Conditioned cues elicit feeding in sated rats: a role for learning in meal initiation.

Pavlovian conditioning was used to teach rats an association between an arbitrary external cue and food. Presentation of the conditioned cue elicited feeding by sated animals. The meal constituted approximately 20 percent of daily intake, and it was compensated for by a reduction of subsequent intake.

Cytokines and food intake: the relevance of the immune system to the student of ingestive behavior.

The aims of this paper are to provide a selective review of the literature relating immune system mediators, especially cytokines, to the control of eating and to indicate why this literature is particularly relevant to the student of ingestive behavior. Four reasons are given. Firstly, many immune system mediators influence eating, providing excellent examples of neuroimmunological controls of behaviour. Secondly, the immune system appears to be involved in the profound eating pathology associated with several clinical conditions. Thirdly, cytokines affect both energy intake and energy expenditure. Fourthly, the anorexia typically associated with activation of the immune system provides an informative model for the analysis of gut-brain communication in the control of eating.

Reactivity of normal and VMH-lesion rats to quinine-adulterated foods: negative evidence for negative finickiness.

Much of the evidence for the existence of a negative finickiness component in the ventromedial hypothalamic (VMH) syndrome comes from studies comparing the relative reactivities of VMH and normal rats to quinine adulteration. The present experiments addressed two major questions regarding the response of normal and VMH animals to quinine: (a) Do the anorexic properties of quinine depend on quinine's sensory properties (i.e., its bitter taste) or on its postingestive effects; (b) do VMH rats in fact overrespond to quinine adulteration? These issues were examined by comparing the feeding adjustments to quinine by VMH and normal animals in a sham-feeding situation and under normal feeding circumstances, on animals' initial exposure to this drug. The results were consistent with the view that the sensory properties of quinine alone were sufficient to induce large changes of food intake in both groups. In terms of whether lesion rats were more reactive to the taste of quinine, it is argued that previous research had measured reactivity in two dissimilar ways. The present data were used to illuminate how use of these two procedures for measuring reactivity lead to diametrically opposed conclusions regarding the existence of negative finickiness in the VMH syndrome. It is suggested that when the more appropriate measure of reactivity is adopted and when the confound of body weight differences between normal and VMH animals is eliminated, little evidence exists for a conclusion that VMH rats are more reactive than normals to quinine-adulterated foods.

Inhibition of satiety by a cholecystokinin antagonist is independent of gastric emptying.

The ability of a cholecystokinin antagonist Proglumide to inhibit satiety induced by intraperitoneal injections of cholecystokinin octapeptide (CCK-OP) and bombesin was examined in rats equipped with chronic gastric cannulae. Both CCK-OP and bombesin significantly suppressed sham feeding. Proglumide administered alone did not alter sham feeding but it abolished the suppression of feeding induced by CCK-OP. In contrast, Proglumide did not inhibit the effect of a low dose of bombesin, but partially inhibited satiety induced by a high dose of bombesin, thus confirming our previous findings. These results indicate that the effect of Proglumide is independent of its recently described effects on gastric emptying in rat.

Comparison of the metabolic and behavioral disturbances following paraventricular- and ventromedial-hypothalamic lesions.

Lesions of the ventromedial hypothalamus (VMH) result in an obesity syndrome with several metabolic and behavioral manifestations. It has also been reported that damage to the paraventricular hypothalamus (PVH) leads to changes characteristic of obesity. However, little is known about the consequence of PVH lesions, especially in contrast to the extensive documentation of VMH lesion-induced effects. To assess the basic features of the two hypothalamic obesity syndromes, rats underwent VMH, PVH, or sham lesions and, for 15 weeks, were maintained ad lib on a series of test diets. Both lesions groups were hyperphagic and showed similar weight gains. Although both lesion groups became obese (measured by % carcass fat), VMH rats were fatter than PVH animals. Similarly, only VMH rats were hyperinsulinemic. Further tests were conducted in PVH and VMH rats restricted to control body weights. VMH, but not PVH, rats developed a persisting elevation in basal gastric acid secretion. As well, only VMH, and not PVH, animals developed an obesity when restricted to normal weights. These data indicate similarities in PVH and VMH rats maintained ad lib but experiments on restricted animals reveal fundamental differences in the two obesities and point to different etiologies.

