food motivation in hypothalamic hyperphagic rats reexamined

Neuroscience & Biobehavioral Reviews, Vol. 2, pp. 339-355. Printed in the U.S.A.

Food Motivation in Hypothalamic Hyperphagic Rats Reexamined

A N T H O N Y S C L A F A N I

Brooklyn College of the City University of New York, Brooklyn, N Y 11210

(Rece ived 30 May 1978)

SCLAFANI, A. Food motivation in hypothalamic hyperphagic rats reexamined. NEUROSCI. BIOBEHAV. REV. 2(4) 339-355, 1978.--The food motivation of rats made hyperphagic with ventromedial hypothalamic (VMH) knife cuts was examined in bar pressing tests on variable interval (VI) and fixed ratio (FR) schedules. Compared to normal rats, nondeprived VMH rats did not bar press reliably more for food during brief tests on a VI schedule, but did respond significantly more when prefed just prior to VI testing, and when tested on FR schedules. VMH rats also bar pressed more than controls during 24 hr/day tests on a FR-64 schedule. During 24 hr/day tests on a VI schedule, in which they were rewarded with entire meals, VMH rats overate by taking large meals, but they did not bar press more than controls to obtain these meals. When prevented from eating large meals the VMH rats continued to overeat by increasing their meal frequency and total VI responses, but their responses/meal again did not differ from controls. Food-deprived VMH rats did not respond more than did controls during VI or FR tests, although they ate more when food was freely available. The results indicate that under ad lib conditions VMH rats are motivated to eat larger or more frequent meals than do normal rats, although their motivation to initiate any given meal is not elevated, but that under conditions of food deprivation and reduced food accessibility VMH rats are not more motivated to eat than are normal animals.

Hypothalamic hyperphagia VMH knife cuts Feeding motivation Meal patterns Feeding motivation model

FOLLOWING damage to the ventromedial area of the hypothalamus (VMH) rats overeat and rapidly gain weight [6]. The changes in food motivation associated with this hyperphagia and obesity have been extensively studied but still are not well understood. Early studies suggested that VMH-lesioned rats, despite their hyperphagia, have a reduced motivation to eat [18,40]. This conclusion was based on the inferior performance of VMH-lesioned rats in a number of food motivated tasks. More recent studies, however, indicate that VMH-damaged (lesions or knife cuts) rats display normal or even enhanced performance in a variety of food motivated tasks when tested under the appropriate conditions, that is, when they have been pretrained on the task and are not obese at the time of testing [13, 14, 27, 29, 34].

Nevertheless, a detailed analysis of recent reports does not provide a clear picture of the motivational state of hypothalamic hyperphagic rats. A number of studies have reported that the food motivated performance of nonobese VMH rats does not differ from control rats when the animals are food deprived and tested in bar pressing, latency to eat, or straight alley tasks [13, 14, 24, 26, 27, 29, 30, 34]. Yet food deprived VMH rats eat more food in their home cage than do

similarly deprived intact rats [13,32]. In the same behavioral tests minimally deprived or nondeprived VMH rats have been observed in some studies to display enhanced performance [1, 13, 25, 29, 30]. In other studies, however, the food motivated performance of minimally deprived VMH rats did not differ from control animals [26,34]. Thus, although VMH rats readily overeat when palatable food is freely available, they do not consistently display an enhanced motivation to eat, and a satisfactory explanation for this discrepancy is lacking.

The present study attempted to resolve this issue by ex- amining in detail the conditions under which rats in the dynamic phase of the hyperphagia syndrome do and do not display enhanced food rewarded bar pressing behavior. The results revealed that both reinforcement schedule and deprivation level are critical factors determining the bar pressing performance of hyperphagic rats, and a feeding model is presented to describe the motivational state of VMH damaged rats. VMH knife cuts rather than electrolytic lesions were used in this study because knife cuts, although fully effective in producing the hyperphagia syndrome, produce less neural damage and behavioral disruption than do electrolytic lesions [29].

~This research was supported by National Institute of Mental Health Grant MH-21563, and by the Research Foundation of the City University of New York Grants 10103, 11182, and 11802. The preparation of this report was supported by National Institute of Mental Health Research Fellowship MH-07299. The author gratefully acknowldges the assistance of Paul Aravich, Marty Landman, Mark Schachter, Jeffrey Schwartz, and JoAnn Toffs in the collection of the data, and of Kay Collins in the preparation of the manuscript. The author is also grateful to Dr. Carlos Gffjalva and Dr. Donald Novin for their critical reading of an earlier draft of this paper, and to Dr. Donald W. Thomas for access to his unpublished data.

Copyr igh t © 1978 A N K H O In t e rna t iona l Inc.--0149-7634/78/040339-17502.20/0

340 SCLAFAN 1

G E N E R A L METHOD

Animals

Adult female rats of the CFE or CD strain (Charles River Labs, MA) were used. Ninety-six rats were included in this study while additional animals were excluded due to postoperative death or illness, or failure to display hypothalamic hyperphagia. Except where noted, the animals were singly housed in wire mesh cages in a colony room under a 12:12 hr light-dark cycle, and were given unlimited access to Purina Lab Chow and tap water.

Surgery and Histology

Surgery was performed under Equi-Thesin anesthesia (2.5 ml/kg BW) in all experiments except Experiment 3 in which ether was used. Bilateral parasagittal knife cuts through the lateral aspect of the VMH were made in the experimental animals using the encephalotomy technique of Sclafani [29]. Control animals were given sham surgery in which the skull and dura were exposed, but brain left intact. At the end of behavioral testing the position of the knife cuts was histologically verified. In general, the cuts were situated just lateral and rostrolateral to the ventromedial nuclei and extended approximately 3 mm from the anterior to posterior hypothalamus. Further description of this type of knife cut is provided in previous reports [29,34].

Apparatus

Up to 12 operant chambers (BRS/LVE No. 143-22) enclosed in sound attenuation boxes (BRS/LVE No. 132-02) were used. The operant chambers were equipped with two response bars on the right wall which were programmed to deliver either a 45 mg pellet (Noyes standard formula) or 0.1 ml of a sweetened milk diet (Borden's Magnolia milk and water 1:2). Additional test chambers of special design were used in Experiment 3 and are described in the method section of that experiment.

Diet Analysis

T-tests were used to assess the significance of individual comparisons, whereas multiple comparisons were assessed using analysis of variance followed, when appropriate, by Newman-Keuls tests or t-tests.

EXPERIMENT 1

In a recent study Kent and Peters [13] reported that VMH rats bar pressed significantly more on a variable interval 1 rain (VI-I ' ) schedule for food rewards than did controls when tested at 100% and 110% of preoperative weight levels. However , Sclafani anf Kluge [34] and Porter and Allen [26] observed that VMH rats at 100% of their preoperative weight did not respond significantly more on a VI- I ' schedule than did control animals. This discrepancy cannot be explained by the type of food rewards used, all three studies used Noyes pellets and Sclafani and Kluge [34] used a milk diet as well, or by the type of VMH damage employed, Kent and Peters [13] and Porter and Allen [26] used VMH lesions while Sclafani and Kluge [34] used VMH knife cuts. Since Kent and Peters [13] observed the largest difference in response rates at the 110% weight level it is possible that the other investigators would have obtained significant differ-

ences between VMH and control groups had the rats been tested at 110% of their preoperative body weight.

On the other hand, the significance of the elevated VI response rates reported by Kent and Peters [13] is open to question. In order to maintain the 10tY% and 110% body weight levels the rats were given a restricted food ration after each daily test session. The VMH rats apparently consumed their food ration more rapidly than did the control animals (see [13], Experiment 3), and therefore were deprived of food for longer periods prior to daily VI tests, and this difference, rather than the body weight level per se, may have been responsible for the elevated response rates obtained by Kent and Peters [13]. In fact, not all of the control animals in their experiment attained the 110% weight level and the controls were tested "under essentially ad lib feeding condi- t ions" [13]. Sclafani and Kluge [34] tested both VMH and control animals under nondeprived conditions, i.e., ad lib chow in the home cage, and observed that while the VMH rats tended to respond more for a palatable milk diet on a VI- I ' schedule, this effect was not consistently significant. When prefed some milk immediately prior to the VI tests, however, the VMH rats responded reliably more than did the controls. Kent and Peters [13] also observed that prefeeding increased the difference between the VI response rates of the VMH and control groups.

