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

Physiology & Behavior, Vol. 32, pp. 403-408. Copyright©PergamonPress Ltd., 1984. Printed in the U.S.A.

0031-9384/84$3.00 + .00

Meal Initiation Controlled by Learned Cues: Effects of Peripheral Cholinergic Blockade and Cholecystokinin H A R V E Y P. W E I N G A R T E N

Departments o f Psychology and Medicine, M c M a s t e r University Hamilton, Ontario, Canada L8S 4K1 R e c e i v e d 2 M a y 1983 WEINGARTEN, H. P. Meal initiation controlled by learned cues: Effects of peripheral cholinergic blockade and cholecystokinin. PHYSIOL BEHAV 32(3) 403-408, 1984.--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. Feeding Meal initiation Cephalic phase

Hunger

Satiety

Energy balance

I D E N T I F I C A T I O N of the physiological signals which control the initiation and cessation of feeding represents a traditional research concern in physiological psychology. With respect to meal initiation, the level of plasma glucose and the rate of glucose utilization have received the most attention. Mayer's [21] glucostatic hypothesis represents the prototype of such theories; it suggests that the rate of glucose utilization (signalled by AAV plasma glucose) is the physiological signal controlling the occurrence of feeding. Contemporary views also tend to focus on glucose, although there is disagreement as to the exact nature of the glucose-related signal and the location of the receptor for glucose utilization (e.g., [11, 19, 20]). The reasons for emphasizing the role of glucose-related variables in meal initiation are compelling. As summarized by Mayer [21], they include consideration that glucose levels are regulated in blood, and that glucose is a major metabolic fuel and the major energy source utilized by brain. Glucose-related variables are further implicated in meal initiation by experimental demonstrations that administration of agents which reduce glucose availability, such as insulin or 2-DG, are followed by feeding [5, 10, 15, 33]. Implicit in the consideration of glucose as a signal for feeding, however, is the idea that feeding and hunger are initiated in response to a state of energy depletion signalled, presumably, by some glucose-related event. Recent analyses indicate, however, that feeding is initiated in response not only to a depletion state but also to factors not necessarily

Atropine

Cholecystokinin

linked to energy depletion. In fact, some analyses argue that social and cognitive factors are as important as (if not dominant over) internal depletion signals in controlling feeding behavior [2, 4, 9, 34]. In recent experiments, the behavioral properties of one cognitive control of meal initiation were identified [38,39]. These studies confirm the work of others [24,35] that exposing animals to external cues which they have learned to associate with feeding reliably leads to initiation of a meal. This control does not depend on the existence of an energy depletion state and it appears to represent one of the normal mechanisms modulating the occurrence of feeding in the rat. Just as one may investigate the physiological underpinnings of feeding in response to a depletion state, one may also study the physiological mediators of feeding motivated by learned external controls. Such an analysis represents the focus of the presently-described experiments. In this study, I evaluate the hypothesis, based on several recent reviews that argue that cephalic phase visceral secretory-motor events play a critical role in meal initiation [3, 12, 26, 32], that cephalic phase events underlie meal initiation controlled by presentation of external stimuli conditioned to food. It is suggested that when associations between particular external stimuli and food are learned, cephalic phase visceral secretions (e.g., insulin, gastric acid secretion) are also brought under stimulus control. Subsequent exposure to these external cues, therefore, results in the following sequence; (1) a conditioned release of anticipatory cephalic

403

404

WI~IN(;ARTEN

Feeding Behaviour

TABLE I CUMULATIVE AMOUNrl OF TIME (IN SECONDS) NOSEPOKING INTO FOOD CUP WHILECS~ IS ON BUT BEFORE FOOD IS DELIVERED, I.E., IN ANTICIPATION OF FEEDING l e s t ('ondition

Mean (n=7) 1 S.E.M. t-value

J Periphery

®

// //

//

Cephalic Visceral Secretions (e.g. gastric acid, insulin) FIG.

1. Schematic representation outlining the way in which

cephalic phase visceral secretions may mediate externallycontrolled feeding. Circled numbers detail the proposed sequence of events.

