Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations
1980 Influence of amphetamine and phenylpropanolamine on food intake, activity, and body temperature in rats with ventromedial hypothalamic or dorsolateral tegmental damage Paul Jeff elW lman Iowa State University
Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Behavior and Behavior Mechanisms Commons, Biological Psychology Commons, and the Other Psychiatry and Psychology Commons
Recommended Citation Wellman, Paul Jeff, "Influence of amphetamine and phenylpropanolamine on food intake, activity, and body temperature in rats with ventromedial hypothalamic or dorsolateral tegmental damage " (1980). Retrospective Theses and Dissertations. 6774. https://lib.dr.iastate.edu/rtd/6774
This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. INFORMATION TO USERS
This was produced from a copy of a document sent to us for microfilming. While the most advanced technological means to photograph and reproduce this document have been used, the quality is heavily dependent upon the quality of the material submitted.
The following explanation of techniques is provided to help you understand markings or notations which may appear on this reproduction.
1. The sign or "target" for pages apparently lacking from the document photographed is "Missing Page(s)". If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting through an image and duplicating adjacent pages to assure you of complete continuity.
2. When an image on the film is obliterated with a round black mark it is an indication that the film inspector noticed either blurred copy because of movement during exposure, or duplicate copy. Unless we meant to delete copyrighted materials that should not have been filmed, you will find a good image of the page in the adjacent frame.
3. When a map, drawing or chart, etc., is part of the material being photo graphed the photographer has followed a definite method in "sectioning" the material. It is customary to begin filming at the upper left hand comer of a large sheet and to continue from left to right in equal sections with small overlaps. If necessary, sectioning is continued again—beginning below the first row and continuing on until complete.
4. For any illustrations that cannot be reproduced satisfactorily by xerography, photographic prints can be purchased at additional cost and tipped into your xerographic copy. Requests can be made to our Dissertations Customer Services Department.
5. Some pages in any document may have indistinct print. In all cases we have filmed the best available copy.
Universify Microfilms International 300 N, ZEEB ROAD, ANN ARBOR, Ml 48106 18 BEDFORD ROW, LONDON WC1R 4EJ, ENGLAND 8019676
WELLMAN, PAUL JEFF
INFLUENCE OF AMPHETAMINE AND PHENYLPROPANOLAMINE ON FOOD INTAKE, ACTIVITY, AND BODY TEMPERATURE IN RATS WITH VENTROMEDIAL HYPOTHALAMIC OR DORSOLATERAL TEGMENTAL DAMAGE
lom State University PH.D. 1980
University Microfilms Intern StiO n si 300 N. zeeb Road, Ann Arbor, MI 48106 18 Bedford Row, London WCIR 4EJ, England PLEASE NOTE:
In all cases this material has been filmed in the best possible way from the available copy. Problems encountered with this document have been identified here with a check mark .
1. Glossy photographs
2. Colored illustrations
3. Photographs with dark background
'4. Illustrations are poor copy
5. °rint shows through as there is text on both sides of page
6. Indistinct, broken or small print on several pages throughout
7. Tightly bound copy with print lost in spine
8. Computer printout pages with indistinct print
9. Page(s) lacking when material received, and not available from school or author
10. Page(s) seem to be missing in numbering only as text follows
n. Poor carbon copy
12. Not original copy, several pages with blurred type
13. Appendix pages are poor copy
14. Original copy with light type
15. Curling and wrinkled pages
16. Other
Universirv MiardFiims Intemarional 300 \ Z=== 30. ANN AASOP MIJS'06'313: 761-4700 Influence of amphetamine and phenylpropanolamine on food
intake, activity, and body temperature in rats with ventro
medial hypothalamic or dorsolateral tegmental damage
by
Paul Jeff Wellman
A Dissertation Submitted to the
Graduate Faculty in Partial Fulfillment of the
Requirements for the Degree of
DOCTOR OF PHILOSOPHY
Major: Psychology
Approved :
Signature was redacted for privacy. In Charge of Major Work
Signature was redacted for privacy. For the Major Department
Signature was redacted for privacy. For the G/âduatè College
Iowa State University
Ames, Iowa
1980 ii
TABLE OF CONTENTS
Page INTRODUCTION 1
GENERAL METHOD 4
Protocol 4
EXPERIMENT 1 11
Method 11
Results 14
Discussion 19
EXPERIMENT 2 21
Method 21
Results 21
Discussion 24
EXPERIMENT 3 27
Method 2 7
Results and Discussion 28
EXPERIMENT 4 34
Method 3 4
Results 36
Discussion 36
EXPERIMENT 5 40
Method 40
Results 42
Discussion 51 iii
Page
GENERAL DISCUSSION 54
REFERENCE NOTE 59
REFERENCES 60
FOOTNOTES 69
ACKNOWLEDGEMENTS 71
APPENDIX A: THE PERIPHERAL REGULATION OF FEEDING 72
INTRODUCTION AND OVERVIEW 73
Preabsorptive Satiety 75
Postabsorptive Satiety 85
REFERENCES 108
APPENDIX B: HISTOLOGICAL ANALYSES 125 1
INTRODUCTION
Damage in the dorsolateral tegmentum (DLT)^ that presum
ably interrupts ascending fibers of the ventral noradrenergic
bundle (VMB) produced an obesity syndrome (Ahlskog & Hoebel,
1973) ostensibly similar to the classic obesity syndrome pro
duced by destruction in the ventromedial hypothalamus (VMH;
Hetherington & Ranson, 1940; Brobeck, Tepperman & Long, 1943).
A role for the VNB in the VMH obesity syndrome was suggested
by Gold (1973) who demonstrated that the most effective VMH
lesions destroy tissue rostral and lateral to the ventro
medial hypothalamus, an area known to be traversed by the VNB
(Ungerstedt, 1971). This analysis suggests that alterations
of feeding behavior that are common to both syndromes might
be attributed to interruption of the VNB.
Subsequent analyses of feeding behaviors of VMH and DLT
rats, however, reveal few syndrome communalities other than
hyperphagia. One apparent dissimilarity is the mediation of
anorexia induced by amphetamine. 2 Logically, if amphetamine
induces anorexia via a putative satiety mechanism in either
the VMH or the DLT, than damage to either of these regions 3 should diminish the anorexic properties of amphetamine.
Although DLT rats display an attenuated amphetamine response
(Ahlskog, 1974; Carey, 1976; Garattini, Jori, & Samanin, 1976;
Zacharko & Wishart, 1978), VMH rats display an amphetamine 2
response comparable to or even larger than that observed in neurologically intact rats (Epstein, 1959; Kennedy & Mitra,
1963; Reynolds, 1959; Sclafani & Berner, 1977; Stowe & Miller,
1957; Wishart & Walls, 1973; Zacharko & Wishart, 1978).