The present experiment further examined the food motivated performance of VMH and control rats on a VI- l ' schedule of reinforcement. The response rates of nondeprived VMH and control rats working for a milk diet were compared since previous research indicates that VMH rats overconsume the milk diet when it is freely available but do not respond reliably more for it on a VI schedule [34,3.5] (see also Experiment 2). The effects of prefeeding on the VI response rate were also systematically examined in both nondeprived rats and rats deprived to 90% of their preoperative weight. Previous findings demonstrate that prefeeding causes nondeprived VMH rats to respond reliably more than controls [34], but whether prefeeding produces a similar effect in deprived VMH rats is not known. Finally, the effect on VI response rates of restricting the daily food intake of VMH rats to control levels was assessed. If the above analysis of Kent and Peters ' [13] results is correct, VMH rats restricted to control intakes should respond significantly more for food rewards during brief VI tests than do control subjects.

METHOD

The 15 rats used in this experiment were deprived to 80% of their ad lib weight and trained to bar press for milk diet during daily 30 min sessions. After seven training sessions in which the animals were reinforced for each bar press response (continuous reinforcement (CRF) schedule), the rats were trained for 3 days on a VI- I ' schedule. On this schedule the animals were rewarded with 0.1 ml milk diet for the first response which occurred 1 rain, on the average, after the last reward. Thus during the 30 rain session the maximum amount of milk the rats could receive was 3 ml (30 rewards) which was considerably less than what they would consume if the milk was freely available during that time (see Experiment 2). Following this initial training the animals were given chow ad lib in their home cage and were tested for six additional sessions on the VI schedule. The rats were then divided into two groups equated for their VI response rates and were given either bilateral VMH knife cuts (n=8)

FOOD MOTIVATION AND HYPOTHALAMIC HYPERPHAGIA 341

TABLE 1

MEAN (_+SEM) PRE AND POST-OPERATIVE FOOD INTAKE, BODY WEIGHT AND VI-I ' RESPONSES OF VMI-I AND CONTROL GROUPS

Food Intake (g) Body Weight (g) VI-I' Responses

N Pre-Op Post-Op Pre-Op Post-Op Pre-Op Post-Op

VMH 8 27.2 46.0 236.0 298.8 205.1 182.3 _+0.6 _+2.1 -+2.4 _+7.9 _+29.7 +_27.2

CON 7 26.8 27.1 237.0 246.0 206.7 133.7 _+0.8 _+1.3 +_4.6 +_4.9 _+28.1 _+7.5

Note: Food intake data represent daily means based on pre-op days 1 and 2, and post-op days 9 and 10. Body weight data are based on pre-op day 1 and post-op day 10. VI responses based on 30 min/day tests conducted on pre-op days 1 to 3 and post-op days 13 to 15.

or sham cuts (n=7). Food remained available ad lib after surgery, except for Day 1, and beginning with postoperative Day 10 the rats were given five daily test sessions (30 rain/day) on the VI- l ' schedule. Six additional tests were conducted in which the rats were prefed, for 3 sessions each, 8 ml and then 12 ml of the milk diet in their home cage l0 min prior to the daily VI test session.

In the second phase of the experiment the animals were food restricted and reduced to approximately 90% of their preoperative body weights. After their weight had stabilized at this level they were tested on the VI-I ' schedule for 5 days without prefeeding, and then for three days each, following a prefeeding of 8, 12 and 16 ml of milk diet. The animals were next tested on a CRF schedule for 3 days (30 min/day) before being returned to the ad lib feeding condition.

In the third phase of the experiment the rats were again tested on the VI schedule while food remained freely available in the home cage. The food intake of all animals was then restricted to 22 g/day, the mean intake of the control group, for the next 10 days. During the first 5 days the food ration was given to the rats in the afternoon at the end of the daily VI test session (PM condition), while during the next 5 days the ration was given to the rats in the morning approximately 5 hr prior to the daily VI test session (AM condition).

RESULTS

As indicated in Table 1, the VI response rates of the VMH and control groups were well matched prior to surgery, as were their daily ad lib food intake and body weight. Follow- ing surgery the bar pressing responses declined in both groups (p <0.02), and although the VMH rats now responded more than did the controls this difference failed to be significant. At the time of the postoperative VI tests the VMH rats were eating considerably more chow (/9<0.01) and weighed more (p<0.01) than did the controls (Table 1).

The results of the first prefeeding tests (ad lib condition) are presented in Fig. 1. Analysis of variance revealed a significant group effect (p<0.02) and prefeeding effect (p<0.01), but not a significant group by prefeeding interaction. That is, the VMH rats responded more than did the controls under all conditions, and both groups showed simi-

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AMOUNT PREFED (ML)

FIG. I. Experiment 1. Mean (+- SEM) VI-l' responses of nondeprived VMH and control groups. The subjects were prefed 0, 8, or

12 ml of milk diet prior to the daily 30 min tests.

lar decreases in their response rates as the amount of prefeeding increased. However, as indicated above, the postoperative response rates of the VMH and control groups did not significantly differ under the no-prefeeding condition. The response rates obtained during the prefeeding tests, on the other hand were reliably different (p <0.01).

Figure 2 summarizes the results of the second prefeeding test (deprived condition). The analysis of variance indicated a significant prefeeding effect (p<0.01), but neither the group effect nor the group by prefeeding interaction were statistically significant. Thus, although the VMH rats responded more than did the controls during the various prefeeding tests these differences were not reliable, and the two groups showed similar decreases in response rates as a function of

342 SCLAFANI

500

4 0 0

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100

0 4 8 12 16

AMOUNT PREFED (ML)

FIG. 2. Experiment 1. Mean (_+ SEM) VI-I' responses of food deprived VMH and control groups tested at 90% of their preoperative body weight. The subjects were prefed 0, 8, 12, or 16 ml of milk diet

prior to the daily 30 min tests.

prefeeding. When tested on the CRF schedule for three days, however, the food deprived VMH rats responded significantly more for the milk diet than did the control rats (266 vs 227 responses/30 min, p<0.05).

The results of the final phase of the experiment are presented in Fig. 3. The VMH rats again failed to respond reliably more than did the controls when tested on the VI schedule with food available ad lib in the home cage. When next given restricted amounts of food (22 g/day) after the daily VI tests (PM condition) the VMH rats responded significantly more (p<0.05) for the milk diet than did the controls. The VMH rats were observed to eat their food ration overnight while the controls usually still had food in their cages the next morning. The food ration was then given in the morning prior to the daily test sessions (AM condition) and under this condition the VMH rats reduced (p<0.05) their VI responding, relative to the PM condition, and although they still responded more than did the controls, the difference was no longer significant. All rats had food in their cages prior to the daily VI tests during the AM condition, but the VMH rats consumed more of their ration during the 5 hr period than did the controls (13.8 vs 5.0 g, p<0.01).

DISCUSSION

The finding of this experiment that non-deprived VMH rats did not respond reliably more on the VI- I ' schedule than did the controls confirms the previous results of Scla- fani and Kluge [34]. As predicted on the basis of the Kent and Peters ' study [13], the VMH rats did bar press significantly more than the controls when daily food intake was restricted to control levels, but this f'mding is confounded by the fact that the VMH rats were without food for longer

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FIG. 3. Experiment 1. Mean (_+ SEM) VI-I' responses of VMH and control groups tested under food ad lib and food restricted conditions. In the restricted PM condition the rats were given the food ration (22 g) in the afternoon following the daily 30 min tests, and in the restricted AM condition the rats were given the food ration in the

morning 5 hr prior to the 30 min tests.

periods prior to the daily test sessions than were the intact rats. In order to prevent this differential deprivation effect the food rations were given in the morning prior to the test sessions and under this condition the VMH rats did not respond reliably more than did the control animals. This finding is also confounded, however, since the VMH rats ate considerably more food prior to the VI tests than did the control rats. Thus, although food restriction can, in some situations, produce elevated VI response rates in VMH rats this effect is difficult to interpret because of the faster eating rate of the VMH rats relative to control animals.

Although the nondeprived VMH rats did not respond reliably more than did the controls for the milk diet, they did so when prefed some milk prior to the VI tests and this rep- licates the earlier findings of Sclafani and Kluge [34]. Pre- feeding, however, did not cause the VMH rats to respond significantly more than controls when they were tested under food deprived conditions. Yet on the CRF schedule the food deprived VMH rats bar pressed more for the milk diet, and presumably ate more, than did the control rats. These findings are discussed further in Experiment 2. The present results also revealed that under both ad lib and food deprived conditions prefeeding produced similar reductions in the VI response rates of the VMH and control subjects. This finding is consistent with the reports that VMH-damaged animals are fully sensitive to the satiating effects of ingested or intubated nutrients [5, 17, 21].