Saline

AMN ( I mg/kg)

Saline

C('K ( I 1.2/~g/kg)

24.9 6.3

26.7 5.8

21.4 6.1

17.0 4.5

0.94

1.66

ditioned cues. Cholecystokinin (CCK), an intestinal peptide, is one of the leading candidates as a postprandial satiety agent based largely on demonstrations that administration of exogenous CCK reduces food intake [36,37]. In general, CCK has been shown to be effective in reducing meal size in eating motivated by mild or severe food deprivation [14,18]. The present experiment evaluates the responsiveness of meals initiated by presentation of food-conditioned cues in sated rats to CCK. I f C C K represents a critical satiety agent, as has been proposed, then its ability to suppress meal size should be apparent regardless of the procedure used to elicit the meal. To date, CCK has been shown effective in suppressing meal size in rats feeding in response to a depletion state. The present study examines its effectiveness on mealtaking in sated rats when feeding is controlled by a different class of mechanisms, i.e., learning. EXPERIMENT 1

phase peripheral responses is elaborated; (2) the occurrence of these digestion-related secretions is detected by the brain, and; (3) the organism responds to this state by mobilizing feeding. This hypothesis is diagrammed in Fig. 1. The suggestion that a cephalic phase release mediates externally-controlled eating is supported by several lines of evidence. First, at a practical level, the physiological mechanism underlying learned controls of feeding must operate within certain time constraints. Externally-driven intake has a phasic and rapid onset. Such dynamic behavioral adjustments immediately suggest a neural (as opposed to a slower hormonal) mode of action. Second, correlational data examining the relationship between cephalic phase secretions and feeding support the mechanism proposed in Fig. 1. It is known that cephalic responses are elicited in situations where food is expected [23, 29, 42] and that these secretions can be brought under stimulus control [6,39]. Finally, as indicated before, a mechanism of this sort (that the brain initiates feeding in response to cephalic phase release) is implicit in a number of treatments of the role of these physiological responses in the control of food intake [3, 13, 26, 32]. Since the cephalic phase responses most often implicated in the control of feeding (e.g., insulin and gastric acid) are cholinergic [27, 28, 30, 31, 43], the strategy employed here is to use a peripheral cholinergic blocker, atropine methyl nitrate (AMN), to block elaboration of cholinergic cephalic phase responses and thus evaluate their contribution to meal initiation controlled by external cues. This experiment also evaluated the effects of a proposed satiety agent on meals initiated by presentation of con-

METHOD

Subjects were 7 male rats weighing between 400 and 460 g at the beginning of conditioning. F o r the first 11 days of the experiment, a Pavlovian conditioning procedure was used to teach rats an association between an arbitrary external cue, a conditioned stimulus (CS+), and food. Rats were housed individually and received six conditioning trials daily by delivering six equally-sized meals per day preceded by a 41/2 minute C S + . The average intermeal interval was 3.5 hours. The cumulative daily intake from these meals totaled 71)% o f a d lib intake. The CS+ consisted of a buzzer and light presented in combination. The meal was delivered during the last 30 seconds of the C S + . Throughout this study, the diet used was an evaporated milk-based liquid diet fortified with vitamins, minerals, and additional sucrose. Throughout the 11 day conditioning period, rats were injected once daily (IP) with 1.0 ml of 0.9% saline to adapt them to the injection procedure. The injections were given at times randomly selected between the hours of 10:00 a.m. and 5:00 p.m. and were not related in any consistent way with C S + presentations. After the 11 days of conditioning, rats were placed on ad lib feeding, and were maintained ad lib throughout the testing period. To accomplish ad lib feeding rats were provided with a food bottle containing the liquid diet described before available continuously in the home cage. For the first two days ad lib, rats were undisturbed except for the daily IP saline injection. To evaluate the effects of AMN on the feeding response motivated by CS presentation, the CS+ was

A M N , CCK, A N D M E A L I N I T I A T I O N

'2f÷

I0 m

"g=8 o

I0

o Q

I.l.I 1.1.1 IJ. 0

z

6

405 | ~-

~

8

ab

I0

E Z

8-

,,,8 I--IJ.I

W

6-

4

>0

v- 2

Z

p..

