Paraventricular nucleus lesions abolish the inhibition of feeding induced by systemic cholecystokinin

Peripherally administered cholecystokinin (CCK) initiates a behavioral syndrome which includes reduced food consumption and reduced exploratory behaviors. Previous studies suggest that CCK stimulates receptors in the gut, activating the vagus nerve, which relays sensory information to the nucleus tractus solitarius (NTS) and its ascending pathways. Terminal regions of ascending NTS projections include the paraventricular nucleus of the hypothalamus (PVN), the central nucleus of the amygdala (CNA), and the bed nucleus of the stria terminalis (BNST). Lesions of these three target sites were performed in rats to test the hypothesis that structures postsynaptic to the NTS mediate the behavioral syndrome induced by CCK. Knife cut lesions of the PVN abolished the reductions in feeding induced by CCK (5 and 10 micrograms/kg IP), as compared to sham lesioned control rats. PVN lesions only partially attenuated the reductions in exploration induced by CCK (2.5, 5, and 10 micrograms/kg IP), as compared to sham lesioned control rats. Electrolytic lesions of the CNA partially attenuated the reductions in exploratory behavior induced by CCK (2.5, 5, and 10 micrograms/kg IP), and had no effect on the reductions in feeding induced by CCK (5 and 10 micrograms/kg IP). Electrolytic lesions of the BNST had no effect on either the reductions in feeding or the reductions in exploration induced by CCK. The PVN appears to be one critical forebrain target site for mediating the actions of CCK on feeding. The CNA appears to facilitate the actions of CCK on exploration. Individual components of the behavioral syndrome induced by CCK may be mediated by anatomically distinct forebrain loci.     

Divergent effects of cholecystokinin, bombesin, and lithium on rat exploratory behaviors

Cholecystokinin induces a reduction in exploratory behaviors which could reflect an underlying behavioral state of either satiety or malaise. To investigate these alternative hypotheses, the effects of CCK were compared to the effects of (a) consumption of an extra quantity of palatable food, of (b) bombesin at doses known to inhibit food consumption, and of (c) lithium chloride, at doses known to produce taste aversion. Parameters of exploration of a novel arena surface and investigation of a novel object placed in the center of the arena were analyzed by an automated video-tracking computer-assisted animal behavior monitor. Cholecystokinin reduced all parameters of exploration. Ingestion of at least one gram of chocolate chip cookie also reduced all exploratory parameters. Bombesin reduced only parameters of approach to the novel object and the center of the arena. Lithium chloride reduced only parameters of approach to the novel object and the center of the arena. CCK may influence exploratory behaviors through mechanisms similar to those produced by ingestion of palatable food, but somewhat different from those produced by lithium and bombesin.     

Abrogation of peripheral cholecystokinin-satiety in the capsaicin treated rat

Cholecystokinin (CCK) is a peripheral and central mediator of short-term satiety. When given i.p., CCK decreases food intake in previously fasted rats for a period of 30 min. The effect has been previously shown to be abolished by vagotomy and more specifically by severing of vagal sensory rootlets. These studies were designed to determine the effects on rat feeding behavior, and in particular CCK-satiety, of the sensory neurotoxin capsaicin. In neonates, capsaicin selectively and permanently destroys unmyelinated sensory fibers including those in the vagus nerve. Rat neonates were treated with capsaicin, 50 mg/kg or vehicle, and surviving females studied at 8-10 weeks of age. The weights, 24-h food intake, and feeding responses to insulin were the same in adult capsaicin treated (Cap Rx) and vehicle treated (Veh Rx) rats. CCK (8 micrograms/kg i.p.) reduced 30 min food intake 61 +/- 18% in Veh Rx animals (mean +/- S.D., P less than 0.01). In capsaicin denervated animals, CCK also significantly reduced 30 min food intake from 5.09 +/- 1.10 to 3.92 +/- 0.84 g (P less than 0.01), but the mean reduction, 23 +/- 6%, was significantly less than in Veh Rx rats (P less than 10(-4]. A separate group of females, similarly treated as neonates with capsaicin or vehicle, were subjected to bilateral lesioning of the ventromedial hypothalamus. Both Cap Rx and Veh Rx animals gained significantly and equally more than non-lesioned controls. 24 h vagal transport of substance P was reduced 70% in age matched capsaicin treated animals compared to controls. These studies demonstrate that peripheral CCK-satiety is partly mediated by capsaicin sensitive fibers, presumably in the vagus nerve. Substance P is one possible transmitter mediating this reflex. Further conclusions are that active inhibition of an intact peripheral CCK-stimulated reflex arc is not necessary for full expression of central inducers of feeding, e.g., insulin or lesioning of the ventromedial hypothalamus, and that destruction of these fibers does not alter long-term weight regulation in rats receiving a normal diet.     

