FOOD FOR THOUGHT: A CRITIQUE ON THE HYPOTHESIS THAT ENDOGENOUS CHOLECYSTOKININ ACTS AS A PHYSIOLOGICAL SATIETY FACTOR B. A. BALDWIN*, R. F. PARROTT$ and I. S. EBENEZER%} *Neuro-Behavioural Biology Center, Institute of Science and Technology for Development, Mahidol University, Salaya, Thailand, $MAFF Laboratory of Welfare and Behaviour, Department of Neurobiology, Babraham Institute, Cambridge, CB2 4AT, England and %Neuropharmacology Research Group, School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, PO1 2DT, Hampshire, England (Received 23 December 1997) AbstractÐThis review evaluates the various lines of evidence supporting the hypothesis that cholecysto- kinin (CCK) released from the small intestine during feeding plays a physiological role in mediating sati- ety. Issues considered include, the eects of systemic injection of CCK on consummatory and operant feeding, the role of the vagus nerve, the eects of CCK A and CCK B receptor antagonists, and the neuro- endocrine responses to exogenous CCK. A critical appraisal of this research indicates that while it is clearly demonstratable that exogenous peripheral CCK can alter food intake by acting on CCK A receptors, the mechanism involved may be more closely related to the induction of aversion and nausea, rather than satiety. With regard to peripheral endogenous CCK, the available evidence also does not seem to support a role for the hormone in satiety. In particular, it is doubtful whether plasma concentrations of CCK fol- lowing a meal are suciently high to inhibit feeding. Moreover, CCK A receptor antagonists which do not cross the blood brain barrier fail to increase meal size, as would be expected if peripheral CCK was an eective satiety factor. In addition, the recent literature concerned with the possibility that CCK may have a direct action within the brain in the con- trol of food intake has been reviewed. These studies show that CCK adminstered intracerebroventicularly, or by micoinjection into discrete brain regions, also inhibits feeding via a CCK A receptor mechanism. However, the physiological rel- evance of these ®ndings have yet to be determined. # 1998 Elsevier Science Ltd. All rights reserved CONTENTS 1. Introduction 478 1.1. General background 478 1.2. Anatomical distribution of CCK 478 1.2.1. Distribution of CCK in the periphery 478 1.2.2. Distribution of CCK within the CNS 479 1.3. CCK receptor subtypes and their anatomical distribution 479 1.4. CCK receptor antagonists 480 2. Is peripheral endogenous CCK a satiety factor? 481 2.1. Development of the CCK-satiety hypothesis 481 2.2. Peripheral exogenous CCK and food intake 481 2.3. Peripheral endogenous CCK and food intake 483 2.3.1. Hormonal action of peripheral CCK and satiety 483 2.3.2. CCK antagonists and food intake 483 2.4. Summary 484 3. Problems with the CCK-satiety hypothesis 484 3.1. Studies with CCK receptor antagonists that do not cross the blood±Brain barrier 484 3.2. Vagotomy and devazepide 485 3.3. Diet and devazepide 486 3.4. Devazepide and food intake in chickens 486 3.5. Summary 486 4. How does peripheral exogenous CCK reduce food intake? 486 4.1. Behavioural experiments that question the speci®city of peripheral exogenous CCK on feeding 486 4.2. Brain Lesions and the eects of CCK on feeding 488 4.3. Neuroendocrine and neurophysiological responses to peripheral exogenous CCK 489 4.3.1. Early studies on hypothalamo/pituitary/adrenocortical (HPA) activation 489 4.3.2. Later studies on HPA activation 489 4.3.3. Neurohypophysial responses to exogenous CCK-8S in higher mammals 491 Progress in Neurobiology Vol. 55, pp. 477 to 507, 1998 # 1998 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0301-0082/98/$19.00 PII: S0301-0082(98)00005-7 } Author for correspondence: e-mail: ivor.ebenezer@port.ac.uk. 477