:D 0

i

=E4

W

2-

_1

i!i'ii!i

0

<~

bJ

Z

~"4

=E 4 -

Z

v. 6

0

IZ :D 0

SAL AMN

_1

SAL AMN

2

iii

SAL

CCK

SAL

CCK

FIG. 2. A comparison of the effects of saline (SAL---open bars) or 1 mg/kg atropine methyl nitrate (AMN--shaded bars) pretreatments on latency to feed following meal delivery (left panel) and meal size (fight panel). Vertical bars represent 1 standard error of the mean.

FIG. 3. A comparison of the effects of saline (SAL---open bars) or 11.2/~g/kg cholecystokinin (CCK---shaded bars) pretreatments on latency to feed following meal delivery (left panel) and meal size (fight panel). Vertical bars represent 1 standard error of the mean.

delivered once a day and followed by delivery of a 15 ml liquid diet meal into the food cup. Meal size was determined by measuring the amount left in the food cup Fifteen minutes after meal delivery. Thirty minutes prior to C S + onset rats were injected with either AMN (Sigma), 1 mg/kg, or equivolumes of the control substance, 0.9% saline. There were 3 AMN and 3 saline trials. For two consecutive days following the last test day in the AMN sequence, rats were given 1 CS+-elicited meal/day preceded by a 1.0 ml injection of 0.9% saline administered 15 minutes prior to C S + onset. (The time relationship between injection and C S + onset was adjusted to take into account results from previous studies in our laboratory on the time course of C C K ' s effectiveness on feeding.) On the third day, the same protocol was followed (i.e., 1 C S + elicited meal) but animals were injected with an 11.2 t~g/kg dose of the octapeptide of CCK 15 minutes prior to the C S + . As before, meal parameters following CCK or saline injections were compared.

cholinergic cephalic responses in anticipation of feeding did not affect the conditioned meal. Figure 3 and Table 1 summarize the effects of CCK administrations. CCK did not affect variables related to meal initiation. Rats spent similar amounts of time nosepoking into the food cup in anticipation of feeding following CCK and saline, t(6)= 1.66, p>0.05 (see Table 1). Similarly, the latencies to feed following saline and CCK were not significantly different; t(6)=0.25, p>0.05 (see Fig. 3). CCK, however, did influence meal size; animals took significantly smaller meals after CCK administrations compared to saline, t(7)=8.96, p <0.001 (two-tailed). Figure 4 presents the cumulative amount of time rats feed following CCK and saline. CCK inhibited meal size by accelerating the onset of satiety and not by affecting the initial rate of eating. This was determined statistically by correlated t-tests examining differences in cumulative feeding time at each minute of the meal between the two experimental conditions. F o r the initial 4 minutes, rats pretreated with CCK did not feed for significantly less time compared to saline (each t-test for minutes 1-4, p>0.05). By the Fifth minute of eating, the total feeding time of CCK-treated rats was significantly less than that following saline, t(6)=3.14, p<0.02 (two-tailed).

RESULTS As expected from previous studies, C S + presentations reliably led to the initiation of eating of the liquid diet in the food cup. The effects of peripheral cholinergic blockade induced by AMN are summarized in Table 1 and Fig. 2. Correlated t-tests comparing differences between A M N and saline conditions indicated that peripheral cholinergic blockade had no significant effect on any meal-related parameter. In anticipation of feeding, rats nosepoked for similar durations following AMN and saline (Table 1). Similarly, the latency to initiate feeding, t(6)=0.32, p>0.05 and amount eaten in the single conditioned meal, t(6)= 1.84, p>0.05 were not significantly different (Fig. 2). Thus, preventing the elaboration of

EXPERIMENT 2 The conclusion from the previous experiment, that cholinergic cephalic phase responses do not mediate feeding controlled by external cues, depends on the assumption that the dose of AMN administered in that study was sufficient to suppress cholinergic cephalic responses. This assumption is evaluated in the present study by testing the ability of 1 mg/kg AMN to inhibit a prototypic cholinergic cephalic secretion, the cephalic phase of gastric acid secre-

',V t;:1N(iA RTEN

406

200

m

SALINE

•o

180

u ¢D U~

160

uJ 3E P-

140

Z I..-

100

"'

80

tO

IJJ > -I-,¢ "

m

m

120

m

CCK (11.2pglkg)

RESU I . r s

60 40

=E O

sisting of 0.9~;; lw/v) sterile saline (I IP and I SCi. 1o mobilize the cephalic phase of gastric acid secretion, rats were injected (SC) with 0.25 U/kg regular insulin IConnaught Labs) and IP saline. Finally, to assess the effectiveness of AMN to suppress the cephalic response, rats received 0.25 U/kg insulin SC and 1 mg/kg IP AMN. Only one of the aforementioned three test conditions was used on a given test day. Rats were tested 2 or 3 times per week and maintained ad lib on Purina rat pellets between tests. This sequence of test conditions was repeated twice.