The role of central and peripheral cholecystokinin in mediating appetitive behaviors

Cholecystokinin (CCK) reduces total food consumption in mice, rats, pigs, sheep, monkeys and humans. Behaviors associated with an underlying state of satiety are reported after CCK administration. Reductions in exploration and social interactions by CCK are not due to true sedation or sleep, as measured by cortical EEG recordings. The satiety effects appear to be mediated by peripheral CCK receptors, through a feedback loop involving the vagus nerve. The conceptual link between the behavioral functions of CCK as a putative satiety signal and its established digestive functions are discussed.     

Brain-gut axis in pancreatic secretion and appetite control.

The stimulation of exocrine pancreatic secretion that has been attributed by Pavlov exclusively to various reflexes (nervism), was then found that it depend also on numerous enterohormones, especially cholecystokinin (CCK) and secretin, released by duodeno-jejunal mucosa and originally believed to act via an endocrine pathway. Recently, CCK and other enterohormones were found to stimulate the pancreas by excitation of sensory nerves and triggering vago-vagal and entero-pancreatic reflexes. Numerous neurotransmitters and neuropeptides released by enteric nervous system (ENS) of gut and pancreas have been also implicated in the regulation of exocrine pancreas. This article was designed to review the contribution of vagal nerves and entero-hormones, especially CCK and other enterohormones, involved in the control of appetitive behavior such as leptin and ghrelin and pancreatic polypeptide family (peptide YY and neuropeptide Y). Basal secretion shows periodic fluctuations with peals controlled by ENS and by motilin and Ach. Plasma ghrelin, that is considered as hunger hormone, increases under basal conditions, while plasma leptin falls to the lowest level. Postprandial pancreatic secretion, classically divided into cephalic, gastric and intestinal phases, involves predominantly CCK, which under physiological conditions acts almost entirely by activation of vago-vagal reflexes to stimulate the exocrine pancreas, being accompanied by the fall in plasma ghrelin and increase of plasma leptin, reflecting feeding behavior. We conclude that the major role in postprandial pancreatic secretion is played by vagus and gastrin in cephalic and gastric phases and by vagus in conjunction with CCK and secretin in intestinal phase. PP, PYY somatostatin, leptin and ghrelin that affect food intake appear to participate in the feedback control of postprandial pancreatic secretion via hypothalamic centers.     

Behavioral and neurophysiological evidence for a facilatory interaction between co-existing transmitters: cholecystokinin and dopamine

Cholecystokinin (CCK) and dopamine (DA) co-exist in ventral tegmental neurons which project via the mesencephalic pathway to the nucleus accumbens of the rat. CCK and DA are located in separate neurons in the substantia nigra which projects via the nigrostriatal pathway to the caudate nucleus in the rat. The functional significance of this peptide-amine co-localization was investigated using behavioral and neurophysiological techniques. CCK injected directly into the nucleus accumbens potentiated apomorphine-induced stereotypy and dopamine-induced hyperlocomotion. CCK injected directly into the caudate nucleus had no effect on apomorphine-induced stereotypy or dopamine-induced hyperlocomotion CCK injected alone into either site did not induce stereotypy or hyperlocomotion. The dose-response curve to apomorphine induction of stereotypy was shifted to the left by CCK, indicating increased sensitivity to the dopaminergic agonist. Neurophysiological analysis of the firing rate of ventral tegmental neurons demonstrated that CCK produced a left-shift in the dose-response curve of apomorphine on inhibition of neuronal firing. These data suggest that CCK acts as a modulator of dopamine, increasing neuronal responses to dopaminergic agonists. The potentiation of dopamine by CCK may be specific to the mesolimbic neurons, where CCK and DA co-exist in the rat.     

