Pharmacology Biochemistry andBehavior, Vol.47, pp. 59-63, 1994 0091-3057/94$6.00 + .00 Printedin the U.S.A.All rightsreserved. Copyright© 1993Pergamon PressLtd. Anorectic Response to Amino Acid Imbalance: A Selective Serotonin3 Effect? JENNIFER C. JIANG 1 AND DOROTHY W. GIETZEN 2 Department of Physiological Sciences, School of Veterinary Medicine and Food Intake Laboratory, University of California, Davis, Davis, CA 95616 Received 15 March 1993 JIANG, J. C. AND D. W. GIETZEN. Anorectic response to amino acid imbalance: A selective serotoninj effect? PHARMACOL BIOCHEM BEHAV 47(1) 59-63, 1994.-The anorectic responses to imhalanced amino acid diets (IMB) are ameliorated by pretreatment with large (mg/kg) doses of the serotonin antagonists, tropisetron [3-a-tropanyl-IH-indole-3- carboxylic acid ester, formerly known as ICS-205,930 (ICS)] and MDL 72,222 [loJt,3ct,5cl-H-tropan-3-yl-3,5-~chlor- obenzoate (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-mcthyl-3 [(2-methyl-IH- imidazol-l-yl) methyl] 4H-carbazol-4-one) [ondansetron (OND)], a reportedly 5-HTrselective 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 #g/kg OND fully restored intake of IMB to > 100°70of 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-HT3receptor may have an important role in mediating the rat's anorectic responses to IMB. Rat Amino acids Deficiency Imbalance Physiology Feeding behavior Drug effects Serotonin3receptor Serotonin Pharmacology Ondansctron Anorexia Dietary choice RATS rapidly and reliably reduce their food intake when of- fered a diet that is imbalanced with respect to the essential amino acids (15,21,25,26). The biochemical responses to an amino acid-imbalanced diet (IMB) include a plasma amino acid pattern similar to that seen in severe amino acid defi- ciency (15). A reduction in food intake is the first behavioral sign of a response to the amino acid deficiency induced after the first meal of IMB (1 I). Studies of the postingestive effects of IMB have shown that responses to these diets involve, first, recognition of the imbalance and, second, rejection of the diet. The rejection phase is most likely accompanied by devel- opment of a learned aversion (2,8,10-12,25,26). Serotonin [5-hydroxytryptamine (5-HT)] has been impli- cated in the CNS control of feeding for many years (1,9, 16,19). Peripherally injected 5-HT, which does not cross the blood-brain barrier (22), also affects food intake and has been demonstrated to produce a dose-dependent anorexia (7,23) in 18- and 24-h food-deprived rats. More recent research on 5- HT systems has demonstrated that postsynaptic 5-HT receptor agonists not only cause marked anorexia in rats (9,19) but also exacerbate the anorectic response of rats to IMBs (13). Hammer et al. (14) studied the 5-HT receptor subtype(s) re- sponsible for mediating the anorexigenic effects of IMB. An- tagonists selective at the 5-HT~, 5-HT2, dopamine, and ct- adrenergic sites, or at combinations of these receptor sites, did not affect intake of IMB. In contrast, the 5-HT 3 receptor antagonists, tropisetron [3-c~-tropanyl-lH-indole-3-carboxylic acid ester, formerly known as ICS-205,930 (ICS)] and MDL 72,222 [loJ-I,3t~,5tx-H-tropan-3-yi-3,5-dichlorobenzoate (MDL)], significantlyincreased intake of both mild and severe IMB (14). Thus, it was concluded that the 5-HT3 receptor subtype was the primary 5-HT mediator in this feeding model. Later findings by Dumuis et al. (5) demonstrated the exis- tence of a 5-HT4 receptor (17) that is also antagonized by high doses of ICS and MDL, doses comparable to those used by Hammer et al. (14). This led us to question whether the 5-HT receptor responsible for mediating intake of IMB was the 5- HT3 or 5-HT4 subtype. In the present study, we used the selec- tive 5-HT3 receptor antagonist, 1,2,3,9-tetrahydro-9-methyl-3 [(2-methyl-1H-imidazol-l-yl) methyl] 4H-carbazol-4-one) [on- dansetron (OND)] [as ondansetron HC1 dihydrate, previously known as GR38032F, Glaxo Group Research Ltd. (3,4)]. OND has been used in vitro to block 5-HT 3 receptors in the demonstration of 5-HT4 effects (6,24), showing its lack of i Current address: Saint Louis University Medical School, St. Louis, MO 63103. 2 To whom requests for reprints should be addressed. 59