Critical examination of these reports, however, suggests that it is perhaps premature to conclude that the DLT, but not the VMH, mediates the anorexia induced by amphetamine. One evident problem is the frequent assessment of amphetamine anorexia in obese lesioned rats. Obesity per se (e.g., dietary obesity in neurologically intact rats) produces many of the deficits in appetitive behavior (finickiness, decreased hunger motivation) that are classically attributed to VMH damage
(Mailer, 1964; Beatty, 1978). Assessment of anorexia must therefore be made in lesioned rats maintained at or near control body weight levels.
Further, outcomes derived from experiments in which lesioned rats are demonstrably hyperphagic are difficult to interpret since attenuations of amphetamine anorexia observed in lesioned rats may reflect increased motivation for food rather than an effect of the lesion on the neural substrate for anorexia. Food motivation, operationally defined in terms of baseline intake, can be approximately equated by maintaining lesioned and control rats at 80% of their preoperative body weights (Kent & Peters, 1973). Finally, a more robust hyperphagia and obesity syndrome than previously observed in 3
DLT rats has been reported in this laboratory (Peters, Gunion
& Wellman, 1979; Peters, Wellman & Gunion, 1979). The purpose of the present experiments was to provide comparisons between the anorexic responses to amphetamine and to another anorexic agent, phenylpropanolamine (PPA), for DLT, VMH and control rats maintained at 80% of their preoperative body weights. 4
GENERAL METHOD
Protocol
Animals
The animals were 50 female Long-Evans hooded rats (Blue
Spruce Farms, Inc.) weighing 193-273 g at the beginning of the
experiment. The rats were individually housed either in standard wire-mesh cages or in constant weight cages (described below in the apparatus section) in a temperature controlled (230C) room under reverse illumination (lights on from 2000- 0800 h). Tap water was freely available throughout the experiments except where noted below. Diets Three diets were used in these experiments. A high-fat diet consisted of 1 part by weight melted shortening (Crisco) and 2 parts by weight ground-chow (Purina Rat Diet). The high- fat diet was prepared fresh prior to each intake test or every third day when used as a maintenance diet and was presented to the rats in glass ointment jars (85 mm high with a 71 mm mouth). A pellet diet consisted simply of laboratory
pellets (Teklad Rat & Mouse Diet) and was presented to the rats
in hoppers attached to the cage front. A ground-chow form of the Teklad pellet diet was prepared by pulverizing pellets and was used as the maintenance diet in the constant weight cages. Apparatus
Maintenance of the body weights of lesioned and control rats at some desired value is typically accomplished by daily presenting the rats with a small portion of food. Although 5
body wight is controlled by a single daily feeding, the feeding pattern for lesioned and intact rats is not. Hyper-
phagic VMH and DLT rats consume their daily portion soon after presentation while intact rats consume their food throughout
the day (Luttmers, 1978). Behavioral testing the following day
is therefore confounded in that lesioned rats are food deprived for a longer period than control rats (Sclafani, 1978).
A procedure that effectively controls both body weight
and feeding pattern of lesioned and intact rats employs auto
mated constant weight cages that continuously monitor each rats
body weight and delivers food whenever body weight falls below
a specified value. These devices minimize differences in
feeding patterns since each rat is fed, on the average, every
hour.
Figure 1 presents a photograph of one of 24 constant weight cages constructed by the Iowa State University Instru ment Shop after a description by Ehrenfreund (1960). Each device consisted of a stainless steel cage with a hinged front door suspended from the center post (Fig. lA) of an OHAUS (Model 2610) triple-beam scale mounted on a plywood base. In side each cage, a needle-valve water spout (Fig. IB) was mounted through the left cage wall while an aluminum food hopper (Fig. IC) was on the right wall flush with the floor. A plastic bottle filled with water was suspended from the ply wood base and was connected to the water spout by a plastic tube. Newspapers were placed beneath each cage to collect droppings and urine. Figure 1. A constant weight cage.
A — Center post B — Needle-valve water spout C — Food hopper D — Apparatus set-point E — Feeder switch 1 ("'•' 58 mNMM LJJ.Jp . IJ'jjL ^ JJJ.)', JJJ.J,- 33# aw«»^'v-y tr4 PtefW Èiil
L 8
wood base and was connected, via a plastic tube, to the water spout.
Each cage was counterbalanced by two 1000 g weights suspended from the center arm in an oil bath to dampen travel of the center arm. Assorted weights were placed on the center post to balance the cages.
The body weight value desired for each rat and therefore the set-point (Fig. ID) for the apparatus was determined by the setting of three sliding poise (1.0, 10.0 and 100.0 g) on the triple beam arm. As long as the rats* body weight exceeded the sum of these settings, no food was delivered.
Cage travel in an upward direction, as the rat lost body weight, moved the triple-beam arm downward past the set-point and closed a mercury microswitch. This closure activated a small motor that drove a cylindrical (12.5 mm in diameter and 20.0 cm in length) stainless steel shaft in a horizontal back-and- forth motion through a Plexiglass well containing the Teklad ground-chow diet. With each pass, a small vertical opening in the left end of the shaft captured and deposited into the food hopper a small amount of ground-chow. With the continued deposition of ground-chow, the triple-beam arm rose vertically, opened the mercury microswitch and inactivated the feeding mechanism. A switch (Fig. IE), in series with the feeding mechanism, served to inactivate the feeding mechanism during periods of food deprivation. 9
Surgery and histology
The rats were deprived of food and water for 24 h before
and after surgery. Each rat was anesthetized with sodium
secobarbitol CMyothesia, 42 mg/kg, ip) and given atropine
sulfate ClO.O mg/kg, ip) to reduce respiratory complications.
Electrodes were made from 30-gauge nichrome steel wire
and were insulated except for a 0.5 mm conical tip. Bilateral
lesions were produced in group VMH (n = 18) by passing 2.0 mA
anodal current for 20 seconds between an electrode and a rectal cathode. For VMH lesions, the upper incisor bar of the stereotaxic instrument was placed 5.0 mm above the interaural line while each electrode was positioned 5.8 mm anterior to the interaural line, 0.7 mm lateral from the midline and 0.5 mm above the base of the brain.
Bilateral lesions were produced in group DLT (n = 18) by passing 0.75 mA cathodal current for 20 seconds between each electrode and a rectal anode. For DLT lesions, the upper incisor bar was placed 2.4 mm below the interaural line while each electrode was positioned 2.3 mm anterior to the interaural line, 1.5 mm lateral from the midline and 2.0 mm above the interaural line.
Rats in group CON (n = 10) received scalp incisions but skull holes were not drilled.
At the end of the experiments, lesioned rats were deeply anesthetized with chloroform and perfused intracardially with
0.9% saline: followed by 10% formalin. After fixation in 10% 10
formalin for at least 48 h, unstained IOO-^M sections through
the coronal plane described by Konig and Klippel (1963)
were photographically enlarged to assess the locus and extent
of brain tissue damage.