High fat maintenance diet attenuates hindbrain neuronal response to CCK

Rats maintained on a high fat diet reduce their food intake less in response to exogenous cholecystokinin (CCK) than rats maintained on a low fat diet. In addition, inhibition of gastric emptying by CCK is markedly attenuated in rats maintained on a high fat diet. Both inhibition of food intake and gastric emptying by CCK are mediated by sensory fibers in the vagus nerve. These fibers terminate on dorsal hindbrain neurons of the nucleus of the solitary tract and area postrema. To determine whether diet-induced changes in the control of feeding and gastric emptying are accompanied by altered vagal sensory responsiveness, we examined dorsal hindbrain expression of Fos-like immunoreactivity (Fos-li) following intraperitoneal CCK injection of rats maintained on high fat or low fat diets. Following CCK, there were numerous Fos-li nuclei in the area postrema and in the commissural and medial subnuclei of the nucleus of the solitary tract of rats maintained on a low fat diet. However, Fos-li was absent or rare in the brains of rats maintained on a high fat diet. These data suggest that the vagal sensory response to exogenous CCK is reduced in rats maintained on a high fat diet. Our results also are consistent with our previous findings that CCK-induced reduction of food intake and gastric emptying are both attenuated in rats maintained on a high fat diet. In addition our results support the hypothesis that attenuation of CCK-induced inhibition of food intake and gastric emptying may be due to diet-induced diminution of vagal CCK responsiveness.     

Secretion from acinar cells of the exocrine pancreas: role of enteropancreatic reflexes and cholecystokinin

Although the molecular machinery and mechanism of cell secretion in acinar cells of the exocrine pancreas is well documented and clear, only recently has the pharmacophysiology of pancreatic exocrine secretion come to light. Therefore, we focus in this article on the current understanding of the pharmacophysiology of pancreatic exocrine secretion. The pancreatic secretory response to ingestion of a meal is mediated via a complex interplay of neural, humoral and paracrine mediators. A major role in the control of the intestinal phase of pancreatic secretion is attributed to vago-vagal enteropancreatic reflexes. In the scheme of this control mechanism, afferents originating in the duodenal mucosa, and efferents mediating central input on the pancreatic ganglia, activate intrapancreatic postganglionic neurons. Experiments utilizing specific receptor antagonists demonstrate the involvement of both muscarinic M1 and M3 receptors expressed in pancreatic acinar cells. Cholecystokinin (CCK), originally implicated in the humoral secretion of pancreatic enzymes, through a direct action on acinar CCK receptors, is also essential to the enteropancreatic reflex mechanism. CCK stimulation of the exocrine pancreatic secretion through excitation of sensory afferents of the enteropancreatic reflexes, is a paracrine mode of CCK action, and is probably the only one in humans and the predominant one in rats. In dogs, however, CCK acts on the pancreas via both the humoral and a paracrine route. More recent experiments suggest further possible sites of CCK action. Additionally, at the brain stem, vago-vagal enteropancreatic reflexes may be modulated by input from higher brain centres, particularly the hypothalamic-cholinergic system in the tonic stimulation of preganglionic neurons of the dorsal motor nucleus of the vagus projecting into the pancreas.     