20 //

0

7/0

I I I I I I I I I

2

4

6

TIME FOLLOWING

8

10

12

MEAL DELIVERY

(Minutes)

FIG. 4. Cumulative time eating a liquid diet meal following saline or cholecystokinin (CCK) pretreatments. Time zero represents time of meal delivery. Vertical bars represent I standard error of the mean.

tion elicited by insulin. Administration of insulin peripherally (in appropriate doses) is considered to be one of the most potent stimuli for cephalic gastric acid release [7,17]. The dose of insulin chosen to elicit the cephalic gastric acid secretion in this study, 0.25 U/kg body weight, is in the dose range suggested to provide maximal cephalic phase stimulation [ 1,16].

Since basal acid outputs vary considerably among subjects, the acid data of each animal were normalized by assigning the basal acid output (saline IP/saline SC) a value of 100~ and expressing the acid response of the other 2 conditions as a percentage of basal secretion. The group mean acid outputs in the three conditions are shown in Table 2. As expected, insulin mobilized a profound cephalic phase gastric acid response characterized by a dramatically elevated acid hypersecretion maintained for at least two hours. More importantly for the purposes of this experiment, however. I mg/kg AMN completely abolished the insulin-induced acid response. In fact, the dose of AMN used was sufficient to inhibit gastric acid output almost completely for the twohour sampling period. These results demonstrate that I mg/kg AMN is sufficient to prevent elaboration of cephalic cholinergic responses. It is noteworthy that the cephalic response induced by insulin is substantially larger than that motivated by anticipated feeding 140] and, thus, there is no reason to suspect that the anticipatory cephalic responses instigated by presentation of food-associated external cues is any less affected by this dose of AMN. Furthermore, although gastric acid was used as the index of cholinergic cephalic function, the similar" pharmacological properties of cephalic gastric acid and insulin secretion suggest that cephalic insulin output is also completely suppressed by l mg/kg AMN.

METHOD

Subjects were five male Long-Evans rats weighing 377451 g at the time of data collection. A chronically indwelling gastric cannula was implanted into each rat to allow repeated sampling of gastric acid secretion (details of cannula design and implantation surgery are described in [41]). During a 3-week recovery period rats were maintained ad lib on Purina rat chow pellets and water. Rats were food deprived for 17 hours prior to acid sampling. To collect gastric acid, the rat was removed from its home cage, its fistula was opened, and a 15 cm collecting tube was attached to the open cannula. Stomach juice flowed by gravity force through the gastric fistula, down the collecting tube, and drained into a vial force fit onto the end of the Tygon tube. For the period of gastric acid sampling, rats were housed in Plexiglas cages (21 cm long × 10 cm wide × 10 cm high). Two consecutive one-hour samples of gastric secretion were collected on each test day. The hydrochloric acid content of these samples (expressed as/xEq H+/hour) was determined by titration of the sample to pH 7 with a Radiometer Copenhagen automatic titration system using 0.01 N NaOH. Rats received two injections 15 minutes prior to the initiation of acid sampling; one administered intraperitoneally (IP), the other subcutaneously (SC). To obtain an estimate of basal acid output, rats received two control injections con-

