Journul zyxwvutsrqpo of zyxwvutsrqponmlk Neuroendocrinology, zyxwvutsrqp 1993, Vol. zyxwvuts 5, 697-704 zyxwvutsr Regulation of Cholecystokinin Receptors in the Hypothalamus of the Rat: Reciprocal Changes in Magnocellular Nuclei Induced by Food Deprivation and Dehydration zyx Ross D. O'Shea and Andrew L. Gundlach University of Melbourne Clinical Pharmacology and Therapeutics Unit, Department of Medicine, Austin and Repatriation Hospital, Heidelberg, Victoria 3084, Australia. Key words: cholecystokinin receptor, autoradiography, paraventricular nucleus, supraoptic nucleus, oxytocin. Abstract Cholecystokinin (CCK) has been suggested to mediate satiety in a number of non-primate species via its peripheral actions as well as a possible central mechanism involving magnocellular and parvocellular oxytocin release. Quantitative in vitro autoradio- graphy employing ['251]-B~lton-H~nter labelled CCK-8S ([1251]-CCK-8S) was used to examine the distribution and density of CCK receptors in sections of brain from normal rats and rats deprived of food, water or both food and water for 4 days. In food-deprived rats, specific [lz5I]-CCK-8S binding was reduced by 64+5% in the hypothalamic supraoptic nucleus (SON) and by 44+13% in the paraventricular nucleus of the hypothalamus (PVN). In contrast, water deprivation increased binding of ['251]-CCK-8S by zyx 128i 15% in the SON and by 196f24% in the PVN, while combined food and water deprivation produced smaller increases in both nuclei z (30*5% and 98f26% in SON and PVN respectively). Changes in receptor density in the PVN appeared to be most prominent in the magnocellular (especially oxytocin-rich) subdivisions. None of the treatments employed produced changes in ['251]-CCK-8S binding in the ventromedial hypothalamic nucleus or the reticular thalamic nucleus. Both CCK-A and CCK-B receptor subtypes were visualized in the nucleus of the solitary tract and the area postrema of normal rats, but levels of binding to both of these subtypes were unaffected by the experimental treatments. These selective alterations demonstrate the plasticity of CCK receptors in the SON and PVN, and are probably associated with changes in the level of neurochemical activity of magnocellular oxytocinergic neurones in these areas. These results, together with reports of changes in the level of CCK synthesis in cells of the SON and PVN after hyperosrnotic stimuli, suggest that CCK may act in an autocrine fashion on these neurones and that both CCK receptors and peptide levels are altered in the same direction following cellular activation or inhibition. zyxw Cholecystokinin (CCK) is a 33 amino acid peptide found in both the gastrointestinal tract and the central nervous system (CNS). CCK-like immunoreactivity is widely distributed in the brain, where a number of CCK-related peptides ranging from 4 to 58 amino acids are present (1, 2). The sulphated, carboxy-terminal octapeptide (CCK-8s) is the predominant form present in the CNS (3, 4), and much evidence suggests that it acts as a neurotransmitter or neuromodulator in the regulation of food intake (see ref. 5) and neuroendocrine function (6, 7). CCK has been shown to produce satiety in a number of experimental paradigms, though its precise mode of action remains controversial. While both peripheral (8-10) and central (11-15) effects of CCK on satiety have been demonstrated in the rat, it is likely that some combination of these actions, possibly involving gastric, vagal, brainstem and hypothalamic sites, may be responsible for the physiological effects of this peptide in satiety (5, 10, 16, 17). A role(s) for CCK in the control of neuroendocrine function, via its effects on magnocellular and parvocellular neurones in the hypothalamus, has also been proposed. Immunoreactivity for CCK is co-localized with oxytocin (OT) in magnocellular neur- ones of the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus, neurones which project to the posterior pituitary (18, 19). CCK-like immunoreactivity is also co-localized with vasopressin (AVP) and corticotrophin releasing factor (CRF) in parvocellular PVN neurones (20), which innervate the external median eminence and the dorsal vagal complex in the brainstem (21-25). Systemic CCK has been shown to activate both magno- cellular (OT) and parvocellular (OT and CRF) neurones in the hypothalamus (26, 27), as well as causing pituitary secretion of OT (but not AVP) in rats (28, 29). In addition, CCK has been reported to depolarize PVN and SON neurones in hypothalamic slices and to release OT following central administration (see ref. 6). The increase in pituitary OT secretion in response to a Correspondence to: A. L. Gundlach, Clinical Pharmacology and Therapeutics Unit, University of Melbourne Department of Medicine, Austin Hospital, Heidelberg, Victoria 3084, Australia.