Behavioral states in space and time: understanding landscape use by an invasive mammal

Animal movement models can be used to understand species behavior and assist with implementation of management activities. We explored behavioral states of an invasive wild pig (Sus scrofa) population that recently colonized central Michigan, USA, 2014–2018. To quantify environmental factors related to wild pig movement ecology and spatio-temporal landscape use, we predicted wild pig behavioral states relative to land cover type, landscape structure (i.e., edge and patch cohesion), and weather conditions. We used global positioning system (GPS)-collars and monitored 8 wild pigs from 2014–2018. We fit local convex hulls and calculated movement metrics revealing 3 wild pig behavioral states (resting, exploratory, and relocating) and constructed a 3-level model to predict behavioral state probabilities relative to biotic and abiotic conditions. Probabilities of exploratory and resting behaviors were higher nearer to riparian and open herbaceous cover types (oftentimes emergent marsh), indicating that these cover types provided security cover during activity and bedding. Hard mast cover types had a strong positive association with relocating behaviors. More cohesive patches of agriculture and shrub cover types were associated with higher probabilities of exploratory behaviors, while resting was more likely in continuous patches of agriculture (mostly mid-summer corn). The probability of exploratory behaviors increased exponentially with warming ambient temperature. Our results may be used by managers to develop control strategies conducive to landscape and environmental conditions where the likelihood of encountering wild pigs is highest or targeting wild pigs when in a behavioral state most vulnerable to a particular removal technique.     

An introduction to neuronal cholecystokinin.

This issue of Peptides was inspired by a gathering of CCK researchers at the first Neuronal Cholecsytokinin Gordon Conference. The papers in this issue reflect the diversity of CCK research and demonstrate how the field has matured. Reviews describe the regulation of CCK gene expression and CCK release, the nature of the hormone binding site of the CCK A receptor, interaction of CCK, dopamine and GABA, the role of CCK in thermoregulation, sexual behavior and satiety in rodents and humans. The research articles document features of cardiovascular regulation, reduced cocaine sensitization and decreased satiety in rats that lack the CCK A receptor. Pro CCK processing in neuroblastoma cells and the elevation of CCK levels in CSF in a model of chronic pain are detailed in other articles. Three articles using different behavioral paradigms in rat and sheep examine CCK in learning and memory. Two articles that examine CCK in different behaviors that have a dopaminergic component are included. Other articles describe the interaction between a 5HT(3) antagonist and CCK-induced satiety and c-fos activation and document secretion of oxytocin and vasopressin in female patients and controls in response to CCK 4 administration.There is good reason to believe that the future is bright for research on CCK. With the organization of national and international meetings, CCK researchers have a forum for communication. Opportunities for cooperation and collaboration have never been better. The easy integration of academic basic and clinical science with industrial science bodes very well for the advancement of our understanding of the multiple roles that CCK plays in the brain and for the future development of CCK-based therapies.     

Signaling postprandial hyperthermia: a role for cholecystokinin

(1) Gastric stretch caused by intragastric injection of calorie-free suspension of BaSO₄ activates cholecystokinin (CCK)-A receptors on afferent fibers of the abdominal vagus, resulting in the enhancement of metabolic rate and body temperature, similarly as in postprandial states. (2) Intragastric injection of nutrient suspension acts faster, but this action does not involve the vagus nerve. (3) In transmission of BaSO₄-induced abdominal signals, central CCK-B receptor activation plays an important role. (4) Postprandial hypermetabolism and hyperthermia following intragastric injection of calorie-rich nutrient suspension is independent of peripheral or central CCK-ergic mechanisms.     