G E N E R A L DISCUSSION This experiment was designed to examine physiological properties of meals initiated by sated rats in response to the presentation of food-associated external cues. Two major results were apparent: (1) peripheral cholinergic blockade had no effect on externally-controlled feeding responses, and (2) CCK suppressed the size of the meal motivated by presentation of food conditioned stimuli. The implications of these findings are discussed below. Recently, the role of cephalic phase secretions in normal and abnormal feeding responses has received considerable attention. Several behavioral functions of cephalic phase secretions in relation to feeding have been proposed. Based on an analysis of the parameters affecting the magnitude of cephalic phase release and the temporal association of these responses to feeding, Nicolaidis [26] suggested that these early systemic responses provided a preabsorptive signal capable of controlling meal size. This idea was extended in Powley's "cephalic phase hypothesis" [32] where he argued that an exaggerated level of cephalic phase release was directly responsible for the hyperphagia characteristic of the ventromedial hypothalamic lesion animal. A causal relationship between the amplitude of the cephalic phase responses and feeding has been suggested by others [31. Most recently,

AMN, CCK, A N D M E A L I N I T I A T I O N

407

TABLE 2 NORMALIZED AVERAGEACID OUTPUTS (IN p.Eq H+/HR) Saline IP/satine SC

Saline IP/insulin SC

AMN IP/insulin SC

1st hour

Mean Range

10(FA --

642% 266%- 104(~

1% (F/~4%

2nd hour

Mean Range

10(FA --

406% 131%--659%

2% 0%-8%

Geiselman and Novin [13] argued that a presumed hypoglycemic state induced by cephalic insulin release governs carbohydrate appetite and, specifically, the initiation of carbohydrate meals. The feeding situation employed in these studies provides a ready preparation for testing these suggestions since the occurrence of feeding in response to presentation of foodassociated external cues is so reliable. In essence, this preparation brings meal initiation under stimulus control. The results of the present experiment mitigate against the behavioral roles for anticipatory cephalic responses postulated above. In the model used here, blockade of cholinergic anticipatory visceral secretions failed to affect any element of the feeding response. Specifically, peripheral cholinergic blockade did not reduce the intensity of appetitive responding when food was expected (i.e., anticipatory nosepoking), affect the latency to initiate feeding, or diminished meal sizes. These meal-related parameters were unaffected even though, as demonstrated in Experiment 2, the ability to mobilize the cephalic phase reflexes was markedly suppressed by anticholinergic drug. These results demonstrate that in the feeding situation examined here (i.e., meals initiated by sated rats in response to a food-associated signal) peripheral cholinergic systems are not necessary for meal initiation or instrumental in the control of meal size. Two qualifications to this general conclusion may be made. First, AMN block~ the elaboration of cholinergic cephalic phase events only. Presumably, the cephalic phase of other non-cholinergic digestive responses may contribute to feeding behavior in ways proposed above. It is noteworthy, however, that the cephalic secretions which researchers have stressed as key to meal initiation (especially cephalic insulin) are cholinergic and, as suggested by Experiment 2, were blocked completely by the pharmacological administrations of AMN applied here. Second, while it might be conceded that peripheral cholinergic mechanisms do not contribute to meal initiation in this feeding situation, one could argue a role for these physiological events in other eating situations. This possibility is certainly viable. However, it is important to note, that the behavioral testing situation used here which examines how external events influence feeding, seems ideally tailored to illuminate the contribution of

cephalic phase events to feeding since it is exactly in this aspect of feeding that a behavioral role for these responses has been argued most strenuously. The cephalic phase of digestion has a well-documented physiological function in optimizing the process of digestion [22, 25, 26, 30]. The data presented here indicate, however, that the identification of a behavioral role for these physiological events is still an open question. This study also evaluated the effects of cholecystokinin on feeding in this preparation. As noted before, CCK has been shown to reduce meal size in feeding preparations which use an energy depletion state induced by food deprivation to elicit meal-taking. The present results demonstrate that the satiety action of CCK is also apparent when conditioned stimuli are used to motivate feeding in sated rats. This is consistent with a recent report that CCK reduces meal size in a feeding situation which uses minimal deprivation and where feeding is controlled largely by external food-related stimuli [35]. Furthermore, the stimulus control over the meal permitted by the conditioned feeding preparation used here allows for a demonstration of the specificity of CCK to satiety. In this study CCK had no effect on anticipatory feeding-related behavior or the initial rate of eating. Its effects were manifest exclusively during the terminal portions of the m e a l - - a necessary characteristic of a proposed satiety agent [12]. This latter effect is particularly compelling given that the dose of CCK used here, 11.2 /~g/kg, is a large dose which produces an asymptotic suppression of feeding [8]. It appears, therefore, that CCK contributes to the satiety of externally-controlled meals and this reinforces suggestions that CCK is a physiological satiety factor.