Drugs
A saline solution consisted of 0.9% (w/v) sodium chloride
dissolved in sterile tap water. Amphetamine solutions (0.5, 1.0
and 2.0 mg/ml) were prepared from a stock amphetamine solution
C2.0 mg/ml) consisting of dextro-amphetamine sulfate (obtained
from the National Institute on Drug Abuse) dissolved in the
saline solution. Phenylpropanolamine solutions (5.0, 10.0 and
20.0 mg/ml) consisted of phenylpropanolamine hydrochloride
(Propadrine; Merck, Sharp & Dohme) dissolved in the saline
solution.
Statistical analyses
Food intake following saline preceding each drug treat
ment was analyzed using analysis of variance with lesion and day as the factors. When these analyses indicated that saline intake was stable (i.e., no significant effect of day), the data were collapsed across days for each rat. These saline values were used in subsequent split-plot analyses of variance
(Kirk, 1968) of raw intake and percent change in intake (1.0 - amphetamine intake/saline intake). Planned comparisons between means were made using two-tailed t tests. 11
EXPERIMENT 1
The influence of various dosages of d-amphetamine sulfate
on the intake of a high-fat test diet by VMH, DLT and control
rats was assessed while the rats were maintained at 80% body
weight. Intake tests were conducted at night using the high-
fat test diet because VMH and DLT rats exhibit comparable
overeating when offered this diet at night CLuttmers, 1978).
Method
Procedure
During a 25 day period following their arrival in the lab, the rats were individually housed in suspended wire-mesh cages with the pellet diet and tap-water freely available. This period served to adapt the rats to general maintenance procedures and to the reverse-illumination schedule. Body weights were recorded daily for each rat during the last 7 days of the adaptation period. These measures, along with growth charts for female hooded rats provided by Blue Spruce Farms, Inc., were used to estimate the average weekly gain in body weight for each rat.
Food intake during a 30 minute period following saline injection was measured for each rat during 6 preoperative tests.
The rats were deprived of food, but not water, for a 23 hour period before each test. The rats were offered a measured amount of the high-fat diet 30 min after injection (ip) with
1.0 ml/kg saline. Food intakes were measured to the nearest
0.1 g and were corrected for spillage collected on; paper towels 12
placed beneath the cage. Following each test period, the
rats were offered the pellet test diet until the next depri
vation period. Food intakes were measured every other day to
allow the rats to recover body weight lost during food depri
vation and to minimize cumulative weight losses in the rats.
Body weight was monNtored immediately prior to food depriva tion and to food ir ke tests.
Four rats were discarded from the experiment prior to surgery for failure to consume at least 3.0 g of the high-fat diet during the last 3 food intake tests. The average food intake for each of the remaining rats during these tests was used to form 3 groups of comparable average food intake.
Two rats in each group died immediately following sur gery. On the day after surgery, the remaining rats were offered the high-fat diet for various periods to identify hyperphagic lesioned rats. Because VMH rats displayed con siderable hyperphagia after surgery, these rats were fed the high-fat diet for only 6 days while the DLT and control rats were fed the high-fat diet for 9 days. During these periods, body weights and cumulative 72-hour high-fat intakes were recorded every 3rd day. These measures were used to select hyperphagic VMH and DLT rats (n = 8 each) who, along with control rats (n = 8), served as subjects for the remainder of the experiments. 13
Following the selection of hyperphagic lesioned rats, all
rats were transferred to maintenance in the constant weight
cages and were reduced to 80% of their preoperative body
weight. The value of preoperative body weight for each rat
was its average body weight during the last 3 preoperative in
take tests immediately prior to food deprivation. This value
was corrected upward throughout these experiments (approxi
mately 3-4 grams/week) to allow for normal growth. For
lesioned rats, body weight was reduced to 80% by daily down
ward adjustments of each constant weight cage set-point in
7-10 g steps while the body weight of control rats was re duced using 5-7 g steps per day.
After the rats stabilized at 80% body weight for 3 days, two saline intake tests were conducted using the procedures described above. Preliminary inspection of these intake data and the body weight losses for the rats during these tests dictated several procedural modifications. Because mainte
nance at 80% body weight did not increase control food intakes relative to their preoperative intakes, the length of the in take period was extended to 60 minutes. Further, inspection of changes in body weight produced in each group by 23 hour food deprivation revealed that VMH rats lost only half as much body weight as control and DLT rats (average weight los ses = 7.8, 14.9, and 12.0 g, respectively). At this time, all rats consumed comparable amounts (6-7 g) of high-fat during 14
each 30 minute test. Thus, after each intake test, control and DLT rats were somewhat below 80% body weight and were therefore fed immediately by the constant weight cages. In contrast, VMH rats were at or slightly above 80% body weight after each intake test and were not fed by the constant weight cages until sometime the next day. The interval be tween intake tests was extended to 48 hours for the remainder of the experiments to minimize possible differences in food deprivation.
The amphetamine test sequence consisted of 3 consecutive saline intake tests followed by DRUG-SALINE-DRUG-SALINE-DRUG tests. The three initial saline tests were used to assess the stability of saline food intake while the two saline intake tests separating the three amphetamine tests were used to assess stability of saline intake and possible drug carry over effects. Amphetamine test procedures were identical to saline test procedures except that each rat was injected with
0.5, 1.0, and 2.0 mg/kg d-amphetamine sulfate prior to each intake test. Each rat received each dosage of amphetamine once with amphetamine dosage order randomized for each lesion group.
Results
Table 1 presents the average change in body weight and average 72-hour food intake for hyperphagic lesioned and control rats during free access to the high-fat diet immediately after 15
surgery. Both VMH and DLT rats gained significantly more
weight (t (21) =9.18 and 5.55, respectively, g_(.001)and ate
significantly more high-fat (t(21) = 12.46 and 6,94,
respectively, £ <.001) than did control rats. Moreover, VMH
rats ate and gained significantly more than DLT rats (t(21) =
5.17 and 5.32, respectively, £<.001). The larger food
intakes and weight gains for VMH rats reflect, in part, the
fact that VMH rats overeat both during the day and the night
whereas DLT rats only overeat during the night (Hoebel et al.,
1975; Luttmers, 1978).
The changes in high-fat intake induced by amphetamine in
VMH, DLT, and control rats are presented in Figure 2. Group mean high-fat intake is presented in the left panel while the right panel presents group mean percent change in intake from saline baseline. The saline baseline values in the left panel are the average saline intakes for each rat during the saline intake test preceding each drug test.
Maintenance of the rats at 80% of their preoperative body weight levels did not equate their high-fat intakes. After injection with saline, DLT rats ate significantly more of the high-fat diet than did control rats (t(63) = 2.0, £<.05).
Although VMH rats also ate more of the high-fat diet than control rats after saline, this difference only approached statistical significance. 16
Table 1. Group mean food intake and body weight gain over 3
days for control and hyperphagic VMH and DLT rats
fed a high-fat diet. VMH values are for a 6 day
period while control and DLT values are for a 9
day period following surgery.