Meal initiation controlled by learned cues: effects of peripheral cholinergic blockade and cholecystokinin.

Sated animals can be induced to initiate meals by exposing them to external stimuli which they have learned, via Pavlovian conditioning, to associate with food. This study examined physiological properties of this control of feeding. The initial hypothesis examined was that conditioned feeding depended on the elaboration of cholinergic cephalic phase responses (e.g., anticipatory insulin secretion). This idea was evaluated by comparing feeding responses to presentation of conditioned cues following an injection of either a peripheral cholinergic blocker, atropine methyl nitrate, or a control substance, physiological saline. Peripheral cholinergic blockade had no effect on the meal initiated by presentation of conditioned cues even though the dose of atropine methyl nitrate used was demonstrated to be sufficient to completely suppress cholinergic cephalic phase responses. These results indicate that cholinergic anticipatory digestive secretions do not contribute to feeding in this preparation. The effects of exogenously administered cholecystokinin on feeding controlled by learned cues were also studied. Cholecystokinin suppressed the size of the meal induced by presentation of conditioned stimuli but did not influence the latency, or initial rate of eating. The implications of these results to a conclusion that cholecystokinin is a satiety factor are discussed.

A comparison of taste reactivity changes induced by ventromedial hypothalamic lesions and stria terminalis transections.

A hyperreactivity to the sensory qualities of a food, i.e., finickiness, is a defining feature of the ventromedial hypothalamic (VMH) lesion syndrome. The precise anatomical locus mediating this disturbance has not been determined. This study examines the hypothesis that interruption of amygdalo-hypothalamic connections (either ascending or descending) via the stria terminalis (ST) is involved in VMH lesion-induced finickiness. Taste reactivity was assessed in animals with VMH lesions, ST knife cuts, combined VMH/ST damage, and controls. In sham feeding tests of taste reactivity, ST and VMH rats were equally hyperreactive compared to controls. Rats with combined VMH and ST damage, however, were more reactive than both these groups. None of the brain lesions resulted in an overreactivity to quinine adulteration of the diet. In contrast to sham feeding, ST rats were not hyperphagic when feeding normally, although VMH rats were. In fact, ST damage attenuated VMH-induced hyperphagia and weight gain. We conclude that the taste reactivity changes induced by VMH lesions and ST transections are independent and additive indicating that VMH finickiness does not involve disruption of amygdalo-hypothalamic connections. Nonetheless, disruption of the ST produces a dramatic change in taste reactivity and the properties and origins of this disturbance are discussed.

Dopamine antagonists act on central, but not peripheral, receptors to inhibit sham and real feeding.

We examined the relative contribution of dopamine (DA) receptors in the brain and periphery in the control of sham and real feeding of sucrose solutions. Intraperitoneal (IP) administration of pimozide, an antagonist of peripheral and brain DA receptors, suppressed both sham and real feeding in a dose-related manner. In contrast, IP injections of domperidone, a DA antagonist restricted to peripheral receptors, had no effect on either sham or real feeding. The inability of domperidone to influence sucrose intake did not result from a lack of biological activity of the drug because the identical doses of domperidone that failed to alter eating significantly inhibited gastric acid secretion. The results implicate central, but not peripheral, DA receptors in the control of the ingestion of palatable foods and also suggest that sham feeding is more sensitive to DA antagonism than real feeding.

Taste-to-postingestive consequence conditioning: is the rise in sham feeding with repeated experience a learning phenomenon?

