographic techniques will be applied to test the hypothesis that increased aggressivity results from alterations of central serotonergic uptake affinity and/or distribution. Phase I of the proposal will consist of:1)graduate level course work in molecular neurobiology, cellular and biochemical neuroscience, neurobehavioral pharmacology, and clinical neuroscience, necessary to pursue the research project, 2) rotation through the co-sponsor's laboratory to learn techniques, which include high performance liquid chromatography and in vitro autoradiography and 3) initial work in the sponsor's laboratory to collect baseline behavioral and clinical data. In Phase II a formal research proposal will be prepared and submitted for faculty review.