Group N Food intake Cg) S. E. M. .Weight gain (g) S. E. M.
CON 8 42 +1.4 7 +1.5
DLT 8 64^ +2.1 21^ +2.8
VMH 8 86^'^ + 3.8 44^'^ + 3.2
^Significantly different from control value, £<.001.
^Significantly different from DLT value, £<.001. Figure 2. Group mean Iiigh.—fat intake Cleft panel 1 and percent change in
high-fat intake Cright panel} during a 60 minute period
following either saline or amphetamine CO.5, 1.0 and 2.0 mg/kg) injection. 15 80% BW-HIGHFAT +25
12 0 ^ n X > z < 9 -25 o m
00 8 ^ DLT Z 6 -50 < 8 •—• VMH
8 D—• CON > 7^ -75
0 y/ SAL 0.5 1.0 2.0 0.5 1.0 2.0
DOSAGE (mg/kg)
AMPHETAMINE 19
Intake of the high-fat test diet by control rats was
slightly, but not significantly, elevated after 0.5 mg/kg am
phetamine and was depressed relative to saline intake after
1.0 and 2.0 mg/kg. A significant suppression of intake in
control rats was only obtained using the 2.0 mg/kg dosage of
amphetamine (t (63) = 2.77, £ <.01). Relative to their re
spective saline baselines, VMH and DLT rats displayed no sig nificant changes in their high-fat intake to any amphetamine
dosage. Moreover, between-group comparisons using either in take or percent change in intake revealed no significant differences between either VMH or DLT rats and control rats at the 0.5 and 1.0 dosages of amphetamine. At 2.0 mg/kg amphetamine, however, both VMH and DLT rats ate more of the high-fat diet than control rats (t(21) = 3.06 and 3.99, respectively, £ <.01) and also displayed significantly smaller percent change in intake than control rats (t(42) =
2.48 and 2.98, respectively, £<;.05).
Discussion
Amphetamine did not reliably suppress the intake of the high-fat test diet in either VMH or DLT rats. The attenuated anorexia observed in lesioned rats is difficult to interpret, however, since the responses of control rats to the various dosages of amphetamine were quite variable and a significant suppression of control intake was obtained only at the highest dosage of amphetamine. Further, the magnitude (28%) of the 20
anorexia induced by the 2.0 mg/kg amphetamine dosage in
control rats fed a high-fat test diet was substantially less
than that (75-85%) typically observed (Ahlskog, 1974) in
control rats fed standard pellet test diets.
After 23-hours food deprivation, VMH rats lost less body weight than either control or DLT rats. These unanticipated weight loss differences may reflect the influence of VMH lesions on peripheral energy metabolism. VMH lesions induce hyperinsulinemia and hypoglycemia and bias energy flow towards lipogenesis, even during periods of fasting
(Friedman & Strieker, 1976). VMH rats may be unable to release energy from lipid, protein, and glycogen stores to maintain blood glucose levels and therefore do not lose as much body weight as neurologically intact rats during a fast. Although little is currently known about the effects on peripheral energy metabolism following DLT destruction, data from Luttmers
(1978) suggest that these rats accumulate more fat as body weight than do control rats even when their food intake is restricted to control levels, an outcome that suggests that
DLT lesions may also bias metabolism towards lipogenesis.
It should be noted, however, that this metabolic effect may occur only during the night. Zacharko (Note 1) has noted that
DLT rats are hyperinsulinemic only during the night when they are also hyperphagic. 21
EXPERIMENT 2
The amphetamine test sequence of Experiment 1 was re
peated using a pellet test diet to assess the possibility
that the attenuation of amphetamine anorexia observed in both
VMH and DLT rats was peculiar to the high-fat test diet.
Method
Procedure
The procedures of Experiment 2 were identical to those of Experiment 1 except that during each intake test the rats were offered a pellet test diet (Teklad Rat & Mouse Diet) placed on the floor of the constant weight cage.
Results
The feeding responses of the VMH, DLT and control rats to amphetamine when fed a pellet test diet are presented in
Figure 3. After saline injection, there were no significant between-group differences in pellet intake. In contrast to the outcomes of Experiment 1, amphetamine induced reliable and dose-dependent decreases in the food intakes of control rats (each dose was significantly different from saline,
(t (63) = at least 4.29, p ^.001). These differential effects of amphetamine on control intakes of high-fat and pellet test diets cannot reflect improperly prepared or biologically,inac tive amphetamine solutions as the same solutions were used in
Experiments 1 and 2. Figure 3. Group mean pellet intake Cleft panel) and percent change in
pellet intake (right panel) during a 60 minute period
following either saline or amphetamine CO.5, 1.0 and 2.0 mg/kg)
injection. 10 80% BW- PELLETS 0
8 8^ ^ DLT D) 20 ^ 8•—•VMH n 8 o—° CON % > ^ 6 < •40 Z O
to w Z 4 < -60
80 m
0 SAL 0.5 1.0 2.0 0.5
DOSAGE (mg / kg )
AMPHETAMINE 24
When fed a pellet test diet, VMH rats displayed anorexia to amphetamine that was comparable to that observed in control rats. Although VMH rats consumed significantly more of the
pellet diet than control rats after 0.5 mg/kg amphetamine
CtC631 = 2.07, £<.051, there were no significant differences
in pellet intake between VMH and control rats at the 1.0 and
2.0 mg/kg dosages of amphetamine. Further, there were no
significant differences, using percent change in intake,
between VMH and control rats at any dosage of amphetamine.
Relative to the dose-dependent anorexia induced by amphetamine in control rats, DLT rats displayed attenuated amphetamine anorexia. These rats ate significantly more of the pellet test diet than controls at each dosage of amphetamine
Ct(63) = at least 2.58, £<.02) and displayed significantly smaller percent changes in intake relative to control changes to each amphetamine dosage CtC63) = at least 2.04, £ <.05).
Discussion
The magnitude of the anorexia induced by amphetamine was, at least in part, determined by the palatability of the test diet offered the rats. When an extremely palatable high-fat test diet was used, amphetamine induced small and rather variable suppressions of feeding in control rats and was without effect in both VMH and DLT rats. When these rats were offered a less palatable pellet test diet, however, amphetamine induced reliable and dose-dependent anorexia in control and VMH rats 25
and was less effective in DLT rats. These findings suggest
that diet palatability may override the satiating effects of
drugs such as amphetamine. Others have described similar
interactions between diet palatability and anorexia. Krinsky, Lotter, and Woods C1979) reported that cholecystokinin CCCK;
Appendix A), a putative gut satiety hormone, induced significant anorexia in control and VMH rats fed a pellet test diet but not a high-fat test diet. Campbell and Davis (.1974) , using intraduodenal infusions of glucose to induce anorexia, noted that such infusions induced anorexia when the rats were offered a dilute glucose solution but were ineffective when a sweetened condensed milk diet was used. Finally, Russek (1971) demonstrated that increases in diet palatability may shift the anorexia dose-response curve to the right. Dogs were given intraperitoneal injections of adrenaline, a treatment that presumably induces anorexia by altering glycogenolysis within the liver (see Appendix A). When a single threshold adrenaline dosage was used, dogs displayed considerable anorexia when fed a chow diet but also consumed large amounts of raw meat following adrenaline treatment. Larger dosages of adrenaline were required to produce a given level of anorexia when the dogs were fed the raw meat diet. There is a striking parallel between the failure of amphetamine to induce anorexia in rats fed palatable test diets and its well-known inefficacy as a weight control substance in obese humans whose diets are not 26
limited to less calorically dense (and also less palatable)
foods (Mayer, 1966; Thorpe, 1967).
