Increased binding at 5-HT1A, 5-HT1B, and 5-HT2A receptors and 5-HT transporters in diet-induced obese rats

5-Hydroxytryptamine (5-HT, serotonin), synthesized in midbrain raphe nuclei and released in various hypothalamic sites, decreases food intake but the specific 5-HT receptor subtypes involved are controversial. Here, we have s tudied changes in the regional density of binding to 5-HT receptors and tra nsporters and the levels of tryptophan hydroxylase, in rats with obesity in duced by feeding a palatable high-energy diet for 7 weeks. We mapped bindin g at 5-HT receptor subtypes and transporters using quantitative autoradiogr aphy and determined tryptophan hydroxylase protein levels by Western blotti ng. In diet-induced obese (DiO) rats, specific binding to 5-HT1A receptors ([H-3]8-OH-DPAT) was significantly increased in the dorsal and median raphe by 90% (P < 0.01) and 132% (P < 0.05), respectively, compared with chow-fe d controls. 5-HT1B receptor binding sites ([I-125]cyanopindolol) were signi ficantly increased in the hypothalamic arcuate nucleus (ARC) of DiO rats (5 8%; P < 0.05), as were 5-HT2A receptor binding sites ([H-3]ketanserin) in b oth the ARC (44%; P < 0.05) and lateral hypothalamic area (LHA) (121%; P < 0.05). However, binding to 5-HT2C receptors ([H-3]mesulgergine) in DiO rats was not significantly different from that in controls in any hypothalamic region. Binding to 5-HT transporters ([H-3]paroxetine) was significantly in creased (P < 0.05) in both dorsal and median raphe, paraventricular nuclei (PVN), ventromedial nuclei (VMH), anterior hypothalamic area (AHA) and LHA of DiO rats, by 47%-165%. Tryptophan hydroxylase protein levels in the raph e nuclei were not significantly different between controls and DiO rats. In conclusion, we have demonstrated regionally specific changes in binding to certain 5-HT receptor subtypes in obesity induced by voluntary overeating of a palatable diet. Overall, these changes are consistent with reduced 5-H T release and decreased activity of the 5-HT neurons. Reduction in the hypo phagic action of 5-HT, possibly acting at 5-HT1A, 5-HT1B and 5-HT2A recepto rs, may contribute to increased appetite in rats presented with highly pala table diet. (C) 1999 Elsevier Science B.V. All rights reserved.