Although the progressive increase in intake with repeated sham feeding experience is assumed to reflect the extinction of learned satiety, the involvement of associative learning in this phenomenon has never been directly demonstrated. We show that: a) animals attenuate sham feeding on initial exposure only with foods tasting like those they have fed normally before, and b) latent inhibition, which retards the formation of CS-US associations in classical conditioning preparations, prevents the association of a taste with its postingestive consequences. These data suggest both that learning plays a role in the development of sham feeding and that associative linking of a food's taste with its postingestive consequences occurs during ingestion. The present results identify properties of taste-to-postingestive consequence conditioning and indicate how the sham feeding preparation can be used to identify the physiological events mediating this learning.

Facial expressions and genetic sensitivity to 6-n-propylthiouracil predict hedonic response to sweet.

Individuals differ in their hedonic response to sweet: sweet likers show increasing liking with increasing sucrose concentration, while sweet dislikers show increasing dislike with increasing concentration. Our results indicated that naive raters can correctly classify sweet likers and dislikers by observing subjects' facial responses to the taste of sucrose. Also, for both adults and children, the sweet liker/disliker distinction correlated strongly with the genetically determined ability to taste 6-n-propylthiouracil (PROP): PROP nontasters were almost always sweet likers, whereas sweet dislikers were almost always PROP tasters. Sweet dislikers also reported a purer sweet sensation than likers, who perceived nonsweet components in pure sucrose solutions. These results suggest that the sweet liker/disliker distinction is robust and valid, and that sensitivity to PROP may influence preference for sweet by altering the quality of sweet.

Mechanisms of conditioned meal initiation.

Three experiments investigate behavioral and biological mechanisms of meal initiation controlled by learning. Animals were classically conditioned to initiate a meal in response to a conditioned stimulus paired with food. We demonstrate that: a) aversion to the signalled food markedly reduces consumption but has no effect on eating-related behaviors anticipatory to ingestion; b) naloxone reduces the amount eaten but has no impact on food-anticipatory behaviors; c) dopamine antagonism attenuates food-anticipatory behaviors without influencing amount eaten, and d) satiety signals arising from food in the gut reduce both food-anticipatory behaviors and amount eaten. These results demonstrate that anticipatory (appetitive) and consummatory components of meal initiation can be dissociated and are controlled by different biological mechanisms. Cues conditioned to food elicit eating by selectively activating appetitive systems. The implications of the appetitive/consummatory distinction for contemporary theories of meal initiation are discussed.

Flavor-postingestive consequence associations incorporate the behaviorally opposing effects of positive reinforcement and anticipated satiety: implications for interpreting two-bottle tests.

Rats consuming distinctively flavored solutions containing different numbers of calories learn to associate each flavor with the ensuing postingestive effects ("flavor-postingestive consequence learning"). The hallmark of such learning is preferential consumption of one of the flavors in two-bottle tests (both flavors presented in nutrient-identical solutions). Two experiments were conducted to characterize the relationship between the number of calories associated with flavors and subsequent preferences in two-bottle tests. In Experiment 1, three groups of rats each associated distinctive flavors with real-fed sugar and with sham-fed sugar. The groups differed in the concentration of sucrose (8%, 14%, 24%) with which they were trained. In two-bottle tests rats trained with 8% sucrose preferred the real-fed flavor, whereas rats trained with 24% sucrose preferred the sham-fed flavor. Rats trained with 14% sucrose were intermediate to the other groups. In Experiment 2, two groups of rats associated distinctive flavors with two concentrations of real-fed sucrose. In two-bottle tests, the group trained with 1% and 5% sucrose preferred the flavor paired with the higher concentration, whereas the group trained with 5% and 30% sucrose preferred the flavor paired with the lower concentration. These findings suggest that flavor-postingestive consequence learning incorporates both positive reinforcement, which has the behavioral effect of increasing intake of the associated flavor, and anticipated satiety, which has the behavioral effect of suppressing intake of the associated flavor. When a flavor is associated with relatively few calories, the positive reinforcing effect predominates over anticipated satiety. However, when a flavor is associated with a greater number of calories, anticipated satiety predominates over the positive reinforcing effect.

Dissociation of palatability and calorie effects in learned flavor preferences.