In Experiments 1 and 2, DLT rats displayed an attenua
tion of amphetamine anorexia that was independent of test
diet palatability. This attenuation is not likely the result
of increased hunger motivation in DLT rats since these rats
were not hyperphagic relative to control rats when fed a pel
let test diet. Further, these tests were conducted while the
rats were maintained at 80% body weight and were additionally
deprived of food for 23 hours prior to each intake test.
The outcomes of Experiments 1 and 2 clearly confirm and ex tend the notion that the DLT, but not the VMH, contains a por tion of the mechanism that mediates amphetamine anorexia. 27
EXPERIMENT 3
Amphetamine induces anorexia and also produces marked
psychomotor arousal. Carlton 01963), Cole (1972), and, more
recently, Lyon and Bobbins (1975) argue that amphetamine
anorexia may result, in part, because feeding is incompatible
with the arousal behaviors (hyperactivity, stereotypy) produced
by amphetamine. DLT lesions typically encompass portions of
the brainstem reticular formation, a region long implicated in
behavioral arousal (Moruzzi & Magoun, 1949). The attenuation
of anorexia observed in DLT rats may therefore reflect an
influence of these lesions on that portion of amphetamine
anorexia that results from increased arousal. Experiment 3,
therefore, examined the feeding behavior of VMH, DLT, and
control rats to phenylpropanolamine (PPA), an anorexic drug
structurally similar to amphetamine that does not produce
marked psychomotor arousal (Epstein, 1959).
Method
Procedure
The rats continued maintenance at 80% body weight during two series of food intake tests. An initial series consisted of two intake tests, each separated by 48 hours, in which the rats were deprived of food, but not water for 23 hours. In the first test, each rat received 1.0 ml/kg saline (ip) 30 minutes prior to 60 minutes access to the pellet test diet 28
while in the second test, each rat received 10.0 mg/kg PPA.
A second series of intake tests used 5.0, 10.0, and 20.0
mg/kg PPA and the procedures of Experiments 1 and 2 to demon
strate that the anorexia induced by PPA was does-dependent.
Results and Discussion
Figure 4 presents group mean pellet intake following sa
line and 10.0 mg/kg PPA. Both VMH and DLT rats ate signifi
cantly more of the pellet test diet than control rats after
saline injection (t(21) = 2.3 and 3.14, £<.05, £<.01, re
spectively). PPA, at a dosage of 10.0 mg/kg, significantly suppressed pellet intake in all rats (t(21) = at least 3.75,
£<.01). A further analysis, using the difference between saline and PPA intake for each rat, revealed no significant between-group differences in the magnitude of anorexia in duced by 10.0 mg/kg PPA (F(2, 21) = 2.14, £<.14).
Figure 5 presents group mean pellet intake following saline and 5.0, and 10.0 and 20.0 mg/kg PPA. Although VMH and
DLT rats ate slightly more of the pellet test diet than con trol rats after saline injection, these differences were not significant. All rats displayed similar suppressions of pel let intake to each of the PPA dosages. Relative to their respective saline baselines, all rats ate significantly less of the pellet diet to 10.0 mg/kg PPA (t(63) = at least 2.6,
£<[.05) and to 20.0 mg/kg PPA (t (63) = at least 5.0,
£
saline (Test 1) and following 10.0 mg/kg PPA (Test 2). 80% BW-PELLETS
8 D)
CO
U) o Z 4 < LU
2
SAL 10 SAL 10 SAL 10
CON VMH DLT Figure 5. Group mean pellet intake Cleft panel} and mean percent
change in intake Cright panelI during a 60 minute test
period following either saline or phenylpropanolamine
C5.0, 10.0 and 20.0 mg/kg) injection. 15 80% BW- PELLETS +25
12 0 ^ O) n 8 ^ ^ D L T % UJ > 8 •—• VMH < 9 --25 z 8 °—a CON o U) to Z 6 -50 < > - -75
0 y/- 10 20 10 20
DOSAGE (mg/kg)
PHENYLPROPANOLAMINE 33
using either the difference between saline and PPA intake or
percent change in intake to PPA, revealed no significant between-
group differences in the magnitude of anorexia induced by any
dosage of PPA.
PPA induced moderate suppression of pellet intake in all
rats across a wide range of dosages with no differences between
groups in the magnitude of anorexia induced by PPA. Thus, DLT
rats exhibited attenuated anorexia to amphetamine, yet displayed
normal anorexia to PPA. These differential effects in DLT rats
were unexpected in view of the reported similarities of these
anorexic substances. Both amphetamine and PPA induce anorexia,
easily cross the blood-brain-barrier, indirectly effect the release of catecholamines but PPA is thought to be devoid of central nervous system arousal properties (Kornblith & Hoebel,
1976; Hoebel, 1976; Aviado, 1970). 34
EXPERIMENT 4
DLT lesions differentially influenced the anorexia induced
by anorexic drugs that are similar in structure but dissimilar
in arousal-inducing properties (Experiments 2 and 3). DLT
lesions attenuated amphetamine anorexia but did not influence
phenylpropanolamine anorexia. These outcomes support the notion
that attenuated amphetamine anorexia observed in DLT rats
reflects an influence of DLT lesions on the arousal produced
by amphetamine. Carey (1976) demonstrated that radio-frequency
lesions of the DLT attenuated both the anorexia and the hyper
activity induced by amphetamine. Experiment 4 therefore
provided comparisons between the effects of amphetamine (2.0
mg/kg) and phenylpropanolamine (20.0 mg/kg) on locomotor
activity in DLT, VHM and control rats.
Method
Apparatus
The locomotor activity apparatus was located in an
experimental room under continuous illumination and temperature control (21°C). The apparatus was a chamber (60 X 60 X 46 cm) constructed of plywood with a hinged plywood lid and a wire- mesh floor. The inner surfaces of the chamber were painted a dull gray and were lined with Plexiglass. The interior of the apparatus was divided into 25 rectangular sections by 4 photo- beams arranged 15 cm apart and 5 cm above the wire-mesh floor along each axis of the chamber. Photobeams were passed 35
through infrared filters inset in the chamber walls. Inter
ruption of each photobeam was measured using photocell relays
(Hunter model 335S) and electromagnetic programming equipment.