Boldness behavior and stress physiology in a novel urban environment suggest rapid correlated evolutionary adaptation

Novel or changing environments expose animals to diverse stressors that likely require coordinated hormonal and behavioral adaptations. Predicted adaptations to urban environments include attenuated physiological responses to stressors and bolder exploratory behaviors, but few studies to date have evaluated the impact of urban life on codivergence of these hormonal and behavioral traits in natural systems. Here, we demonstrate rapid adaptive shifts in both stress physiology and correlated boldness behaviors in a songbird, the dark-eyed junco, following its colonization of a novel urban environment. We compared elevation in corticosterone (CORT) in response to handling and flight initiation distances in birds from a recently established urban population in San Diego, California to birds from a nearby wildland population in the species' ancestral montane breeding range. We also measured CORT and exploratory behavior in birds raised from early life in a captive common garden study. We found persistent population differences for both reduced CORT responses and bolder exploratory behavior in birds from the colonist population, as well as significant negative covariation between maximum CORT and exploratory behavior. Although early developmental effects cannot be ruled out, these results suggest contemporary adaptive evolution of correlated hormonal and behavioral traits associated with colonization of an urban habitat.     

Long-term Behavioral Tracking of Freely Swimming Weakly Electric Fish

Long-term behavioral tracking can capture and quantify natural animal behaviors, including those occurring infrequently. Behaviors such as exploration and social interactions can be best studied by observing unrestrained, freely behaving animals. Weakly electric fish (WEF) display readily observable exploratory and social behaviors by emitting electric organ discharge (EOD). Here, we describe three effective techniques to synchronously measure the EOD, body position, and posture of a free-swimming WEF for an extended period of time. First, we describe the construction of an experimental tank inside of an isolation chamber designed to block external sources of sensory stimuli such as light, sound, and vibration. The aquarium was partitioned to accommodate four test specimens, and automated gates remotely control the animals'' access to the central arena. Second, we describe a precise and reliable real-time EOD timing measurement method from freely swimming WEF. Signal distortions caused by the animal''s body movements are corrected by spatial averaging and temporal processing stages. Third, we describe an underwater near-infrared imaging setup to observe unperturbed nocturnal animal behaviors. Infrared light pulses were used to synchronize the timing between the video and the physiological signal over a long recording duration. Our automated tracking software measures the animal''s body position and posture reliably in an aquatic scene. In combination, these techniques enable long term observation of spontaneous behavior of freely swimming weakly electric fish in a reliable and precise manner. We believe our method can be similarly applied to the study of other aquatic animals by relating their physiological signals with exploratory or social behaviors.     

The effect of luminal ghrelin on pancreatic enzyme secretion in the rat

Ghrelin, a 28-amino-acid peptide produced predominantly by oxyntic mucosa has been reported to affect the pancreatic exocrine function but the mechanism of its secretory action is not clear. The effects of intraduodenal (i.d.) infusion of ghrelin on pancreatic amylase outputs under basal conditions and following the stimulation of pancreatic secretion with diversion of pancreato-biliary juice (DPBJ) as well as the role of vagal nerve, sensory fibers and CCK in this process were determined. Ghrelin given into the duodenum of healthy rats at doses of 1.0 or 10.0 microg/kg increased pancreatic amylase outputs under basal conditions or following the stimulation of pancreatic secretion with DPBJ. Bilateral vagotomy as well as capsaicin deactivation of sensory fibers completely abolished all stimulatory effects of luminal ghrelin on pancreatic exocrine function. Pretreatment with lorglumide, a CCK(1) receptor blocker, reversed the stimulation of amylase release produced by intraduodenal application of ghrelin. Intraduodenal ghrelin at doses of 1.0 or 10.0 microg/kg increased plasma concentrations of CCK and ghrelin. In conclusion, ghrelin given into the duodenum stimulates pancreatic enzyme secretion. Activation of vagal reflexes and CCK release as well as central mechanisms could be implicated in the stimulatory effect of luminal ghrelin on the pancreatic exocrine functions.     