EXPERIMENT 2

In Experiment 1 the VMH rats responded at higher rates for food on the VI - I ' schedule than did the controls, but the ~0 differences were statistically significant in only a limited number of cases. In order to increase the reliability of these findings Experiment 2 repeated the VI tests in additional animals. Of particular interest was the food motivation of the VMH rats food restricted to the 90% preoperative weight '~ level. In the preceding experiment the food deprived VMH ~- rats bar pressed significantly more than did the controls dur- ILl ;~0 ing the CRF test, but failed to do so during the VI prefeeding v tests. The difference in the VI response rates of the VMH and control groups increased, however, as the amount of z milk prefed increased, and it is possible that significant a : differences would have emerged if the rats had been prefed -l- greater quantities of the milk diet. ta 10

z 0 METHOD

The 22 rats used in Experiment 2 previously served in a study on the effects of preoperative weight reduction on the development of hypothalamic hyperphagia [32]. At the end of that study (Day 14 postoperative) the 12 VMH rats re- tained for the present experiment were eating twice as much food as were the 10 control rats (40.2 vs 20.7 g, p<0.01) and weighed considerably more than the controls (372.4 vs 260.5 g, p<0.01). For the present experiment all the subjects were food restricted and maintained at 90% of their preoperative ad lib weight baseline. The rats were offered milk diet in their home cage (1 hr/day) for 6 days and their milk intake was measured to the nearest ml. The animals were then trained to bar press for the milk diet and were tested on a CRF schedule (1 hr/day) for 5 days. The rats were next tested on a VI- I ' schedule (30 rain/day) for 7 days and were then prefed, for 3 sessions each, 12, 16, 20, 24 and 28 ml of milk diet 15 to 30 min prior to the VI test sessions. As described in the results section, the 20 ml prefeeding test was repeated a second time.

At the end of these tests the rats were given chow ad lib in their home cage and one week later VI testing resumed as food remained freely available. The rats were tested for 5 days (30 rain/day) on the VI- I ' schedule without prefeeding, and then, for 3 days each, after being prefed 8 and 12 ml of milk diet 10 min prior to the VI test sessions. Finally, the rats were offered the milk diet in their home cage (30 min/day) for 3 days while lab chow and tap water remained available ad lib except during the 30 min tests.

RESULTS

As illustrated in Fig. 4, when tested at the 90% preoperative weight level the VMH rats consumed 27% more milk (p <0.02) during the 1 hr/day intake test, and bar pressed 33% more (p <0.01) during the CRF test than did the controls. The results of the VI tests (deprived condition) are presented in Fig. 5. The response rates of the VMH rats were slightly below that of the controls during the no-prefeeding test, and slightly above control levels during the prefeeding tests. Analysis of variance confirmed that the prefeeding effect was significant (p<0.001), while the group effect and the group by prefeeding interaction were not. The largest difference, but still not significant, between the VI response rates of the VMH and control groups occurred during the 20 ml prefeeding test and this test was repeated after a new baseline was established. As illustrated in Fig. 5, and con-

INTAKE TEST CR 400

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m

100

CON I VMH

FIG. 4. Experiment 2. Mean (-+ SEM) milk intake and responses of deprived VMH and control groups tested at 90% of their preoperative body weight during separate 1 hr/day consumption and CRF bar

pressing tests.

firmed by analysis of variance, there was no difference between the response rates of the VMH and control groups, and the two groups displayed similar reductions (p <0.001) in their VI response rates following the 20 ml prefeeding.

The second series of VI tests was conducted with chow available ad lib in the home cage and during this time the VMH rats were eating more chow than were the controls (33.0 vs 23.1 g/day, p<0.001). Analysis of the VI response rates, which are presented in Fig. 6, indicated that the group effect (p<0.01), prefeeding effect (p<0.001), and group by prefeeding interaction (p<0.01) were all significant. Indi- vidual comparisons revealed that the VMH rats responded significantly more (,o<0.01) than did the controls during the two prefeeding tests, but not during the no-prefeeding test. Further analysis revealed that, as a result of their reduced response rates the control rats earned less food rewards than did the VMH rats during the 8 ml (21.2 vs 27.6 rewards, p<0.01) and 12 ml (12.7 vs 26.7 rewards, p<0.01) prefeeding tests. When the VI performance of the VMH and control groups was analyzed in terms of responses per reward the two groups did not significantly differ. Finally, in the milk intake test which followed the VI tests the VMH rats consumed almost twice as much milk as did the controls (27.6 vs 14.0 ml/30 min, p<0.001).

DISCUSSION

These results confirm and extend the findings obtained in Experiment 1. Compared to controls, the ad lib fed VMH rats did not bar press more for the milk diet on the VI- I ' schedule (no-prefeeding test), although they did bar press more following a prefeeding and consumed considerably

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FIG. 5. Experiment 2. Mean ( _+ SEM) V I - I ' responses of deprived V M H and control groups tested at 90% of their preoperative body weight. The animals were prefed 0, or 12 to 28 ml of milk diet pr ior to the daily 30 rain tests. Inset: Mean ( _+ SEM) V I - I ' responses of deprived V M H and control groups during the second 0 and 20 ml prefeeding

tests.

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, CON

344 SCLAFAN1

0 I I I I 0 4 8 12

AMOUNT PREFED (ML)

FIG. 6. Experiment 2. Mean (_+ SEM) VI-I' responses of nondeprived VMH and control groups. The animals were prefed 0, 8, or 12

ml of milk diet prior to the daily 30 min tests.

more of the milk diet in their home cage. These findings suggest that when offered the palatable milk diet VMH rats are initially no more motivated to eat the diet than are the controls, as measured by the VI test, but once they have consumed some quantity of milk they are more motivated than are the controls to continue eating. Consistent with this interpretation is the finding that on a CRF schedule nondeprived VMH rats do not initially bar press at faster rates than do controls for milk diet, but respond for a longer period of time [34].

The present results also revealed that food deprived VMH rats maintained at 90% of their preoperative weight consumed more milk diet and bar pressed more for the milk on a CRF schedule than did the similarly deprived controls. When required to bar press for the milk diet on the VI-I ' schedule, however, the response rates of the deprived VMH rats did not differ from that of the controls both in the no- prefeeding as well as the prefeeding tests. This was true even in those tests (24 and 28 ml prefeeding tests) in which the animals were prefed amounts of milk greater than that consumed by the controls during the 1 hr intake test (see Fig. 4). (That the controls continued to bar press after such large prefeeds is consistent with the "resistance to satiation" effect observed in other studies (see [19]). The explanation of this paradoxical result is not readily apparent, although findings from a latter experiment suggest a possible resolution (see Experiment 6).

The results obtained in Experiments 1 and 2 were very similar except that in the ad lib VI tests of the present experiment prefeeding produced less of a response suppression in the VMH rats than in the controls, whereas in the first experiment the effects of prefeeding were similar in the VMH and


control groups. However , a direct comparison between the VI results obtained in the two experiments revealed that while the rats in Experiment 2 responded at higher rates than the rats in Experiment 1, the two VMH groups displayed similar reductions in VI response rates when prefed 8 and 12 ml of milk diet. Furthermore, in the VI tests conducted under the food deprived condition the prefeeding effects in the two VMH groups, relative to the control groups, were very similar. Thus, the differences between the two experiments may be more apparent than real, although whether or not nondeprived VMH rats are less responsive to prefeeding than are control animals remains an unresolved question.

EXPERIMENT 3

In both Experiments 1 and 2 ad lib fed VMH rats failed to bar press reliably more than did control animals for milk diet on the VI- I ' schedule. Yet, the VMH rats consumed considerably more of the milk when it was offered in the home cage, and bar pressed more for it than did controls when prefed some milk prior to the VI tests. Previous work further demonstrates that VMH knife cut rats overeat when maintained on the milk diet used in the present study, and they do so by more than doubling their meal size [33].

