Pharmacology Biochemistry and Behavior, Vol. 62, No. 3, pp. 487–491, 1999 © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0091-3057/99 $–see front matter PII S0091-3057(98)00212-3 487 CCK A and 5-HT 3 Receptors Interact in Anorectic Responses to Amino Acid Deficiency S. M. AJA, J. A. BARRETT AND D. W. GIETZEN Department of Veterinary Medicine: Anatomy, Physiology and Cell Biology, and the Food Intake Laboratory, University of California–Davis, Davis, CA 95616 Received 15 August 1997; Revised 15 June 1998; Accepted 15 August 1998 AJA, S. M., J. A. BARRETT AND D. W. GIETZEN. CCK A and 5-HT 3 receptors interact in anorectic responses to amino acid deficiency. PHARMACOL BIOCHEM BEHAV 62(3) 487–491, 1999.—Serotonin 3 (5-HT 3 ) receptors in the pe- riphery mediate anorectic responses to the amino acid deficiency, which occurs after eating amino acid-imbalanced diets (IMB). However, other neurochemical systems, notably cholecystokinin (CCK), are known to affect food intake. We pre- treated rats systemically with tropisetron, a 5-HT 3 receptor antagonist, alone and combined with antagonists of CCK A and CCK B receptors, and measured intake of an IMB. Devazepide, a CCK A receptor antagonist, appeared to interact with tro- pisetron in the anorectic responses to IMB, blunting the usual remediation of IMB anorexia by tropisetron. The CCK B recep- tor antagonist, L-365, 260, increased intake of both IMB and an amino acid-balanced basal diet (BAS) and did not interact with tropisetron. Our data suggest that activation of CCK A receptors is interactive with 5-HT 3 receptor activity in mediating IMB anorexia in the aminoprivic feeding model. © 1999 Elsevier Science Inc. Amino acid imbalance Rat Nutrition Food intake Tropisetron Devazepide L-365,260 Serotonin 3 receptor CCK A receptor CCK B receptor THE use of amino acid imbalanced diets (IMB) is a nutri- tional model for establishing a selective essential amino acid deficiency in animals (17,24,25). Rats demonstrate their rec- ognition of the deficient state by a rapid reduction of IMB in- take. The anorectic response is rapid, reaching significance within a few hours, depending on the degree of amino acid disproportionality and the prefeeding regimen (13,25). Sero- tonin (5-HT) appears to be involved in the reduced intake of IMB (14), an effect selective for the 5-HT 3 receptor (16,20,34). Ondansetron, a highly selective 5-HT 3 antagonist, injected into the anterior piriform cortex, increases IMB intake (15,34), suggesting a central site for 5-HT in the response to IMB. Systemic injections of the 5-HT 3 antagonist, [1H]-indole- 3-carbonic acid-tropine-ester hydrochloride, also known as tro- pisetron (TROP, formerly ICS 205-930), or its quaternized form, attenuate the anorectic response equally (19). In addi- tion, both total subdiaphragmatic vagotomy and capsaicin blunt the antianorectic effect of TROP on IMB [(36); Dixon et al., unpublished]. Thus, peripheral 5-HT 3 receptors are likely to be involved in the depressed consumption of IMB, as well. The finding that pretreatment with TROP only increases IMB intake to 80–85% of a baseline basal diet (BAS) intake (16) prompted us to ask whether the 5-HT 3 receptor acts alone in the responses to IMB, or whether other systems may be involved. Since the early recognition of the importance of serotonin in feeding control [reviewed in (3)], considerable research has demonstrated potential interactions between ser- otoninergic activity and that of other systems. Cholecystokinin (CCK) has been well-studied as a satiety agent. Exogenous CCK-8 decreases food intake in rats (12), monkeys (11), and humans (22). Antagonism of CCK A recep- tors in the periphery (29), but not CCK B receptors in the brain (33), blocks the anorectic response to intraperitoneal (IP) CCK-8 in fasted rats. However, in sated rats, blockade of CCK B receptors has been shown to be more potent than an- tagonism of CCK A receptors for increasing feeding and post- poning onset of satiety (10). Capsaicin-sensitive vagal affer- ents have been implicated as a link between CCK activities in the gastrointestinal system and the brain for mediating satiety (37). As noted above, the full effect of TROP is dependent on an intact vagus as well (36). 5-HT 3 and CCK receptors coexist at many sites in both central and peripheral feeding–control Requests for reprints should be addressed to Dorothy W. Gietzen, Dept. of Veterinary Medicine: Anatomy, Physiology and Cell Biology, One Shields Avenue, University of California, Davis, CA 95616-8732.