Procedure
The rats were maintained at 80% body weight in the con stant weight cages throughout the activity test sequence and were deprived of food, but not water, for 23 hours prior to each test. Because of time constraints imposed by using only one activity apparatus, half of the rats in each group were randomly assigned to one of two squads (n = 12 each) with each tested in the activity apparatus every other day. Because locomotor activity is initially elevated in a novel apparatus, the rats were adapted to the activity apparatus on two tests.
Each rat was injected (ip) with 1.0 ml/kg saline and placed into a plastic cage (without food or water) for 30 minutes.
The rat was then piaced into the apparatus and locomotor ac tivity was measured during a 30 minute interval. Immediately after an activity test, the rats were rapidly returned to 80% body weight using pellets and were maintained at 80% body weight in the constant weight cages until the next deprivation period.
The activity test sequence consisted of 3 tests, using the procedures described above, in which the rats received saline, 2.0 mg/kg amphetamine sulfate and 20.0 mg/kg PPA.
These dosages were used in the activity sequence because large 36
differences in food intake were obtained in Experiments 2 and
3 to these dosages. Each rat received each dosage once with
drug order counterbalanced for each lesion group. Any effects
of time of testing on activity were controlled by counterbal
ancing time of testing (within two-hour blocks) for each
lesion group across the 3 test periods.
Results
Because preliminary inspection of the activity data re
vealed that group activity means and variances were propor
tional, the data were subjected to a log^Q transformation
(Kirk, 1968). Figure 6 presents group mean log^g activity
counts during a 30 minute period after saline, 2.0 mg/kg am
phetamine and 20.0 mg/kg PPA. Although VMH rats were slightly
hypoactive following saline treatment (Teitelbaum, 1957;
Sclafani, Belluzzi & Grossman, 1970), there were no signifi
cant between-group differences. Amphetamine reliably in
creased activity in all rats (t(42) = at least 2.66, £ < .05)
with all rats displaying comparable increases in activity
(difference between saline and amphetamine; F(2,21) = 0.13,
p>.87). All rats were slightly hypoactive after administra
tion of PPA, but this effect was only significant in VMH rats
(t(42) = 2.11, £ <.05).
Discussion
The outcomes of Experiment 4 did not support the hypothe sis that the attenuated anorexia observed in DLT rats Figure 6. Group mean log^g activity counts during a 30 minute period
following 0.9% saline (S), 2.0 mg/kg amphetamine sulfate CA),
and 20.0 mg/kg phenylpropanolamine hydrochloride (P)
injections. MEAN LOG^o ACTIVITY/30 MIN
O —i hO CO 1 , 1
n O > z
CO < ^ > % -U
(/) >
"D
se 39
in Experiments 1 and 2 resulted from a blockade of an arousal
component of amphetamine anorexia. Although, the anorexia
induced by amphetamine was attenuated by DLT destruction, the
hyperactivity induced by amphetamine was not. The failure of
these DLT rats to display both attenuated anorexia and also
attenuated hyperactivity to amphetamine is puzzling since Carey
(1976) observed just such effects after DLT lesions. These
inconsistencies may be attributable to a number of procedural
differences, including type of lesion (radio-frequency vs elec-
trolyticl, body weight levels at the time of activity, testing,
and the use in these «experiments of food deprivation prior to activity testing. It should be noted, however, that more recent data suggest that competing arousal responses may not be related to the magnitude of anorexia observed in intact rats (Koob, Riley, Smith, & Robbins, 1978).
Relative to the changes in locomotor activity observed in control and also DLT rats, VMH rats unexpectedly displayed significantly larger decreases in activity to a 20.0 mg/kg dosage of PPA. This outcome, along with the observation that
VMH rats displayed a nonsignificant, trend toward larger suppression of pellet intake to this PPA dosage, suggests that
VMH rats may, in some fashion, be sensitized to the pharma cological effects of PPA. Epstein (1959) also reported a small and nonsignificant trend for larger PPA anorexic effects in VMH rats fed a wet-mash diet. 40
EXPERIMENT 5
Carey (19791, in a report that appeared only at the end of
Experiment 4, demonstrated that the paradoxical suppression
of responding for brain stimulation reward by large (5 mg/kg)
dosages of amphetamine is due to debilitation associated with
hyperthermia induced by amphetamine. When amphetamine-hyper-
thermia was prevented by cooling the rats prior to and during
testing, amphetamine increased responding for brain-stimulation
reward. This outcome, along with the demonstration that
amphetamine, at dosages as low as 1.0 mg/kg, will support a
conditioned taste aversion (Wise, Yokel & DeWit, 1976; Carey,
1973; Stolerman & D'Mello, 1978; Booth, D'Mello, Pilcher & Sto-
lerman, 1976) suggests that a part of the anorexia induced by
amphetamine may result from malaise, perhaps associated with
hyperthermia. Because the attenuated amphetamine anorexia ob
served in DLT rats may reflect attenuated hyperthermia.
Experiment 5 examined the influence of amphetamine (2.0 mg/kg)
and PPA (20.0 mg/kg) on rectal temperature in VMH, DLT and con
trol rats.
Method
Procedure
Because the hyperphagia induced by destruction of either
the VMH or the DLT is infrequently and unexplicably transient
(Irwin, 1975; Grossman & Grossman, 1977), it was deemed of some importance to determine that the lesioned rats were hyperphagic 41
at the completion of drug testing in Experiment 4, 136 days
after surgery. Food intake and body weight changes were
therefore monitored during a 30 day period at the end of
Experiment 4. The rats were transferred to maintenance in
standard wire-mesh cages and were maintained on the high-fat
diet and tap-water. Body weight and 72-hour cumulative food
intake was measured every 3rd day throughout the 30 day main
tenance period. In addition, food intake was measured at the
beginning of each light (2000 h) and dark (0800 h) portion of the reverse illumination schedule during Days 19-20 of the 30 day maintenance period. These day/night food intake measures served to demonstrate that the rats had shifted their intakes to match the reverse-illumination schedule and to demonstrate that the DLT rats were hyperphagic during the night portion of this schedule.
Assessment of rectal temperature changes to atmphetaraine and PPA was carried out during Days 21-25 of the maintenance period. As a consequence, VMH and DLT rats were considerably obese during these tests. Rectal temperatures were recorded every day during the night portion of the reverse-illuminâtion schedule (approximately 1250 h). No attempt was made to control body weight during these tests and the rats were not deprived of either food or water prior to each temperature assessment. 42
The rats were adapted to the procedure in 2 tests in
which temperature assessment was carried out 30 minutes after
injection of 1.0 ml/kg saline (ip). With each rat lightly re
strained between the experimenter's arm and chest and its
tail slightly elevated, a probe (1.5 ram in dicimeter and 31 ram in length; Thermy Mura Corp.) was fully inserted into the rat's rectum. The resistance of the probe tip was measured approximately 20 seconds after insertion using a Hewlett-
Packard (Model 3476A) multimeter. Resistance values (K/L) were subsequently converted to temperature values using: temperature (C°) = (-6.9696 (K/i, ) + 69.4121).