The failure of the VMH rats to display enhanced food motivated performance in the VI (no-prefeeding) tests may be related to the fact that they were hyperphagic on the chow diet which was available ad lib in the home cage. That is, since the VMH rats were eating more chow than were the controls it is probable that they had more recently eaten prior to the daily VI tests than had the controls. This is especially likely since the tests were conducted during the light phase of the light-dark cycle, and it is known that VMH-damaged rats do not restrict their feeding to the dark phase as do intact animals (e.g., [12,33]).

In order to eliminate the possibility that their home cage food intake might influence their bar pressing for milk diet the animals in the present experiment were tested in operant chambers 24 hr/day and were required to bar press for all their food on a VI schedule. Since the prefeeding results of the preceding experients indicate that VMH rats respond more than do controls once they have consumed some milk diet, the present experiment focused on their motivation to initiate their meals, rather than on their motivation to continue their meals once they had begun. This was accom- plished by rewarding the animals with unlimited amounts of milk diet, that is, an entire meal, rather than with small rewards as used in Experiments 1 and 2.

An alternative explanation for the VI results obtained in the first two experiments is that VMH damage specifically impairs the neural system responsible for the cessation of meals and does not affect the system controlling meal initiation. This possibility was tested in Experiment 3 by examin- ing the food intake and VI performance of VMH rats prevented from eating larger than normal meals.

METHOD

Apparatus

In addition to the standard operant chambers described in the General Method section, four specially constructed test chambers were used in Experiment 3. The chambers con- sisted of a wire mesh rodent cage (7x7×9 in.) with a remov- able clear Plexiglas top. On the right wall of the cage was a

0.75 in dia. hole through which the rat could lick a stainless steel spout connected to a bottle containing the sweetened milk diet used in Experiments 1 and 2. The milk bottle was mounted on a cam-operated sliding device such that the milk spout was ordinarily out of reach to the rat. A response bar was located on the right side wall adjacent to the milk spout access hole, and depression of the bar allowed the rat to operate the sliding device and bring the milk spout in reach. The bar itself was retractable (BRS/LVE 123-05) but was kept in the cage in the present experiment. Licking at the milk spout was monitored with an electronic drinkometer circuit (BRS/LVE DR-901) and the number of licks and bar press responses were recorded on printout counters and a 20-channel event recorder. Water was continuously available to the rat from a water bottle mounted on the front wall of the cage. The test chambers were enclosed in sound attenuation boxes and were maintained on the same 12:12 light-dark cycle and ambient temperature as the animal colony room.

Procedure

The 8 rats used were food deprived to 80% of their ad lib body weight and were trained to bar press for milk rewards (0.1 ml) on CRF, VI - I ' , and VI-4' schedules in the standard operant chambers. The animals were then given ad lib food for at least 1 week before they were housed in the specially-constructed test chambers and required to bar press for all their food (24 hr/day) on a modified VI-4' schedule. The rat 's first bar press response started the VI timer and the first response within 30 sec after the variable interval (range: 2 to 6 min) elapsed activated the sliding device and brought the milk spout in reach of the rat. The milk diet remained available to the rat as long as the animal continued to drink, but after the rat stopped drinking for 10 min, which defined the end of the meal, the milk bottle was automatically retracted. If the rat failed to respond during the 30 sec limited-hold period which followed the variable interval then its next response restarted the VI timer. The limited hold period prevented the rat from gaining access to the milk spout by emitting only occasional responses during the 24 hr period. In this manner the rats were required to bar press for all their meals. In addition to measuring daily milk intake and body weight in g, printout counters recorded the number of responses emitted to obtain each meal, the time interval over which they were emitted, the size of the meal, and the duration of the meal and intermeal intervals.

The rats were maintained in the test chambers on the VI-4' schedule for at least 10 days before surgery. They all quickly adapted to the schedule and gained weight during this time. VMH knife cuts were then produced in 4 rats under ether anesthesia, while the remaining 4 rats served as sham operated controls. Immediately after surgery the rats were returned to the test chambers and were tested under the conditions described above for 4 days. In the next 4 day period the meal sizes of the VMH rats were limited to preoperative levels by automatically retracting the milk tube after the appropriate number of licks had been emitted in each meal. The VMH rats were then allowed in the final four day period to again eat unrestricted meals as in the first postoperative period.

RESULTS

As indicated in Table 2, prior to surgery the VMH group

346 S C L A F A N 1

TABLE 2 MEAN (-+SEM) PREOPERATIVE BASELINE BODY WEIGHT, FOOD INTAKE, MEAL SIZE, MEAL

NUMBER, AND BAR PRESS RESPONSES OF VMH AND CONTROL GROUPS

Body Total Meal Meal Total Responses N Weight (g) Intake (g) Size (g) Number Responses Per Meal

VMH 4 253.0 58.3 5.85 10.3 429.4 39.8 ±9.3 ±1.1 ±0.53 _±1.0 ±141.6 ±11.7

CON 4 282.0 69.5 7.29 9.8 329.1 31.1 ±12.6 ±3.3 ±0.99 ___1.6 -+130.4 ±12.9

ate slightly less milk per day and per meal, and weighed less than did the controls, but they bar pressed slightly more for the milk diet per day and per meal than did the controls. Because of these differences the postoperative results are expressed in Fig. 7 as percentages of the preoperative val- ues.

In the first 4 days following surgery (Post-op 1) the VMH rats increased (p<0.01) their food intake by 76% by increasing (p<0.05) their meal size by 81% while their meal frequency remained unchanged (Fig. 7). The control rats, on the other hand, showed only small changes in their food intake and meal pattern, and ate considerably less than did the VMH animals (62.4 vs 102.8 g/day, p<0.01). The mean VI response rates of the VMH rats, both total responses per day and responses per meal, also increased following surgery, but these increases failed to be significant: two rats increased their responses, while two rats decreased them. Compared to the control group, which displayed small increases in their VI response rates, the changes in the response rates of the VMH rats were not statistically reliable.

In the second four-day period (Post-op 2), when the meal sizes of the VMH rats were restricted to preoperative levels, the VMH rats continued to overeat (107 g/day) by increasing their meal frequency by 80%. Since they had to bar press to obtain each meal the total responses per day of the VMH rats also increased, and compared to controls, the VMH rats were eating more meals (p<0.05), and bar pressing more (p<0.01) per day. As indicated in Fig. 7, however, while the VMH rats increased their total bar press responses, their responses per meal did not change, and did not differ reliably from that of the control group.

It should be noted that although the milk spout was retracted after the VMH rats consumed a normal size meal the rats were free to immediately bar press and return the milk spout. Initially the VMH rats often did return the milk spout soon after it was retracted, but eventually they only in- frequently did so. The meal pattern data for the Post-op 2 period were analyzed using a 20 min intermeal criterion so that if the VMH rats returned the milk spout within 20 min after it had been retracted this was not counted as a second meal, but a continuation of the previous meal.

When allowed to eat unrestricted meals again in the Post-op 3 period the VMH rats increased their meal size and decreased their meal frequency, relative to the preceding period (Post-op 2), although not completely to the levels displayed during the first post-operative period. The VMH rats also decreased their bar press responses per day, but again there was no change in their responses per meal. Com- pared to the controls, the VMH rats ate significantly more food per day (/9<0.01) and per meal (p<0.05) during the third

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FIG. 7. Experiment 3. Mean (± SEM) percent change from preoperative baseline in total intake (milk diet/day), mean meal size, mean meal number, total responses (VI-4' bar press responses/day), and responses per meal (VI-4' bar press responses/meal) of VMH and control groups. In Post-op 1 and 3 the VMH rats were allowed to eat meals of unlimited size, in Post-op 2 they were limited to meals no larger than their mean preoperative meal size. Data represent

means for the 4-day postoperative periods.

postoperative period, while their meal frequency and VI response rates (per day and per meal) did not reliably differ from that of the controls.

DISCUSSION

The results of this experiment confirm many previous findings that VMH-damaged rats overeat by greatly increas-


ing their meal size rather than their meal f requency (e.g., [33,41]). But despite the fact that they eat much larger meals the present findings indicate that VMH rats do not press reliably more on a VI schedule (per meal) than do normal animals to obtain their meals. Although based on a small number of animals these results are fully consistent with the findings of the first two experiments. The present results are also compatible with data obtained by Thomas (unpublished findings). Thomas also examined the VI performance of VMH and control rats in a 24 hr test, although in his experiment the rats were rewarded with small amounts (0.3 ml) of a liquid diet rather than with an entire meal. The VMH lesioned rats bar pressed significantly more than did the controls on the VI- I ' schedule and earned more than twice as many food rewards, but their response rate, expressed as the number of responses emitted per reward, which is similar to the responses per meal measure used here, was nearly identical to that of the control animals.

