EFFECT OF CHRONIC TREATMENT WITH TFMPP, A 5-HT(1)-RECEPTOR AGONIST, ON FOOD-INTAKE, WEIGHT-GAIN, PLASMA-INSULIN AND NEUROPEPTIDE MESSENGER-RNA EXPRESSION IN OBESE ZUCKER RATS

1-[3-(trifluoromethyl)phenyl)piperazine (TFMPP), a 5-HT1 receptor agon ist, decreases food intake in rats when given acutely. The present inv estigation was performed to study the chronic effects of TFMPP on food intake and weight gain in genetically obese Zucker rats. Neurochemica l and endocrine data on possible mechanisms involved in the action of TFMPP were collected at the end of the study. TFMPP (4 mg/kg per day s .c.) significantly reduced food intake on the lst and 7th days, but no longer on the 14th and 28th days. Reduced food intake was associated with decreased body weight gains during the first two weeks of treatme nt, but no effect was found thereafter. Plasma insulin concentration w as significantly lowered by TFMPP treatment without impairment of gluc ose homeostasis. In situ hybridization analysis did not reveal changes in the expression of preprocorticotropin-releasing factor mRNA in the paraventricular nucleus or preproneuropeptide Y mRNA in the arcuate n ucleus. Chronic TFMPP administration significantly reduced the density of 5-HT2 receptors, as measured by quantitative receptor autoradiogra phy, in the claustrum and cerebral cortex, but not 5-HT1C receptor den sity in the choroid plexus. It is concluded that the anorectic and wei ght gain-lowering effects of TFMPP decrease during long-term treatment in obese Zucker rats.