Effect of peripheral cholecystokinin receptor agonists on c-Fos expression in brain sites mediating food consumption in rats (original) (raw)
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Brain regions where cholecystokinin suppresses feeding in rats
Brain Research, 2000
The gut-brain peptide, cholecystokinin CCK , inhibits food intake when injected either systemically or within the brain. To determine Ž. whether CCK's effect in the brain is anatomically specific, CCK-8 0.8, 4, 20, 100, 500 pmol was microinjected into one of 14 different brain sites of rats, and its impact on subsequent food intake was measured. CCK-8 at 500 pmol significantly suppressed intake during the Ž first hour post-injection following administration into six hypothalamic sites anterior hypothalamus, dorsomedial hypothalamus, lateral. Ž hypothalamus, paraventricular nucleus, supraoptic nucleus, ventromedial hypothalamus and two hindbrain sites nucleus tractus. Ž solitarius, fourth ventricle. Although lower doses were sometimes effective anterior hypothalamus, dorsomedial hypothalamus, nucleus. tractus solitarius , there appeared to be no significant difference in potency among sites. Injections into the medial amygdala, nucleus accumbens, posterior hypothalamus, dorsal raphe, and ventral tegmental area were either ineffective or produced a delayed response. The higher doses required for most sites, as well as the widespread effectiveness of CCK-8 within the hypothalamus, suggest that spread of Ž. CCK-8 to adjacent brain sites, and or to the periphery, may have been required for anorexia to occur. Findings reported in an Ž. accompanying paper provide strong evidence that paraventricular nucleus injection of CCK-8 500 pmol did not increase plasma CCK-levels sufficiently to suppress feeding by a peripheral mechanism. Together, these results suggest that CCK may be acting as a neurotransmitter or neuromodulator within two different brain regions to produce satiety-one region which includes the nucleus tractus solitarius in the hindbrain, and another more distributed region within the medial-basal hypothalamus.
Vagal mediation of the cholecystokinin satiety effect in rats
Physiology & Behavior, 1982
Central (intracerebroventricular) and peripheral (intraperitoneal) injections of the octapeptide of cholecystokinin (CCK-8) were compared to determine the most effective route of administration to elicit satiety for food intake in the rat. Subdiaphragmatic bilateral vagotomy and spinal cordotomy (T2-T3) were also performed to investigate the importance of visceral nerves for the satiety effect. CCK-8 suppressed feeding and elicited satiety resting behavior when injected peripherally but it was less effective when injected centrally. The satiety effect of CCK-8 or CCK-33 following peripheral injections was blocked by vagotomy whereas spinal cordotomy had no effect. The results indicate that some component of the vagus is required to mediate the peripherally induced cholecystokinin satiety effect, but the splanchnic nerves are not necessary. The weak effect of CCK-8 following ventricular administration is additional evidence suggesting that cholecystokinin of intestinal origin acts in the periphery rather than directly on the brain to elicit its typically Tapid satiety effect in rats. Feeding behavior Satiety behavior Cholecystokinin Vagotomy Ventricular route Intraperitoneal route Spinal cordotomy
Cholecystokinin and satiety: current perspectives
Nutrition, 2000
In the almost 30 years since the ability of peripheral administration of the brain/gut peptide cholecystokinin (CCK) to inhibit food intake was first demonstrated, significant progress in our overall understanding of the role of CCK in ingestive behavior has been made. A physiologic role for endogenous CCK in the control of meal size has been demonstrated and sites and mechanisms of action for CCK in food intake have been investigated. Recent work has uncovered roles for the CCK satiety pathway in the mediation of the feeding modulatory actions of estradiol, insulin, and leptin. The availability of the Otsuka Long Evans Tokushima Fatty (OLETF) rat, a strain lacking CCK A receptors, provides a unique model for the study of how deficits in a within-meals satiety signaling pathway may result in long-term changes in food intake and body weight.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2007
We hypothesized that endogenous CCK reduces food intake by activating the dorsal vagal complex (DVC) and the myenteric neurons of the gut. To test this hypothesis, adult rats were given camostat mesilate; a nonnutrient releaser of endogenous CCK, by orogastric gavage, and Fos-like immunoreactivity (Fos-LI) was quantified in the DVC and the myenteric plexus. The results for endogenous CCK were compared with those for exogenous CCK-8. Exogenous CCK-8 reduced food intake and stimulated Fos-LI in the DVC and in myenteric neurons of the duodenum and jejunum. In comparison, endogenous CCK reduced food intake and increased DVC Fos-LI but did not increase Fos-LI in the myenteric plexus. Similar to CCK-8, devazepide, a specific CCK 1 receptor antagonist, and not L365,260, a specific CCK2 receptor antagonist, attenuated the reduction of food intake by camostat. In addition, Fos-LI in the DVC in response to both exogenous CCK-8 and camostat administration was significantly attenuated by vagotomy, as well as by blocking CCK 1 receptors. These results demonstrate for the first time that reduction of food intake in adult rats by endogenous CCK released by a nonnutrient mechanism requires CCK 1 receptors, the vagus nerve, and activation of the DVC, but not the myenteric plexus.