A second major finding of Experiment 3 is that while VMH rats overeat by taking very large meals they will continue to be hyperphagic when limited to normal-size meals by increasing their meal frequency. Thomas and Mayer [42], using a different testing procedure, have recently reported similar results in VMH-lesioned rats. In the present experiment the VMH rats increased their meal frequency even though they had to bar press to obtain each meal, and therefore, they can be considered to have been motivated to increase their meal frequency. Nevertheless, their motivation to initiate any given meal, as measured by their responses per meal, did not reliably differ from that of the control animals.

The normal meal size (6 to 7 g/meal) referred to above is actually larger than that consumed by intact rats when the milk diet is freely available (approximately 3 g/meal, [33]). Collier, Hirsch and Hamlin [7] have previously demonstrated that requiring rats to bar press for all their meals on a FR schedule increases their meal size and decreases their meal frequency, and the present results extend this effect to include VI schedules. The elevated meal sizes produced by the VI schedule explains why the VMH rats displayed only an 80% increase in the size of their meals in the present study, but a 160% increase in a previous experiment in which the milk diet was freely available [33].

The results of this experiment demonstrate that even when home cage food intake is not a confounding factor (as in Experiments I and 2) VMH rats do not bar press reliably more on a VI schedule than do controls to obtain palatable food rewards. The present results also argue against the hypothesis that VMH damage affects only a meal termination system, since the VMH rats readily overate by increasing their meal frequency when prevented from eating larger than normal meals. Taken together, the results of the first three experiments suggest that VMH rats are motivated to overeat, but at the time they begin a meal their motivation does not differ from that of normal animals.

E X P E R I M E N T 4

In Experiment 4 and the following two experiments the food motivated bar pressing performance of VMH and control rats was compared using fixed ratio (FR) schedules of reinforcement. This was of interest because FR schedules, unlike the VI schedules used in Experiments 1 and 2, do not restrict the VMH and control subjects to the same fixed

amount of food during brief test sessions. If, as suggested above, VMH rats are motivated to eat more than controls, then they should bar press more for food than do controls on FR schedules.

Peters et al. [25] have, in fact, reported that VMH- lesioned rats bar pressed at elevated rates on a FR-64 schedule when tested at 100% and 110% of their preoperative weight. Sclafani and Kluge [34], however, failed to obtain significantly elevated response rates on an FR-32 schedule in VMH knife cut rats tested at 100% of preoperative body weight. Furthermore, as in the case of the VI results discussed in Experiment 1, the interpretation of the FR response differences reported by Peters et al. [25] is open to question. That is, the VMH rats may have bar pressed more than did the controls because they were food deprived for longer periods prior to the daily FR tests. A similar criticism can be raised concerning the findings of Beatty [1] that VMH-lesioned rats pair-fed to intact animals bar pressed significantly more than did the intact controls for sucrose rewards on FR schedules 1 to 64. In the present experiment, therefore, the FR performance of VMH and control rats was compared both under food ad lib and food restricted conditions.

METHOD

The animals were food deprived to 80% of their ad lib body weight and were trained to bar press for 0.1 ml milk diet rewards. They were then allowed to recover their ad lib body weight and were tested for 5 daily 30-min sessions on a CRF schedule for the milk diet while chow remained available in the home cage. The rats were divided into two groups and received either VMH knife cuts (n=7) or sham surgery (n=9). Beginning with the sixth postoperative day the rats were returned to the operant chambers and tested for 3 days (30 min/day) on the CRF (or FR-1) schedule, followed by 3 days each on FR schedules 4, 8, 16 and 32 while food remained freely available in the home cage. Starting with postoperative Day 16 the rats were all restricted to 22 g of food per day, which represented the mean intake of the control group, and they were tested for 2 days each on the FR schedules 1 to 32. The food ration was given to the animals immediately after the daily bar pressing test sessions.

RESULTS

Prior to surgery the ad lib baseline response rate of the VMH group on the CRF schedule was slightly less than that of the control group, while the baseline food intake and body weight of the two groups were very similar (Table 3). Follow- ing surgery the VMH rats doubled their daily food intake and rapidly gained weight while the control animals showed little change in their food intake and body weight. As indicated in Table 3 the VMH rats also significantly (p<0.01) increased their bar pressing for the milk diet following surgery, and their response rate was significantly above that of the control group (p <0.01).

Figure 8 summarizes the results of the first FR test series in which the animals were tested under nondeprived conditions. The VMH rats responded more than did the controls on all FR schedules, and the two groups displayed similar changes in their response rates as a function of the FR schedule. Analysis of variance confirmed that the group effect (p<0.02) and schedule effect (p<0.01) were significant, while the group by schedule interaction was not.

348 SCLAFAN 1

TABLE 3

MEAN (_+SEM) PRE- AND POST-OPERATIVE FOOD INTAKE, BODY WElGHT AND CRF RESPONSES OF VMH AND CONTROL GROUPS

Food Intake (g) Body Weight (g) CRF Responses

N Pre-Op Post-OP Pre-Op Post-Op Pre-Op Post-Op

VMH 7 20.2 41.7 249.9 305.7 97.4 175.6 _+0.5 _+0.8 _+4.7 _+9.1 _+9.9 _+12.0

CON 9 19.7 21.8 248.0 245.9 115.4 99.4 _+0.6 _+0.8 -+5.1 _+4.8 _+15.0 _+11.3

Note: Food intake data represent daily means based on pre-op days 1 and 2, and post-op days 5 and 6. Body weight data are based on pre-op day 1 and post-op day 6. CRF responses are based on 30 rain/day tests conducted on pre-op days 1 and 2, and post-op days 7 and 8.

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FIG. 8. Experiment 4. Mean (+ SEM) responses of nondeprived VMH and control groups during daily 30 min tests on FR schedules

1 to 32.

For the second FR test series all animals were restricted to 22 g of food per day and it was observed that the VMH rats were always out of food prior to the FR test sessions, while the control rats often still had food left in their cage. The results of the FR tests are presented in Fig. 9 and analysis of these data revealed a significant group effect (p<0.02), schedule effect (p<0.01), and group by schedule interaction (,o<0.05). That is, the VMH rats responded more than did the controls on all FR schedules, and their response rate increased more than that of the controls as the FR schedule became more demanding. A comparison of the first and second FR series indicated that both groups increased (p<0.01) their rate of responding in the second series, and the increase was significantly greater (,o<0.05) for the VMH group than for the control group.

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FIG. 9. Experiment 4. Mean (_+ SEM) responses of food restricted VMH and control groups during daily 30 min tests on FR schedules

1 to 32.

DISCUSSION

The results of this experiment demonstrate that VMH rats bar press significantly more for food than do intact animals when nondeprived and tested on FR schedules. Even greater group differences in FR response rates are obtained when the VMH rats are pair-fed to controls but this effect is due, at least in part, to the VMH rats being food deprived for longer periods prior to testing than are control animals. Thus, while confirming previous studies which have used food restriction procedures [ 1,25], the present results demonstrate that food restriction is not necessary in order to obtain enhanced FR performance in VMH rats, and since this procedure produces differential deprivation in VMH and control animals it should be avoided.


The present findings of elevated bar pressing rates in nondeprived, non-prefed VMH rats contrasts with the failure of the VMH rats in Experiments 1 and 2 to bar press at significantly elevated rates on the VI- I ' schedule when tested under similar conditions. The VI test can be considered to be a measure of the animal 's motivation at the beginning of a meal, since only a small and fixed amount of food is provided during the test session, while the FR test can be considered to be a measure of how much food the animal is motivated to eat in the meal, since the amount of food the animal receives is determined by its response rate. The FR results, therefore, confirm the view that VMH rats are motivated to overeat , at least under ad lib conditions, and do not argue against the proposal that their motivation at the time of meal initiation does not differ from that of normal rats.

EXPERIMENT 5

Experiment 4 revealed that nondeprived VMH rats bar press reliably more than do controls for palatable milk rewards when tested on FR schedules during daily 30 min tests. In the course of another experiment, however, it was discovered that this result is not always obtained. Because of the relevance to the present study these data are reported here.

