In an effort to reduce heart disease, all Americans are currently advised to reduce their consumption of dietary fat and cholesterol, and millions of individuals are additionally prescribed cholesterol-lowering medications if cholesterol reduction achieved through diet modification is deemed inadequate. However, the potential effects of cholesterol lowering on mood, behavior and general well-being are poorly understood. Research on these associations is warranted as a matter of general medical prudence, particularly because such intervention is recommended for initially healthy individuals. A more specific rationale devices from a recent meta-analysis of primary prevention trials of cholesterol lowering which indicated that, compared with controls, treated men experienced increased mortality from suicides and trauma. This has prompted speculation that cholesterol lowering may be associated with disturbances of social function. Our preliminary studies conducted on cynomolgus monkeys reveal that animals consuming diets low in saturated fat and/or cholesterol are more aggressive behaviorally and show lower CNS serotonergic activity than monkeys fed diets of high lipid content. The findings in relation to brain serotonin are of potential interest, as diminished serotonergic function has been associated with heightened irritability, aggression and suicidality. Consequently, we propose a study of cholesterol reduction among 60 socially housed, male and female cynomolgus monkeys in a within subject design involving 3, seven-month treatment periods: 1) a diet low in fat and cholesterol, modeled after current dietary recommendations; 2) a diet high in fat and cholesterol, modeled after typical American consumption; and 3) the high fat diet supplemented with the cholesterol-lowering drug, cholestyramine. Two groups of 30 animals will be studied sequentially for 25 months each. During each treatment period, plasma cholesterol concentrations, social behavior (aggressive, affiliative and neutral), cerebrospinal fluid monoaminergic metabolites, and neural, endocrine, and behavioral responses to standard provocations will be measured. Use of this animal model is appropriate in such investigation since it permits: (a)precise manipulation of pertinent environmental and dietary factors; (b) direct observation of individual behavioral attributes and patterns of social interaction; (c) collection of neurobiologic data by invasive means not feasible in human clinical studies; and (d) equivalent cholesterol reduction by dietary and pharmacologic interventions.
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