Two brain cholecystokinin receptors: implications for behavioral actions
Brain Research, 1986
The distribution and relative specificity of cholecystokinin (CCK) receptors in the rat brain was mapped by in vitro autoradiography with [125I]CCK-33. We identified two distinct binding patterns, suggesting two CCK receptor types. The first is widespread and relatively non-specific. The second, localized to a few subcortical nuclei, has the specificity demonstrated for pancreatic CCK receptors. Localization of this receptor type to the area postrema provides a possible entry site into brain for circulating CCK that (1) would distinguish between CCK and gastrin and (2) could mediate some of CCK's behavioral effects.
Normal feeding and body weight in Fischer 344 rats lacking the cholecystokinin-1 receptor gene
Brain Research, 2009
A large body of evidence has demonstrated that one mechanism by which cholecystokinin (CCK) inhibits food intake through activation of CCK1 receptors (CCK1R) on vagal afferent neurons that innervate the gastrointestinal tract and project to the hindbrain. OLETF rats, which carry a spontaneous null mutation of the CCK1R, are hyperphagic, obese, and predisposed to type 2 diabetes. Recently, by introgressing the OLETF-derived, CCK1R-null gene onto a Fischer 344 genetic background, we have been able to generate a CCK1Rdeficient, congenic rat strain, F344.Cck1r −/− , that in contrast to OLETF rats, possesses a lean and normoglycemic phenotype. In the present study, the behavioral and neurobiological phenotype of this rat strain was characterized more fully. As expected, intraperitoneal injections of CCK-8 inhibited intake of chow and Ensure Plus and induced Fos responses in the area postrema and the gelatinosus, commissural and medial subdivisions of the nucleus tractus solitarius of wild-type F344.Cck1r +/+ rats, whereas CCK-8 was without effect on food intake or Fos induction in the F344.Cck1r −/− rats. F344.Cck1r −/− and F344.Cck1r +/+ rats did not differ in body weight and showed comparable weight gain when maintained on Ensure Plus for 2 weeks. Also, no difference was found in 24-h food intake, and dark-phase meal frequency or meal size between F344.Cck1r +/+ and F344.Cck1r −/− rats. As expected, blockade of endogenous CCK action at CCK1R increased food intake and blocked the effects of peripheral CCK-8 in wild-type F344.Cck1r +/+ rats. These results confirm that in rats with a F344 background, CCK-1R mediates CCK-8-induced inhibition of food intake and Fos activation in the hindbrain and demonstrate that selective genetic ablation of CCK1R is not associated with altered meal patterns, hyperphagia, or excessive weight gain on a palatable diet. Published by Elsevier B.V. ava i l a b l e a t w w w. s c i e n c e d i r e c t . c o m w w w. e l s ev i e r. c o m / l o c a t e / b r a i n r e s
Nucleus tractus solitarius lesions block the behavioral actions of cholecystokinin
Peptides, 1983
Nucleus tractus solitarius lesions block the behavioral actions of cholecystokinin. PEPTIDES 4(5) 743-747, 1983.-Cholecystokinin (CCK) has been implicated as a signal for the syndrome of satiety in a variety of species. Several lines of evidence point to a peripheral site of action for the behavioral effects of CCK. Peripheral CCK receptors appear to activate a gut-brain pathway involving the sensory fibers of the vagus nerve. To investigate the central anatomical substrate of this visceral-behavioral control system, the terminal regions of the sensory tract of the vagus were lesioned. Radiofrequency lesions of the nucleus tractus solitarius abolished the effects of acute doses of CCK on exploratory behaviors. Sham lesions had no effect on baseline exploratory behaviors and did not influence the ability of CCK to decrease spontaneous exploratory behaviors. These findings delineate the first central site along the ascending sensory pathway which appears to mediate the satiety-related behavioral effects of CCK. Cholecystokinin (CCK) Satiety Nucleus tractus solitarius lesions
Neuroscience, 2020
Cholecystokinin (CCK) released from the small intestine increases the activity of vagal afferents that relay satiety signals to the caudal nucleus of the solitary tract (cNTS). A caudal subset of A2 noradrenergic neurons within the cNTS that express prolactin-releasing peptide (PrRP) have been proposed to mediate CCK-induced satiety. However, the ability of exogenous CCK to activate cFos expression by PrRP neurons has only been reported in rats and mice after a very high dose (i.e., 50 μg/kg BW) that also activates the hypothalamic-pituitaryadrenal stress axis. The present study examined the ability of a much lower CCK dose (1.0 μg/kg BW, i.p) to activate PrRPpositive neurons in the rat cNTS. We further examined whether maintenance of rats on high fat diet (HFD; 45% kcal from fat) alters CCK-induced activation of PrRP neurons, since HFD blunts the ability of CCK to suppress food intake. Rats maintained on HFD for 7 weeks consumed more kcal and gained more BW compared to rats maintained on Purina chow (13.5% kcal from fat). CCK-treated rats displayed increased numbers of cFos-positive cNTS neurons compared to noninjected and saline-injected controls, with no effect of diet. In chow-fed rats, a significantly larger proportion of PrRP neurons were activated after CCK treatment compared to controls; conversely, CCK did not increase PrRP neuronal activation in HFD-fed rats. Collectively, these results indicate that a relatively low dose of exogenous CCK is sufficient to activate PrRP neurons in chow-fed rats, and that this effect is blunted in rats maintained for several weeks on HFD.