Rats acquire a preference for a flavor paired with a caloric solution over a flavor paired with a solution providing fewer or no calories. Because the palatability and the caloric value of the solutions typically covary, it is unclear which property of the high-calorie solution reinforces the flavor preference. Two studies were conducted to assess the independent effects of palatability and calories in flavor preference conditioning. In Experiment 1, rats consumed two distinctively flavored solutions having equal palatability but different caloric value. The flavor paired with ingestion of more calories was subsequently preferred, indicating that a caloric advantage is sufficient to establish a flavor preference (flavor-calorie conditioning). In Experiment 2, rats consumed two distinctively flavored solutions having equal calories but different palatability. The flavor paired with the more palatable solution was subsequently preferred, indicating that a palatability advantage is sufficient to establish a flavor preference (flavor-flavor conditioning). This finding demonstrates flavor-flavor conditioning in the context of postingestive stimulation by calories. Taken together, these results demonstrate both flavor-calorie and flavor-flavor conditioning in the context of normal ingestion (i.e., self-paced oral intake of nutritive solutions).

Fos-like immunoreactivity in vagal and hypoglossal nuclei in different feeding states: a quantitative study.

This study characterized the distribution of Fos-like immunoreactivity (FLI) in three hindbrain nuclei: dorsal motor nucleus of the vagus (DMN), nucleus of the solitary tract (NST) and hypoglossal nucleus (HG) in response to eating or activation of specific components of feeding behavior. The degree of FLI was quantified by automated image analysis software that provided an efficient and sensitive method for counting the number of cells labelled with Fos antibody. Ingestion, and anticipation, of a meal both increased FLI in the DMN and HG, but not in the NST. Sham feeding 1 M sucrose was a more potent stimulus for FLI activation in DMN and NST than combined oral plus gastric/postingestive stimulation provided by real feeding the same food. The results indicate that the physiological stimulus of eating is sufficient to elicit FLI in the hindbrain and that specific components of the feeding act, especially oral stimulation provided by sham feeding, can activate FLI. The results suggest further that, under specific experimental conditions, gastric and/or postgastric stimulation may decrease FLI in the NST and DMN.

Sham feeding as a procedure for assessing the influence of diet palatability on food intake.

Most of the methods used to evaluate the role of taste factors on food intake are confounded by the postingestional consequences of the ingested diet which interfere with measurements of consumption based strictly upon the stimulus properties of the food. The present experiment examines the utility of sham feeding in the gastric fistulated rat as a means of isolating, and thereby evaluating, the contribution of hedonically positive (sweet) and hedonically negative (bitter) taste factors on the magnitude of food intake. Rats equipped with open gastric cannulae sham fed solutions varying in their sucrose or quinine concentrations. The results revealed that the magnitude of sham feeding in a fixed time period varied systematically with the taste properties of the food. It is concluded that sham feeding represents a useful technique for isolating the influence of diet palatability on food intake. Furthermore, the present data identify one of the parameters that influences the magnitude of the sham feeding response, information that is important for studies using this preparation as a means of examining oral sensory controls of food intake control systems.

Hedonic response of sucrose likers and dislikers to other gustatory stimuli.

The majority of individuals can be classified as sweet likers or dislikers based on their hedonic (pleasure) response to sucrose solutions of varying concentrations. Our results indicate that the sweet liker/disliker distinction generalizes to sugars other than sucrose, i.e., glucose and fructose. As well, these individual hedonic response patterns are maintained even when a flavor and color are added to sucrose solutions. However, whether one is a sweet liker or disliker does not predict hedonic response to nonsweet tastes such as salt. These results indicate that the sweet liker/disliker distinction is a robust phenomenon which appears to generalize over, but is restricted to, sweet-tasting substances. The possibility that individual differences in hedonic response may predict preferences for, and intake of, complex tastes characteristic of foods encountered in the real world, is discussed.

Role of oropharyngeal stimulation in cholecystokinin-induced satiety in the sham feeding rat.