The drug sequence used the procedures described above and the sequence procedures of Experiment 4. Each rat was tested once after saline, 2.0 mg/kg d-amphetamine sulfate and
20.0 mg/kg PPA hydrochloride treatment, with drug order counterbalanced for each lesion group.
Results
Figure 7 presents group mean rectal temperature CC°) recorded 30 minutes after injection of saline, 2.0 mg/kg amphetamine, and 20.0 mg/kg PPA. After injection of saline, there were no significant differences in rectal temperature between control and DLT rats, but VMH rats were significantly hypothermic, relative to control rats CtC21) = 2.14, £<.05).
There were no significant changes in rectal temperature in any Figure 7. Group mean rectal temperature 30 minutes after saline (S),
2.0 mg/kg amphetamine CAj, and 20.0 mg/kg PPA CP). The
figures above each, group are the average group body weight
during assessment of rectal temperature in Experiment 5. 40.0 r 285 381 484g oU
LU Œ:
< OL uu o_ 39.0 -
LU
u LU z 38.0 < 1 S A A P S A
CON DLT VMH 45
group after injection of 20.0 mg/kg PPA. Amphetamine, at
a dosage of 2.0 mg/kg, however, reliably increased rectal
temperature (hyperthermia) in both control and VMH rats (t(42) =
3.55 and 3.63, respectively, £<.001) but was without signif
icant effect in DLT rats.
The influence of VMH or DLT destruction on body weight and
day/night food intake is depicted in Figures 8 and 9,
respectively. Maintenance of these lesioned rats on the high-
fat diet for 30 days resulted in substantial increases in body
weight. As was the case immediately after surgery, both VMH
and DLT rats gained significantly more body weight than control
rats (overall means; t(21) = 12.83 and 5.83, respectively,
2 <.001) with VMH rats also gaining significantly more body
weight than DLT rats (overall means; t(21) = 6.99, £<.001).
As expected, differences in body weight gain between the
lesioned and control rats were paralleled by differences in
day/night food intake (Figure 9). VMH rats ate significantly
more food than control rats during the day and night portions of the reverse-illumination schedule (t(21) = 10.11 and 5.47, respectively, £<.001). DLT rats ate significantly more food than control rats during the night (t(21) = 4.38, £<.001) and their night intake was not significantly different from that of VMH rats. During the day, however, DLT food intake was not significantly different from control food intake and these rats ate significantly less food than VMH rats (t(21) = 8.95, £<;.001). Figure 8. Group mean cumulative body weight gains for. VMH, DLT and
control rats fed a high-fat maintenance diet for 30 days
CDays 137-167 after surgery). 400 D)
< 320 O VMH
9 240 LU y LU - 160 A —A— ^ DIT /C.
S 3 80 u •—•—-o CON z < LU J L J 1 ' : I I I 1 2 18 24 30
DAYS Figure 9. Group mean day (Dl and night CN) high-fat intake for VMH, DLT
and control rats maintained under a reverse-illumination
schedule. Each value represents the average of 2 consecutive
12-hour intake periods. 617 50
Thus, the rats were entrained to the reverse-illumination
schedule in that control rats displayed a normal diurnal
feeding pattern, VMH rats were hyperphagic both during the day
and night while DLT rats were hyperphagic only during the
night portion of the day/night cycle.
Although others (Irwin, 1975; Grossman & Grossman, 1977)
report that the hyperphagia induced by destruction of the
VMH or the DLT may in some measure be transient, both VMH and,
to a lesser extent, DLT rats in the present experiments dis
played substantial hyperphagia and weight gain both immedi
ately after surgery and some 136 days later.
Appendix B presents selected unretouched photomicro
graphs of tissue damage produced by electrolytic lesions of
the VMH and the DLT.
VMH lesions were typically quite large and involved sub
stantial portions of the ventromedial hypothalamus. Damage was largely restricted to an area bounded dorsally by the
dorsomedial hypothalamic nucleus, laterally by the plane of
the fornix, ventrally by the base of the brain and extending longitudinally between the anterior hypothalamic nucleus and the premammillary region. Although tissue damage was mostly unilateral in one rat (VMH-15), its data were not discarded because it displayed substantial hyperphagia and weight gain both after surgery and during the 30 day maintenance period following behavioral testing. 51
DLT destruction was typically columnar in appearance with
destruction characteristically smaller dorsally than ventrally,
presumably because dorsal destruction of tissue is due to gas
bubbles trailing the electrode as it exits the brain. DLT
destruction typically extended from the ventrolateral edge of
the central gray, through the reticular formation to a
horizontal plane through the ventral edge of the superior
cerebellar peduncle. Tissue destruction extended rostrally
to the posterior portion of the interpeduncular nucleus and
caudally throughout much of the length of the locus coeruleus.
These lesions were often asymmetrical with one lesion slightly
more lateral than the other. Finally, these lesions were
somewhat posterior and dorsal to those previously obtained with
these lesion parameters (Peters, Gunion, & Wellman, 1979;
Peters, Wellman, & Gunion, 1979).
Discussion
Although PPA and amphetamine induced anorexia in neuro-
logically intact rats, these drugs differentially influenced
both activity (Experiment 4) and also rectal temperature
(Experiment 5). PPA reliably induced anorexia at a dosage of
20.0 mg/kg in control rats, but was without effect on either
activity or rectal temperature. These findings suggest that
PPA may be the anorexic agent of choice since it, unlike amphetamine, apparently does not alter a number of metabolic parameters (activity, core temperature) that might indirectly 52
influence feeding. Although no report has specifically assessed the malaise properties of PPA, the present findings demonstrate that PPA does not non-specifically suppress on going behavior. Further, Hoebel (1976) has argued that the appetitive motivation of an animal can be indexed by the rate of self-stimulation CSS) and the rate of stimulation-escape
CSE) obtained from chronically implanted electrodes within the lateral hypothalamus (see Appendix A for a further discussion of this paradigm). Satiety, in this paradigm, is indexed by a shift in responding from primarily SS to mostly
SE. This satiety pattern of responding has recently been obtained by Kornblith and Hoebel C1978) after PPA injection.
Lastly, the increase in responding for SE after PPA injection rules out general malaise or sedation as contributing to the anorexia induced by PPA.
