Anorectic response to amino acid imbalance: a selective serotonin3 effect?

The anorectic responses to imbalanced amino acid diets (IMB) are ameliorated by pretreatment with large (mg/kg) doses of the serotonin antagonists, tropisetron [3-alpha-tropanyl-1H-indole-3-carboxylic acid ester, formerly known as ICS-205,930 (ICS)] and MDL 72,222 [1 alpha H,3 alpha,5 alpha-H-tropan-3-yl-3,5-dichlorobenzoate (MDL)], effects earlier attributed to the 5-hydroxytryptamine3 (5-HT3) receptor. Subsequent identification of the 5-HT4 receptor, and recognition that ICS and MDL also bind to 5-HT4 receptors, led us to question whether the results seen with these drugs were due to activity at the 5-HT3 or 5-HT4 receptor subtype. 1,2,3,9-Tetrahydro-9-methyl-3 [(2-methyl-1H-imidazol-1-yl) methyl] 4H-carbazol-4-one) [ondansetron (OND)], a reportedly 5-HT3-selective receptor antagonist, has been used to block 5-HT3 receptors in demonstrating the 5-HT4 receptor, and so seems securely selective for the 5-HT3 receptor type. Therefore, we tested the effects of OND on the rat's feeding responses to IMB. Pretreatment with 0.1 or 1 micrograms/kg OND fully restored intake of IMB to > 100% of control between 6 and 12 h after introduction of IMB. We conclude that the previous similar increases in IMB intake seen after ICS and MDL were due to their antagonist activity at the 5-HT3 receptor and that the 5-HT3 receptor may have an important role in mediating the rat's anorectic responses to IMB.