The belief that oropharyngeal stimulation potentiates the satiety produced by cholecystokinin (CCK) is based on the demonstration that the ability of 20% pure CCK to suppress feeding is enhanced the closer it is injected to a meal. The increase efficacy of CCK with closer temporal proximity to a meal might simply reflect increased peptide levels at the time of feeding. Further, since oropharyngeal synergy has never been demonstrated with pure CCK, studies were performed to evaluate the role of oropharyngeal stimulation in CCK-induced satiety. Rats equipped with gastric fistulae were injected IP with CCK-8 15 min before a test sham feed. In one condition, rats sham fed for 15 min prior to CCK injection; in the other, they did not. CCK-8 suppressed eating in only those cases when its administration was accompanied by oropharyngeal stimulation. Thus, oropharyngeal cues enhance the satiety action of exogenous CCK. A second experiment examined whether oropharyngeal synergy requires oropharyngeal stimulation prior to peptide delivery. CCK-8 was injected into rats coincident with the initation of a test sham feed. Rats had either sham fed, or not sham fed, for 15 min prior to CCK administration. Both conditions produced similar and significant suppressions of eating during the test sham feed. Thus, oropharyngeal cues enhance the action of CCK and oropharyngeal amplification needs only contiguous pairings of oropharyngeal stimulation and feeding.

Pyloroplasty does not disrupt liquid phase gastric emptying or CCK-induced satiety.

To assess the hypothesis that cholecystokinin (CCK) induces satiety by constricting the pylorus and inhibiting the rate of gastric emptying, we impaired pyloric function in 8 experimental animals using a Heincke-Mikulicz pyloroplasty procedure. Liquid phase gastric emptying was measured with a double-sampling procedure. We found that pyloroplasty did not disrupt the pattern of gastric emptying of saline or nutrient under control conditions. CCK also showed emptying in both pyloroplasty and control animals. Finally, pyloroplasty did not affect the ability of CCK to induce satiety. We provide functional and morphological evidence that the pyloroplasty procedure successfully impaired constriction of the pyloric sphincter. These findings suggest that the pylorus is not critical to the control of liquid phase emptying and, together with the absence of a pyloroplasty effect on CCK-induced satiety, seriously question the adequacy of the pyloric mediation hypothesis.

A procedure for within-trial repeated measurement of gastric emptying in the rat.

A double sampling procedure, developed originally for investigation of liquid phase gastric emptying in humans, is adapted for use in the rat. The double sampling technique permits repeated measurement of gastric volume, allowing a determination of a time course of emptying in a single experimental session. Further, the method allows determination of the amount of gastric secretion, volume emptied into the intestines, and amount of initial gastric load remaining in the stomach. Experiments are presented which: demonstrate the utility of the technique; validate its accuracy in determining gastric volume; indicate the stability of measurements obtained with this procedure; and indicate a procedure for quantitative evaluation of data obtained with this technique. The limitations of the double sampling method are also discussed.

Modulation of behavioral and insulin responses by contextual stimuli paired with food.

A context-like conditioned stimulus (CS) previously paired with a food unconditioned stimulus (US) enhanced both food-related activity and insulin secretion in rats. Experiment 1 documented the effectiveness of an appetitive conditioning procedure in which a 10 sec visual CS ("x") was followed by food when embedded within one 35 sec auditory CS ("A"), but not another ("B"). Approach to a food magazine during x was enhanced (facilitated) when x was within A, as compared to within B or alone. Experiment 2 documented the adequacy of blood sampling and insulin assay procedures that could be accommodated to the conditioning procedure. Plasma insulin was observably different after unconditioned deliveries of glucose solutions of different intensities. In Experiment 3, training as in Experiment 1 was followed by testing for food magazine approach and changes in insulin levels following x alone or in the presence of A or B. It was demonstrated that the A cue enhanced both responses. The results support the view [e.g., (18,19)] that insulin secretion is in part under the control of environmental cues, and findings (22) that show that conditioned context-like cues can modulate consummatory responding to punctate CSs.