Acute intracerebroventicular infusions of 5-HT2 receptors agonists activate the sympathetic nervous system and increase blood pressure. Preliminary data indicate that activation of a subset of the 5-HT2 receptors in the brain, the 5-HT2C receptors, is a contributory factor to deoxycorticosterone-salt induced hypertension. The central 5-HT2C receptor are also involved in reducing food intake and body weight, 5-HT2C receptor are also involved in reducing food intake and body weight, 5-HT2C receptor knock-out mice becoming obese. This suggests that 5-HT2C receptor activation could be a link between obesity and hypertension. Specifically, this proposal examines the hypothesis that obesity causes 5-HT2C receptor activation to reduce body weight that chronic activation of this system cause hypertension. This hypothesis is supported by preliminary data that the hypertension induced by intracerebroventricular infusions of leptin, a hormone involved in reducing body weight, is blocked by 5-HET2C receptor antagonists. Leptin is secreted by adipose tissue, is transported into brain as the blood- brain and blood-CSF barriers and has hypothalamic actions. The choroid plexus (the site of the blood CSF barrier) have the highest densities of leptin and 5-HT2C receptor activation modulates blood to brain leptin transport as a feed-back mechanism. This project has four specific aims. 1) To determine chronic 5-HT2C receptor activation can induce hypertension. 2) To examine whether 5- HT2C receptor activation is the cause of hypertension in rats fed a high fat diet. 3) To determine whether leptin activities 5-HT2C receptors to produce a pressor effect. 4) To examine whether 5-HT receptor activation alters blood to brain leptin transport. Hypertension related to obesity is a major cause of morbidity and mortality in the USA. A better understanding of the basic mechanisms linking these two factors would have major therapeutic relevance.
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