In the present study, we investigated the influence of blockade of the serotoninergic and histaminergic neurotransmitter system on the anorectic effect of IP-injected amylin in rats. In 12- or 24-h food-deprived rats, blockade of central and peripheral serotonin (5-HT) receptors with the 5-HT1 and 5-HT2 receptor antagonist metergoline (0.5 or 0.05 mg/kg, IP, respectively) did not seem to influence the anorectic effect of IP injected amylin (1 microgram/kg). Similarly, inhibition of 5-HT synthesis and release with the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (200 micrograms/kg, IP) did not diminish amylin's (5 micrograms/kg, IP) anorectic effect in 24-h food-deprived rats whereas that of CCK (3 micrograms/kg, IP) was blocked under comparable conditions. Pretreatment of rats with the histamine H3 receptor agonists R-alpha-methylhistamine (MH: 3 mg/kg, IP) and Imerit (3 mg/kg, IP), which block transmission in the histaminergic system by inhibiting release of endogenous histamine, attenuated amylin's (1 microgram/kg) anorectic effect in 24-h food-deprived rats. These results suggest that the histaminergic system in involved in transduction of IP amylin's inhibitory effect on feeding in rats. In contrast, the serotoninergic system does not seem to be involved in mediating amylin's anorectic effect.