METHOD

Twenty rats were maintained at 85% of their ad lib body weight and were trained (30 min/day) to bar press for 0.1 ml milk rewards first on a CRF schedule, and then, for 10 days, on a FR-8 schedule. The rats were then given food ad lib in their home cage and were tested for an additional 6 days on the FR-8 schedule prior to surgery, at which time they received either VMH knife cuts (n=10) or sham surgery (n=10). On postoperative Days 6-10 the animals were returned to the operant chambers and were tested on the FR-8 schedule during 30 min sessions, while on postoperat ive Days 11-15 1 hr daily sessions were used.

RESULTS

As illustrated in Fig. 10, prior to surgery the VMH group responded more, but not significantly so, than did the control group during the 30 min FR-8 tests. Following surgery the VMH rats decreased their bar pressing somewhat (p>0.05), and now bar pressed only slightly more than did the control animals. When the test session was extended to 1 hr/day, however, the FR-8 response rate of the VMH rats was significantly higher (p<0.05) than that of the control animals.

Before surgery the food intake baselines of the VMH and control groups were similar (22.3 vs 23.3 g/day) as were their body weights (280.5 vs 274.6 g). By the beginning of the postoperative FR tests (Day 6) the VMH rats were eating considerably more food (42.3 vs 25.8 g, p<0.01), and had gained significantly more weight (73.0 vs 5.5 g, p<0.01) compared to the control animals.

DISCUSSION

In contrast to Experiment 4 in which the VMH rats bar pressed 71% more than did the controls on the FR-8 schedule, in the present experiment they responded only 7% more during the 30 min test sessions. The major difference between the two experiments is that in the present one the

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PRE-OP POST-OP I POST-OP 2

CON ~ VMH

FIG. 10. Experiment 5. Mean (-+ SEM) responses of nondeprived VMH and control groups tested on FR-8 schedule during daily 30

min or 1 hr tests.

rats were trained on the FR-8 schedule prior to surgery whereas in Experiment 4 they were not. Presumably as a result of this pretraining the FR-8 response rates observed in the present experiment exceeded those obtained in Experi- ment 4 (compare Figs. 8 and 10). Thus the failure of the VMH rats in this experiment to bar press more than the controls during the 30 rain sessions may have occurred because, prior to surgery, both the VMH and control groups were responding at steady, and perhaps optimal, rates on the FR-8 schedule. The results of the first three experiments indicate that VMH damage does not increase the rat ' s rate of responding for food, but rather increases the duration over which the rat will continue to respond. As indicated by the data from the 1 hr FR test, the 30 min sessions were not sufficiently long, under the conditions of the present experiment, to reveal this effect of VMH damage.

Several previous studies have also found that preoperative training on partial reinforcement schedules facilitates postoperative performance [2, 14, 26, 38]. However , in these experiments, in which the animals were tested under food deprived conditions, the VMH-damaged rats were the most affected by the pretraining experience, while in the present study it was the control rats that benefited the most from pretraining. The control group in this experiment bar pressed 129% more (p<0.01) than did the control group in Experi- ment 4, whereas the difference between the two VMH groups was only 43% (p>0.05). In light of the earlier reports it is interesting that the VMH rats in Experiment 4, who were not pretrained on the FR schedules, responded more than did the controls, while the VMH rats in the present experi-

350 SCLAFAN1

ment, who were pretrained, did not (30 min session). Obvi- ously pretraining is not always necessary or sufficient to produce enhanced food motivated behavior in VMH- damaged animals.

EXPERIMENT 6

In Experiment 6 the food motivated FR performance of VMH and control rats was studied in both 24 hr/day and 1 hr/day tests. Previous work indicates that VMH-lesioned rats bar press considerably more than do control rats when required to obtain all their food 24 hr/day on demanding FR schedules [14,16]. The purpose of the present experiment was to replicate this finding in VMH knife cut rats and to compare the levels of hyperphagia maintained by VMH rats on the FR schedule and on ad lib chow.

A second purpose of Experiment 6 was to examine the FR performance of VMH rats under food deprived conditions. Although they respond more than do normal rats when nondeprived (Experiments 4 and 5) VMH rats have repeatedly been found not to bar press more than do controls on FR schedules when food deprived and maintained at 80--90% weight levels [2, 14, 15, 24, 25, 29, 38]. Yet, as previously discussed, deprived VMH rats eat more than do controls when offered food in their home cage, or during a CRF test (Experiments 1 and 2; [13,32]). One possible explanation for the failure of deprived VMH rats to display elevated FR response rates, suggested by the results of Experiment 5, is that the test sessions used in previous experiments (0.5 to 4 hr/day) may have been too short. That is, if the rats, because of their pretraining and deprived state, are responding at a steady and maximum rate throughout the test session, then it may not be possible for the VMH rats to display increased bar pressing for food. In the present experiment, therefore, the FR performance of food deprived VMH and control rats was examined in both brief (1 hr/day) and prolonged (24 hr/day) sessions.

METHOD

The 15 rats used in this experiment were food deprived to 85% of their free feeding body weights and were trained (1 hr/day) to bar press for 45 mg food pellets (Noyes standard formula) on the following schedules for 2 days each: CRF, FR-4, FR-8, FR-16, FR-32, and FR-64. (The food pellet rewards rather than the milk diet used in the previous experiments were used because the liquid diet dispensers could not provide sufficient amounts of milk for 24 hr sessions.) Fol- lowing this initial training, the rats were given chow ad lib for at least 2 weeks before they were returned to the operant chambers and required to bar press 24 hr/day on the FR-64 schedule. Water was available ad lib from a bottle suspended on the inside front wall of the operant chambers. The animals were tested on the FR-64 schedule for at least 10 days before surgery, at which time they received either VMH knife cuts (n= 10) or sham surgery (n =5). On the first postoperative day the rats were allowed to recover in their home cage and were given 17 g of chow, which represented their mean preoperative intake. The rats were then returned to the operant chambers for 8 days of testing on the FR-64 schedule, followed by 8 days of ad lib chow in their home cage. In addition to measuring total responses and reinforcements per day in the operant chambers, printout counters were occasion- ally used to record the latency in seconds between the successive reinforcements on the FR-64 schedule.

In the second phase of the experiment the animals were food restricted and their body weights were maintained at 85% of their postoperative (Day 17) ad lib level. The animals were then tested for 1 hr/day in the operant chambers on a CRF (FR-1) schedule for 4 days, followed by, for 2 days each, on FR-4, FR-8, FR-32, and FR-64 schedules. The rats were rewarded with 45 mg food pellets and water was available ad lib during the test sessions. On the day after the last 1 hr FR-64 test the animals, who were still at the 85% body weight level, were returned to the operant chambers to begin 24 hr/day testing on the FR-64 schedule. Ten days later the animals were removed from the operant chambers and given ad lib chow in their home cage.

RESULTS

Following surgery five of the 10 VMH rats greatly increased their responding on the FR-64 schedule, while the remaining five VMH rats initially decreased their responding. Based on the clear difference in their FR responses the VMH rats were divided into two groups, with the VMH-1 group containing the 5 rats which increased their responses, and the VMH-2 group containing the 5 rats which decreased their bar press responses.

As indicated in Fig. 11, prior to surgery the total daily FR responses of the VMH-1, VMH-2, and control groups were similar, and averaged about 24,000 responses per day. When tested following surgery the VMH-1 rats more than doubled their responses per day and by the end of the 8 day test they were responding at 254% (range: 181 to 331%) of their preoperative rates. The VMH-2 rats, in contrast, all initially reduced their bar pressing following surgery. Three of the VMH-2 rats then increased their FR responding to 127, 137 and 155%, respectively, of their preoperative baseline by the end of the test, but their responses remained below that of the VMH-1 animals. A fourth VMH-2 rat continued to respond below its preoperative level (77%) throughout the test, while the remaining rat, which responded at about 50% of its preoperative baseline, was removed from the operant chamber on the sixth day of testing because of continued weight loss. The bar pressing performance of the control rats showed a small decline following surgery, but then returned to preoperative levels (range: 94 to 110%).

The rate of responding on the FR schedule was further analyzed by computing for each rat the mean interval between successive pellet reinforcements (IPI=interpellet interval). The mean IPI of the VMH-1 rats decreased from 46.3 sec prior to surgery (Day 2) to 37.9 sec after surgery (Day 6). The control group showed a similar decrease, from 47.7 to 36.5 sec, in their IPI following surgery. The VMH-2 group, on the other hand, not only had a high IPI prior to surgery, compared to the other two groups, but also increased it postoperatively, 69.7 to 123.2 see. There was con- siderable intragroup variability however, and analysis of the IPI data did not reveal significant differences. The preoperative behavior of the VMH-2 group further differed from the other groups in that when initially switched from ad lib chow to the FR-64 schedule the VMH-2 rats lost more body weight (22.0 g) than did the VMH-1 (10.8 g) and control (11.4 g) groups, although these differences failed to be statistically reliable.

