Appetite, 1986, 7, Supplement, 127-140 8-0H-OPAT -Induced Hyperphagia: Its Neural Basis and Possible Therapeutic Relevance C. T. DOURISH, P. H. HUTSON, G. A. KENNETT and G. CURZON Department of Neurochemistry, Institute of Neurology, London The pharmacological and neurochemical bases of hyperphagia induced by the serotonin agonist 8-0H-DPAT were examined. In addition, the possible therapeu- tic potential of 8-0H-DPAT and related drugs in the treatment of anorexic pathology was assessed in an animal model of anorexia (as induced by acute immobilization stress). In normal rats 8-0H-DPAT elicited feeding after peripheral injection and after intracerebral application to the brainstem raphe nuclei. Feeding elicited by peripheral injection of the drug was attenuated by pretreatment with the serotonin synthesis inhibitor para-chlorophenylalanine. Following a hyperphagic dose of 8-0H-DPAT, brain serotonin metabolism was reduced, particularly in midbrain and pons-medulla. Our interpretation ofthese data is that 8-0H-DPAT elicits feeding via an agonist action on serotonin autoreceptors in the raphe nuclei. These receptors are probably of the 5-HT 1A subtype as 8-0H-DPAT has a high affinity for this receptor and other putative 5- HT I A agonist (i.e. buspirone, TVX Q 7821) also elicit feeding. In contrast, putative 5-Hi lB agonists (i.e. RU-24969 and quipazine) decrease feeding and cause anorexia. 8-0H-DPAT and other 5-HT lA agonists attenuated the anorexia and body weight loss caused by immobilization stress. Therefore, it seems possible that 5-HT lA agonists may be clinically useful in the treatment of anorexia. INTRODUCTION Considerable experimental evidence suggests relationships between serotonin metabolism and control of food intake. Alterations in either the availability or the composition of food can affect brain serotonin metabolism (see review, Curzon, 1986) while pharmacological manipulation of serotonin metabolism can alter food intake (see review, Blundell & Latham, 1982). In general, drugs which increase serotoninergic activity decrease food intake (Blundell, 1977). For example, the serotonin precursor 5-hydroxytryptophan (5-HTP) reduces food intake in food deprived rats (Joyce & Mrosovsky, 1964; Blundell & Leshem, 1975). Fenfluramine, a potent anorectic drug, releases serotonin and its anorectic action can be blocked by serotonin antagonists, or depleters (Garattini & Samanin, 1976). In addition, there is evidence that hypothalamic serotonin receptors are involved in the inhibition of feeding. Thus, Leibowitz and Papadakos (1978) have reported that 1-10 Ilg serotonin applied to the medial paraventricular nucleus of the hypothalamus produces a dose-dependent suppression of feeding in hungry rats. Correspondence should be addressed to C. T. Dourish, Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K. 0195-6663/86/780127 + 14 $03'00/0 © 1986 Academic Press Inc. (London) Limited