Capsaicin-sensitive vagal afferents and CCK in inhibition of gastric motor function induced by intestinal nutrients

The role of vagal afferent pathways and cholecystokinin (CCK) in mediating changes in gastric motor function after a meal was investigated in urethane-anesthetized rats. Proximal gastric motor function was measured manometrically, and nutrients were infused into an isolated segment of duodenum. Inhibition of gastric motility in response to duodenal infusion of protein (peptone or casein), but not carbohydrate (glucose), was significantly attenuated by administration of the CCK antagonist, L364,718. Selective ablation of vagal afferents by perineural treatment with the sensory neurotoxin, capsaicin, significantly reduced responses to both duodenal protein and glucose. These results suggest that protein in the duodenum decreases proximal gastric motor function via release of CCK and a vagal capsaicin-sensitive afferent pathway. In contrast, glucose acts via a capsaicin-sensitive vagal pathway not involving CCK. Thus separate neural and hormonal mechanisms mediate the effects of different nutrients in the duodenal feedback regulation of gastric motor function.     

Mice lacking Asic3 show reduced anxiety‐like behavior on the elevated plus maze and reduced aggression

Sensing external stimulation is crucial for central processing in the brain and subsequent behavioral expression. Although sensory alteration or deprivation may result in behavioral changes, most studies related to the control of behavior have focused on central mechanisms. Here we created a sensory deficit model of mice lacking acid‐sensing ion channel 3 (Asic3^?/?) to probe behavioral alterations. ASIC3 is predominately distributed in the peripheral nervous system. RT‐PCR and immunohistochemistry used to examine the expression of Asic3 in the mouse brain showed near‐background mRNA and protein levels of ASIC3 throughout the whole brain, except for the sensory mesencephalic trigeminal nucleus. Consistent with the expression results, Asic3 knockout had no effect on synaptic plasticity of the hippocampus and the behavioral tasks of motor function, learning and memory. In anxiety behavior tasks, Asic3^?/? mice spent more time in the open arms of an elevated plus maze than did their wild‐type littermates. Asic3^?/? mice also displayed less aggressiveness toward intruders but more stereotypic repetitive behaviors during resident–intruder testing than did wild‐type littermates. Therefore, loss of ASIC3 produced behavioral changes in anxiety and aggression in mice, which suggests that ASIC3‐dependent sensory activities might relate to the central process of emotion modulation.     

Cholecystokinin- and dexfenfluramine-induced anorexia compared using devazepide and c-fos expression in the rat brain

It has been proposed that there might be a link between the anorectic actions of cholecystokinin (CCK) and serotonin (5HT). The present study compared the patterns of c-fos protein-like immunoreactivity (FLI) induced in rat brain by CCK and the indirect 5HT agonist dexfenfluramine (DFEN), as well as the ability for devazepide, a CCK-A receptor antagonist, to antagonize both anorexia and FLI induced by these agents. Devazepide reversed the anorectic effect of CCK but not that of DFEN in food deprived rats. The FLI induced by CCK and DFEN occurred in similar brain regions, but in different subdivisions. Such regions included the bed nucleus of the stria terminalis (BST), the lateral central nucleus of the amygdala (CeL), and the lateral parabrachial nucleus (LPB). Devazepide abolished the FLI induced by CCK most of these brain regions, but had no effect on FLI induced by DFEN. These results suggest that the LPB-CeL/BST pathway might be responsible for the anorectic effects of both CCK and DFEN, but different parts or neuronal populations in these structures might be differentially engaged by CCK and DFEN. The putative interaction between CCK and 5HT might happen along this pathway, rather than in the periphery.     

CCK(2) receptor nullification attenuates lipopolysaccharide-induced sickness behavior

Systemic infection produces a highly regulated set of responses such as fever, anorexia, adipsia, inactivity, and cachexia, collectively referred to as sickness behavior. Although the expression of sickness behavior requires immune-brain communication, the mechanisms by which peripheral cytokines signal the brain are unclear. Several mechanisms have been proposed for neuroimmune communication, including the interaction of cytokines with peripheral nerves. A critical role has been ascribed to the vagus nerve in mediating sickness behavior after intraperitoneally delivered immune activation, and converging evidence suggests that this communication may involve neurochemical intermediaries afferent and/or efferent to this nerve. Mice lacking functional CCK(2/gastrin) receptors (CCK(2)KO) and wild-type (WT) controls were administered LPS (50, 500, or 2,500 microg/kg; serotype 0111:B4; ip). Results indicate a role for CCK(2) receptor activation in the initiation and maintenance of LPS-induced sickness behavior. Compared with WT controls, CCK(2)KO mice were significantly less affected by LPS on measures of body temperature, activity, body weight, and food intake, with the magnitude of effects increasing with increasing LPS dose. Although activation of CCK(2) receptors at the level of the vagus nerve cannot be excluded, a possible role for these receptors in nonvagal routes of immune-brain communication is suggested.     