The amount of food earned by the three groups during the FR tests is depicted in Fig. 12. Prior to surgery the rats were eating approximately 16 g/day of the 45 mg pellets. Following


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FIG. 11. Experiment 6. Mean bar press responses of nondeprived VMH-l, VMH-2, and control groups during 24 hr/day tests on FR-64 schedule. One VMH-2 rat was removed from the operant chamber during the test and asterisks indicate means based on the remaining four VMH-2 animals. The rats were not tested on the first day after

surgery.

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@ 40 SURGERY

~ ~o

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-½ -2 2 4 6 8 10 12 14 16 DAYS

FIG. ]2. Experiment 6. Mean food intake (g/day) of VMH-1, VMH-2, and control groups during 24 hr/day tests on the FR-64 schedule, and during ad lib access to food in home cage. The animals were not tested on the first day after surgery. (Asterisks: see

Fig. 11).

surgery the VMH-1 rats, as a result of their elevated bar pressing, more than doubled their food intake and by the end of the eight day test they were eating almost 40 g/day. The VMH-2 rats, on the other hand, initially decreased their food intake following surgery, and then increased it to a level slightly above their preoperative level. By the end of the FR test the VMH-1 rats had gained significantly (/9<0.01) more body weight (91.6 g) than did either the VMH-2 (14.8 g) or control (4.6 g) groups.

When the rats were removed from the operant chambers and given ad lib chow in their home cages all groups increased (p<0.01) their food intake (Fig. 12). The VMH-2 rats showed the greatest increase in food intake and they were now hyperphagic relative to the controls (p<0.01), although they continued to eat less than did the VMH-1 animals (p<0.05). The VMH-2 rats also weighed less than did the VMH-1 rats during this period, and when food intake was expressed as intake per kg body weight the VMH-2 group ate slightly more than did the VMH-I group (122 and 115 g/kg BW, respectively, vs 82 g/kg BW for the controls, p<0.01). Both the VMH-1 and VMH-2 groups gained more weight than did the controls during the 8 day period on chow (76,8 and 83.4 g, respectively, vs 27.2 g for controls, p<0.01).

In the next phase of the experiment the rats were food deprived to 85% of their ad lib body weight and were tested on the ascending series of FR schedules during daily 1 hr sessions. Analysis of the FR responses, which are presented in Fig. 13, indicated that the group effect (p<0.05), schedule effect (p <0.01), and group by schedule interaction (p<0.01) were all significant. The responses of the VMH- 1 and control rats were very similar on all FR schedules, and both groups increased their responding as the schedules became more

demanding. The VMH-2 rats, while responding at control levels on the FR-1 and FR-4 schedules, responded less than did the controls and VMH-1 rats on the higher schedules. The 85% weight of the VMH-1 rats (380.2 g) maintained during these tests exceeded (p<0.01) that of the VMH-2 rats (308 g), which in turn was higher (p<0.01) than that of the controls (252 g).

While still at the 85% weight level the animals were tested on the FR-64 schedule for 24 hr/day. Since the number of responses the rats emitted and the amount of food they earned on the FR schedule are directly related, only the food intake data are presented here. As illustrated in Fig. 14, the VMH-1 and control rats initially consumed similar amounts of food during the 24 hr tests, and therefore emitted a similar number of responses. However , while the control group decreased its intake over the 10 day test, the VMH-1 rats maintained their intake at the initial level. Thus, by the sixth day of testing the VMH rats were eating significantly (p <0.05) more than were the controls. The VMH-2 rats, on the other hand, initially ate considerably less than did the controls (Day 1, p<0.05). One VMH-2 rat ate less than 5 g/day and because of its declining weight the rat was removed from the operant chamber on Day 5. The remaining VMH-2 rats ate 11 to 30 g/day by the end of the test and their mean intake was slightly above control levels, but below that of the VMH-1 group (Fig. 14). Over the 10-day test on the FR schedule the VMH-1 rats gained (70.2 g) significantly more (p<0.05) weight than did the controls (48.8 g) and VMH-2 (42.6 g) animals.

When returned to ad lib chow all groups increased (p<0.01) their food intake with the VMH-1 and VMH-2 groups displaying greater increases (p<0.05) than did the

352 SCLAFANI

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FIG. 13. Experiment 6. Mean (-+ SEM) responses of deprived VMH-I, VMH-2, and control rats during daily 1 hr tests on FR

schedules 1 to 64.

control group. The two VMH groups were now eating similar amounts of food and their intake exceeded that of the controls (p<0.01) from the very first day on the chow diet (Fig. 14). Over the 10-day period on the chow the VMH-2 group gained slightly more weight (82.6 g) than did the VMH-I group (77.6 g), and both groups gained more (p<0.01) than did the controls (22.0 g).

DISCUSSION

The results of this experiment demonstrate that VMH knife cut rats are capable of overeating by bar pressing more than do controls when required to obtain all their food on a FR-64 schedule. This finding is consistent with previous reports of increased bar pressing in VMH-lesioned rats during 24 hr/day tests on FR schedules ranging from FR-64 to FR-256 [13,16]. However, not all the VMH cut rats in the present experiment were hyperphagic on the FR-64 schedule, even though they all overate when food was available ad lib. Although the VMH-2 rats bar pressed considerably less than did the VMH-1 rats they were as hyperphagic on the chow diet as were the VMH-1 animals, and histological analysis did not reveal any difference in the knife cuts of the two groups. Furthermore, in diet acceptance tests conducted at the end of this experiment the VMH-2 animals were similar to the VMH-1 rats in their finickiness to quinine and high fat diets. The two groups did differ, however, in their preoperative performance on the FR schedule. That is, although their total responses were similar, the VMH-2 rats bar pressed at slower rates and lost more weight on the FR schedule than did the VMH-1 rats. The inferior postoperative bar pressing performance of the VMH-2 rats, therefore, may have resulted from an inadequate presurgical adaptation to the FR schedule, which perhaps was exacerbated by an

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FIG. 14. Experiment 6. Mean food intake (g/day) of VMH-1, VMH-2, and control groups during 24 hr/day tests on the FR-64 schedule, and during ad lib access to food in home cage. At the start of FR testing (Day 1) the rats were at

85% of their postoperative body weight. (Asterisks: see Fig. 11).


increase in affective reactivity produced by the VMH damage (see [14, 15, 38]). (Four of the VMH-2 rats were tested in the same two operant chambers and it is possible that an undetected problem with these chambers was responsible for the poor adaptation to the FR schedule.) Since the bar pressing performance of the VMH-2 rats does not appear to represent the food motivational effects of the VMH knife cuts, further discussion will be limited to the VMH-1 group.

While the VMH-1 rats bar pressed considerably more than did the controls following surgery, their bar pressing rate, as measured by the interpellet interval, did not differ from that of the controls. This finding is compatible with the results of Experiments 1 to 3 that VMH rats do not respond faster than do controls on VI schedules. King and Gaston [13], however, have reported increased response rates in VMH-lesioned rats tested on a FR-128 schedule. Since they did not present data for the controls rats, but only for the two most hyperphagic VMH animals the significance of their finding is questionable. Larkin [16] also examined the response rates of VMH-lesioned rats tested 12 or 24 hr/day on various FR schedules. In his study the VMH rats bar pressed at the same local rate as did the controls, but they took shorter post-reinforcement pauses than did the controls. The response measure used in the present experiment does not discriminate between local response rate and the post- reinforcement pause, but if the VMH-1 rats took shorter pauses following reinforcement their interpeUet intervals would have been shorter than that of the controls, but they were not.

The present results further revealed that while the VMH-1 rats were hyperphagic on the FR-64 schedule, they were even more so when given free access to food. Even the control rats increased their food intake, although to a lesser degree, when switched from the FR schedule to ad lib food. Other reports have also found that the food intake and body weight levels maintained by intact rats are determined by the amount of work required to obtain food, and, in some re- spects, the effects of decreasing food accessibility are similar to the effects of decreasing the palatability of the food [7, 23, 24]. As in the case of the influence of diet palatability on hypothalamic hyperphagia (e.g., [37,39]), the present findings indicate that the food intake of VMH rats is more de- pendent upon the accessibility of the diet than is the intake of normal rats.