ACKNOWLEDGEMENTS Research was supported by grants from the Canadian Medical Research Council (grant No. MA7799) and Natural Sciences and Engineering Research Council (grant No. A7480). I thank Cecilia Malinski for excellent technical assistance and Dr. M. Ondetti of the Squibb Research Laboratories for the gift of cholecystokinin octapeptide (Batch No. NN012NB).

REFERENCES 1. Baron, J. H., F. I. Izewe, J. Tinker, D. J. Crowley, L. V. Gutierroz and J. Spencer. Dose response of gastric acid to insulin in patients with duodenal ulcer. Gastroenterology 62: 203206, 1972. 2. Bellisle, J. Human feeding behavior. Neurosci Biobehov Rev 3: 163-169, 1979.

3. Berthoud, H. R., D. A. Bereiter, E. R. Trimble, E. G. Siegel and B. Jeanrenaud. Cephalic phase reflex insulin secretion. Diabetoh~gia 20: 221-230, 1981. 4. Booth, D. A. The physiology of appetite. Br Med Bull 37: 135140, 1981.

408 5. Booth, D. A. Modulation of the feeding response to peripheral insulin, 2-deoxyglucose or 3-0-methyl glucose injection. Phy.siol Behav 8: 106%1076, 1972. 6. Booth, D. A. and N. E. Miller. Lateral hypothalamus mediated effects of a food signal on blood glucose concentration. Physiol B(,hav 4: 1003-1009, 1969. 7. Colin-Jones, D. G. and R. L. Himsworth. The secretion of gastric acid in response to a lack of utilizable glucose. J Physiol 2tl2: 97-109, 1969. 8. Collins, S. M., D. Walker, P. Forsyth and L. Belbeck. The effects of proglumide on cholecystokinin-, bombesin-, and glucagon-induced satiety. L(fe Sci 32: 2223-2229, 1983. 9. Davis, J. D. Has a meal trigger been found? Behav Br 5('i 4: 580-581. 1981. 10. Epstein, A. N., S. Nicolaidis and L. Miselis. The glucoprivic control of food intake and the glucostatic theory of feeding behavior. In: Neural lnte~,,ration o f Physiolm,,ical Mechanismx and Behavior. edited by G. J. Mogenson and F. R. Calaresu. Toronto, Ontario: University of Toronto Press, 1975, pp. 148168. I I. Friedman, M. I. and E. M. Stricker. The physiological psychology of hunger: A physiological perspective. Psychol Rev 83: 40%431. 1976. 12. Geary, N. and G. P. Smith. Pancreatic glucagon and postprandial satiety in the rat. Physiol Behav 28: 313-322, 1982. 13. Geiselman, P. J. and D. Novin. The role of carbohydrates in appetite, hunger and obesity. Appetite 3: 203-223, 1982. 14. Gibbs, J., R. C. Young and G. P. Smith. Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245: 323-325, 1973. 15. Gil, K. M. and M. I. Friedman. Caloric compensation following insulin administration in rats. Physiol Behav 29: 847-855, 1982. 16. lsenberg, J. 1., G. F. Stening, S. Ward and M. I. Grossman. Relation of gastric secretory response in man to doses of insulin. (;a.~tro('nterolo~,,y 57: 395-398, 1969. 17. Jogi. P., G. Strom and B. Uvnas. The origin in the CNS of gastric secretory impulses induced by hypoglycemia. Acta Phy~iol S('and 17:212-219, 1949. 18. Kraly, F. S., W. J. Carty, S. Resnick and G. P. Smith. Effect of cholecyslokinin on meal size and intermeal intervals in the sham feeding rat. ,1 ('omp Ph.vsiol Psychol 92: 697-707, 1978. 19. LeMagnen, J. The metabolic basis of dual periodicity of feeding in rats. Behav Br Sci 4: 561-602, 1981. 20. Louis-Sylveslre, J. and J. LeMagnen. A fall in blood glucose level precedes meal onset in free-feeding rats. Neuros('i Bioh(,hav Rev 4: Suppl 1, 13-15, 1980. 21. Mayer, J. Regulation of energy intake and body weight: The glucostalic and lipostalic hypotheses. Am1 N Y Acad S('i 63: 15-43, 1955. 22. Molina, F., T. Thiel, J. A. Deutsch and A. Puerto. Comparison between some digestive processes after eating and gastric loading in rats. Pharnla('ol Biocllem Behav 7: 347-350. 1977. 23. Moore. J. G. and D. Motoki. Gastric secretory and humoral responses to anticipated feeding in five men. GastroenteroloA, y 76: 71-75, 1979. 24. Morgan, M. J. Resistance to satiation. Anita Behav 22: 44%466, 1974.