Lack of interaction between NMDA and cholecystokinin-2 receptor-mediated neurotransmission in the dorsolateral periaqueductal gray in the regulation of rat defensive behaviors

Several neurotransmitters, including GABA, serotonin, glutamate, and cholecystokinin, modulate defensive behaviors in the dorsolateral periaqueductal gray (dlPAG). Although both glutamate and cholecystokinin have been shown to facilitate these behaviors, a possible interaction between them remains to be examined. The present study investigates whether activation or antagonism of N-methyl-D-aspartic acid (NMDA) glutamate and cholecystokinin 2 (CCK(2)) receptors located in the dlPAG would interact in animals tested in the elevated T-maze. The effect of the NMDA (50 pmol) was evaluated in rats pretreated with the CCK(2) receptor antagonist LY225910 (0.05 nmol). In addition, the effect of the CCK(2) receptor agonist CCK-4 (0.08 nmol) was evaluated in rats pretreated with the NMDA receptor antagonist AP-7 (1.0 nmol). Intra-dlPAG injection of NMDA increased risk assessment and inhibitory avoidance behaviors. This NMDA anxiogenic-like effect was unaltered by the pretreatment with LY225910. Similarly, the shortening of escape latencies induced by CCK-4 was unaffected by AP-7. No drug changed the general exploratory activity as assessed in the open-field. These results, showing that the activation of dlPAG NMDA or CCK(2) receptors facilitate anxiety- and fear-related behaviors, further implicate glutamate and cholecystokinin-mediated neurotransmission in this midbrain area on modulation of defensive behaviors. However, the regulatory action of these two excitatory neurotransmitters seems to be exerted through independent mechanisms.     

Estradiol, CCK and satiation.

Estradiol has long been known to inhibit feeding in animals, but the mechanism(s) mediating its effects have not been clear. Demonstrations that estradiol's feeding effects are expressed as decreases in meal size coupled with the emerging consensus that cholecystokinin (CCK) released from the small intestines during meals is a physiological negative-feedback signal controlling meal size (i.e. satiation) suggested a new approach to the problem of the mechanisms of estradiol's inhibitory effect on feeding. Progress on this approach is reviewed here. Experimental manipulations of exogenous and endogenous CCK and estradiol have produced converging evidence that estradiol cyclically increases the activity of the CCK satiation-signaling pathway so that meal size and food intake decrease during the ovulatory or estrus phase of the ovarian cycle. This is a striking example of the modulation of the operation of a control of meal size by the physiological context in which the meal occurs. Estradiol also produces a tonic decrease in meal size, but this apparently does not involve the CCK satiation-signaling pathway. Where and how estradiol acts to increase the potency of the CCK satiating-signaling pathway are not known. Several possible sites are suggested by the observations that estradiol treatment increases feeding- and CCK-induced expression of c-Fos in ovariectomized animals in brain areas including the nucleus tractus solitarius, paraventricular nucleus of the hypothalamus, and central nucleus of the amygdala. Tests with null mutation mice indicate that estrogen receptor-alpha is necessary for estradiol's feeding effects. Finally, the possibilities that estradiol exerts important influences on normal or disordered eating in women are discussed. It is concluded that estradiol exerts a biologically significant action on CCK satiation in animals. Further research to determine whether this action of estradiol has a role in the pathogenesis, course, or treatment of disordered eating in women is indicated.