In contrast to their increased bar pressing performance in the nondeprived 24 hr test, the VMH-1 rats failed to respond more than did the controls when food deprived and tested for 1 hr/day sessions. This finding is consistent with many previous reports [2, 13, 14, 15, 25, 29, 34, 38], but requires explanation since food deprived VMH rats eat more than do controls when offered food in their home cage (Experiment 2; [13,32]). The proposal offered in the introduction that brief test sessions may not be adequate to reveal enhanced FR performance in VMH rats was not supported by the results of the second 24 hr FR-64 test. When switched from the 1 hr to the 24 hr sessions the VMH-1 rats did not bar press significantly more than did the controls until after 5 days of testing, by which time the controls had recovered their ad lib body weight. Rather than test session length, the present results suggest that the discrepancy between the results of the FR bar pressing tests and consumption tests conducted in deprived animals is due to the effect of reduced food accessibility on the intake level of VMH rats. As discussed above, the imposition of a FR schedule reduces the level of hyperphagia maintained by VMH rats, and thus reduces the

food intake difference between VMH and control animals. Food deprivation also reduces the amount by which VMH animals overeat relative to controls during brief intake tests (Experiment 2; [13]), and the combined effect of the FR schedule and food deprivation apparently is sufficient to completely block the hyperphagia of VMH rats. It is likely that the imposition of a VI schedule also reduces the food intake level of VMH rats, and this could account for the failure of the deprived VMH rats in Experiments 1 and 2 to bar press more than did the controls during the VI prefeeding tests.

G E N E R A L DISCUSSION

On the basis of the present results and other recent findings the food motivation of hypothalamic hyperphagic rats can be described in further detail. Discussion will focus first on the motivational state of nondeprived animals.

The available evidence demonstrates that under ad lib feeding conditions VMH-damaged rats are motivated to eat more of a palatable food than do normal rats. This is evi- denced by the elevated food-reinforced bar pressing displayed by VMH rats during both short-term and long-term VI and FR tests (Experiments 1-6; [14,16]). In terms of their meal taking behavior, however, VMH rats do not appear to be more motivated than are intact rats to initiate their meals, but once the meals are initiated they are motivated to consume more food than do normal animals. This analysis is based on the failure of VMH rats to respond at significantly elevated rates on a VI schedule when rewarded with either entire meals (Experiment 3), or with small food rewards (Experiments 1 and 2; [34]). Furthermore, if prevented from eating large meals, as in Experiment 3, VMH rats will work to increase their meal frequency and thereby maintain their hyperphagia, although again their motivation to initiate any given meal does not appear to differ from that of normal animals.

In apparent conflict with the proposal that VMH rats are not more motivated than are normal rats to initiate their meals is the finding that VMH rats have shorter latencies to eat in a novel environment than do intact animals [29,30]. It may be that the latency to eat test is a more sensitive motivational measure than are the bar pressing tests used in the present study, and therefore can detect differences between VMH and normal rats not revealed by the bar pressing tests. Alternatively, the latency to eat and bar pressing tests may measure qualitatively different aspects of feeding behavior since one measures the consummatory response, while the other measures an instrumental appetitive response. On the other hand, the decreased latency to eat displayed by VMH-damaged rats may not result from an increased feeding tendency per se, but may result from a decrease in fear motivated behavior as suggested by Grossman [11]. The latency to eat data are also open to question since lesions of brain regions which do not produce hyperphagia have been found to decrease the latency to eat [8,20]. Thus, while further research is required to resolve this issue, the latency to eat findings do not necessarily contradict the results of the present study.

In contrast to ad lib fed rats, food deprived VMH rats are not motivated to bar press more for food on partial reinforcement schedules than do similarly deprived control rats. This is demonstrated by the results of the present study as well as many previous experiments [13, 14, 15, 26, 27, 29,

354 SCLAFANI

34]. (Two reports of increased food rewarded bar pressing behavior in deprived VMH rats are questionable since neither study included control animals [10,43].) Rather, the food motivated bar pressing performance of VMH rats deprived to 80 or 90% weight levels is similar to that of control animals. However, when food becomes freely available deprived VMH rats overeat, relative to controls, during the first meal as well as the first 24 hr period (Experiment 2; [13,32]). These and other results [36] indicate that VMH damage does not affect the animal 's response to long-term energy depletion, but impairs only its response to energy repletion. Panksepp [22] has argued otherwise but the weight of the evidence cited above does not support his contention that VMH damage interferes with the animal 's response to energy depletion. Obese VMH animals display subnormal food motivation when deprived, but this results from their excessive fat stores rather than from the hypothalamic damage itself [26, 34, 36, 37].

The fact that ad lib fed VMH rats eat considerably more food per day and per meal than do intact rats but do not display an enhanced motivation to initiate their meals, as measured in the present study, does not necessarily represent another VMH "paradox , " but rather may reflect the normal operation of the feeding motivation system in the rat. That is, it is possible that a meal-onset threshold exists in the rat such that post-prandial satiety must decline, and con- versely feeding motivation must increase, to a certain threshold level before the rat begins to eat its next meal (see [4,9]). VMH damage may not alter the postulated meal-onset threshold so that when VMH rats reach the threshold and begin to eat they are at the same motivational level as are intact rats. According to this interpretation, VMH rats eat larger than normal-size meals, and are motivated to do so, not because of an elevated motivation at the beginning of the meal, but because of a delay in the onset of satiety during the meal. Furthermore, VMH rats are motivated to eat more than normal amounts of food per day because of a reduction in the duration of post-prandial satiety. Thus, VMH rats restricted to normal-size meals eat their next meal sooner than do intact rats, while free feeding VMH rats, despite their larger meals, eat their next meal at about the time that normal rats do: in both cases the VMH rats display reduced satiety ratios (postmeal interval/meal size; see [3,22]). In terms of the feeding threshold model, following a meal of the same size satiety declines to the meal-onset threshold faster in VMH rats than in normal rats, but since the threshold is presumed to be unaltered by medial hypothalamic damage, VMH animals are not more motivated to eat than are con-

trols when they initiate their next meal. Although this model remains speculative it is intuitively attractive, since if at the time they begin their meals ad lib fed hyperphagic rats are more motivated to eat than are controls this raises the question why they do not initiate their meal sooner than they do.

It should be obvious that the motivational model proposed above does not attempt to explain VMH hyperphagia and obesity but attempts only to provide a conceptual framework to describe the motivational changes associated with hypothalamic hyperphagia. In particular, the model does not specify the mechanism(s) by which VMH damage alters the onset of satiety during a meal and the duration of post-prandial satiety. Previous investigators have proposed that VMH damage directly impairs the neural systems mod- ulating meal onset and offset (e.g., [3]) or indirectly affects satiety by resetting a body fat set point (e.g., [34]) or by altering the metabolic disposition of ingested nutrients (e.g., [4,28]), and this remains an unresolved question. It should also be noted that, although emphasizing satiety, the model does not imply that VMH damage reduces the animal 's sen- sitivity to the satiating effects of ingested nutrients in the sense of the classical satiety-deficit hypothesis [18]. As previously discussed, VMH-damaged animals display normal feeding suppressive responses to ingested or intubated nutri- ent loads [5, 17, 21]. Rather, the primary deficit produced by VMH damage appears to be related to the control of long- term energy repletion but this deficit is expressed as a change in short-term satiety.

The terms hunger and appetite have not been used in this report to describe the food motivation of VMH hyperphagic rats. I have previously proposed that VMH-damage enhances the appetite for palatable foods, but not the hunger induced by food deprivation [29, 31, 34, 37], and the present results are consistent with this view. Not all investigators, however, distinguish between appetite and hunger, and VMH damage has been stated to increase hunger drive (e.g., [13]). Although an argument can be made for distinguishing between appetite and hunger (see [31,34]), it is now apparent that as more is learned about hypothalamic hyperphagia neither term is adequate to specify the conditions (e.g., deprivation state; palatability and accessibility of the diet) under which VMH animals overeat, nor do they differentiate between the initiation and continuation of meal-taking behavior. Rather than attempting to label the motivational state of VMH animals future research should concentrate on de- scribing it in greater detail and analyzing its environmental and physiological determinants.

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food motivation in hypothalamic hyperphagic rats reexamined

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