WEINGARIEN

25. Nicotaidis, S. Early systemic responses to orogastric stimulation in the regulation of food anti water balance: fimctional and electrophysiological data. Atilt N ) A('ad Sci 157: 1176-1203, 1969. 26. Nicolaidis, S. Sensory-neuroendocrine reflexes and lheir anticipatory and optimizing role in metabolism. In: ('h~'mi(al .~'cn~e~ aml Nttlriliol~, edited by M. R, Kare and (). Mallei-. New York: Academic Press, 1977, pp. 123-145. 27. Nilsson, G., J. Simon, R. S. Yalow and S. A. Berson. Plasma gastrin and gastric acid responses to sham feeding and feeding in dogs. (;a.stroeltteroloi O" 6 3 : 5 1 - 5 9 . 1972. 28. Nilsson, G. and K. Uvnas-Wallersten. Effect of teasing, sham feeding and feeding on plasma insulin concentration in dogs. Hornt Metah Re~ 5: 91-97, 1974. 29. Parra-Covarrubias, A., I. Rivera-Rodriguez and A. AlmarazUgalde. Cephalic phase of insulin secretion in obese adolescents, l)iahete,s 20: 800-802, 1971. 30. Pavlov, 1. P. 771e Work q/'the D&e,~tive (;laHd,~. translated by W. H. Thompson. London: Charles Griffith and Co. Ltd., 1910. 31. Porte, D., Jr., P. H. Smith and J. W. Ensinck. Neurohumoral regulation of the pancreatic islet A and B cells. Metaholi,wn 25: 1453-1456, 1976. 32. Powley, T. L. The ventromedial hypothalamic syndrome, satiety, and a cephalic phase hypothesis. P.~ychol Rev 84: 8%126, 1977. 33. Rezek, M. and E. A. Kroeger. Glucose anlimetabolites and hunger. J Nutr 106: 143-157, 1976. 34. Rodin, J. Social and environmental determinants of eating behavior. In: The Body Wei~,,ht Re#ulatory Sy.~tem: Normal and l)i~truhed Me('hanisnt.~, edited by L. A. Cioffi et al. New York: Raven Press. 1981, pp. 323-334. 35. Schallert, T., M. Pendergrass and S. B. Farrar, Cholecystokinin-octapeptide effects on eating elicited by "'external'" versus "internal" cues in rats. Appetite 3: 81-90, 1982. 36. Smith, G. P. and J. Gibbs. Postprandial satiety. In: Pro~,,res,~ bt t~sycllohioh)
39. Weingarten, H. P. Learned controls of meal initiation: Basic behavioral properties: Paper presented at the 54th meeting of the Eastern Psychological Association, Philadelphia, PA, April 1983. 40. Weingarten, H. P. and T. L. Powley. Pavlovian conditioning of the cephalic phase of gastric acid secretion in the rat. Phvsiol Be&iv 27: 217-221, 1981. 41. Weingarten, H. P. and T. L. Powley. A new technique for the analysis of phasic gastric acid responses in the unanesthetized rat. Lab Anita Sci 30: 673-680, 1980. 42. Woods, S. C., J. R. Vaselli, E. Kaestner, G. A. Szakmary, P. Milbum and M. V. Vitiello. Conditioned insulin secretion and meal feeding in rats. J Comp Physiol Psychol 91: 128-133, 1977. 43. Woods, S. C. and D. Porte, Jr. Neural control of the endocrine pancreas. Phv,siol Rev 54: 596-619, 1974.