In contrast to the effects obtained with PPA, amphetamine induced hyperthermia in control rats at a dosage C2.0 mg/kg) that also suppressed pellet intake. One interpretation that can be derived from these data is that amphetamine induces hyperthermia, a state that is akin to illness, and this state partially contributes to the anorexia induced by amphetamine. At least one report, however, using mice as experimental subjects, has failed to obtain a correspondence between hyperthermia and anorexia induced by amphetamine
CMantegazza, Muller, Naimzada & Riva, 1970), an outcome that 53
does not support h.ypertherraic malaise as mediating a part of
amphetamine anorexia. It should be noted that this notion of hyperthermic malaise is susceptible to experimentation.
Namely, the hypothesis would be confirmed by the demonstration that amphetamine is less effective as an anorexic agent when hyperthermia is prevented than when hyperthermia is allowed to occur (i.e., neurologically intact rats are treated with amphetamine and then allowed to feed in either a cold or a warm environment).
Finally, and most importantly, DLT rats did not display a significant hyperthermic response to amphetamine, an outcome that parallels the attenuated anorexia induced by amphetamine in these rats. Although the DLT rats were moderately obese
C381 g) during the assessment of rectal temperature, the attenuated amphetamine hyperthermia observed in these rats is not likely an artefact of obesity per se, since VMH rats dis played significant amphetamine hyperthermia yet were far more obese [484 g) than DLT rats. These outcomes clearly support an interpretation of the influence of DLT destruction on amphetamine anorexia as reflecting a blockade of a portion of amphetamine anorexia that is the result of hyperthermic mal aise and not an influence of these lesions on satiety. 54
GENERAL DISCUSSION
The present experiments confirm earlier demonstrations
that destruction of either the VMH or the DLT produces
concomitant elevations of food intake and body weight but
differentially influence the anorexia induced by amphetamine.
VMH destruction, unlike DLT destruction, is without effect on the anorexia induced by amphetamine, thereby precluding
involvement of the VMH in amphetamine anorexia.
Amphetamine, at a conceptual level, presumably induces
a motivational state of satiety by activating a DLT satiety
mechanism. Such a satiety mediational hypothesis implies that the extent of overeating observed after destruction of the
DLT should be directly related to the magnitude of attenuation of amphetamine anorexia induced by DLT destruction. This pre
dicted relation, however, may not always obtain following
DLT lesions. Table 2 presents ranked body weight gains (after
Experiment 4) and ranked anorexic responses Csaline intake- amphetamine intake) to 2.0 mg/kg amphetamine CExperiment 2).
Although, in general, it can be seen that weight gain in DLT rats was positively related to attenuated amphetamine anorexia, this relationship did not hold for all DLT rats. DLT-34, for example, displayed a substantial weight gain yet also exhibited the largest suppression of intake to amphetamine. In contrast,
DLT-45, displayed ..only a minimal weight gain but also displayed only a small (i.e., attenuated) suppression of intake to amphetamine. 55
Table 2. Summarization of the correspondence between weight
gain during a 30 day period after drug testing and
the anorexic effects of 2.0 mg/kg amphetamine on
pellet intake (Experiment 2). Weight gains and the
difference between saline and pellet intakes for
each rat were ranked with smaller ranks reflecting
larger effects. Where ties were found, the average
of the ranks is given.
30 day Ranked Ranked Group Rat weight gain weight gain anorexic effect
9 291 6 4.5 12 299 5 4.5 15 211 10 14 22 309 4 4.5 24 350 3 22 25 358 2 4.5 43 279 7 4.5 44 368 1 4.5
1 228 8 24 4 154 14 12 11 172 11.5 21 13 146 15 11 21 172 11.5 18 23 156 13 23 34 218 9 1 45 126 16 20
3 78 20 9.5 8 65 22 9.5 14 55 24 19 26 93 18 16.5 29 70 21 8 30 95 17 14 32 81 19 14 36 58 23 16.5 56
These individual differences in the relationship between weight gain and attenuated amphetamine anorexia imply that these effects may be dissociable. The agreement between weight gain and attenuated amphetamine anorexia obtained in the remaining DLT rats may be an artefact of the selection procedure used; because of limitations imposed by constant weight cage availability, amphetamine anorexia was not assessed in less hyperphagic DLT rats.
If amphetamine induces anorexia via activation of a putative satiety mechanism within the DLT, other anorexic substances might similarly induce anorexia via this mechanism.
To date, however, only the anorexia induced by amphetamine has been demonstrated to be diminished by DLT destruction. In the present experiments, DLT rats did not display attenuated anorexia to PPA, an anorexic agent similar in structure to amphetamine. Further, Zacharko and Wishart (1978) reported that DLT lesions were without effect on the anorexia induced by fenfluramine, an anorexic agent that may activate serotonergic satiety mechanisms CJesperson & Scheel-Kruger , 1973; Sailer &
Strieker, 1976; Breisch, Zemlan & Hoebel, 1976). Although these findings are in no sense an exhaustive examination of all anorexic agents, the attenuation of anorexia observed in
DLT rats may be peculiar to amphetamine.
Amphetamine is well-known for its anorexic effects in animals and man, but is equally well-known for its ability to induce a myriad of complex biochemical and metabolic effects 57
both centrally and peripherally (Costa & Garratini, 1970),
any one or combination of which may influence feeding.
Amphetamine, for example, is known to possess both rewarding
and also aversive properties in that rats will emit responses
upon which infusions of small amounts of amphetamine are made
contingent, yet will also refuse to consume distinctively
flavored solutions that on prior occasions have been paired
with amphetamine (Wise, Yokel & DeWit, 1976). A demonstration
of a conditioned taste aversion using amphetamine is consistent
with the notion advanced herein that malaise may partially
contribute to the anorexia induced by amphetamine. Further,
the findings of Carey (1979) implicate the hyperthermia
induced by amphetamine as a source of malaise.
Amphetamine and PPA both induce anorexia* however,
a portion of the anorexia induced by amphetamine may be the
result of malaise. Control and VMH rats display comparable
patterns of anorexia to both amphetamine and PPA. In contrast,
DLT rats display normal anorexia to PPA and attenuated anorexia to amphetamine. DLT lesions do not alter the anorexia induced
by PPA and may attenuate amphetamine anorexia, not because of any influence on a putative satiety mechanism, but rather
via a blockade of hyperthermic malaise.
Confirmation of the notion that DLT lesions block hyper thermic malaise will likely come from two experiments. Such a notion would be supported by demonstrating that DLT lesions 58
block the development of a conditioned taste aversion to
amphetamine when the rats are tested in a warm environment
conducive to hyperthermia. Similarly, DLT rats should not
display attenuated amphetamine anorexia , relative to con
trol rats, when food intake tests are conducted in a cool
environment that prevents amphetamine induced hyperthermia.
Finally, the conceptualization of hyperthermic malaise advanced herein is admittedly speculative, but is intended to provide an alternative to the notion that DLT lesions destroy a neural substrate for satiety. As is well-known in the VMH literature, overeating per se does not imply the absence of satiety since VMH rats come to regulate their food intake after attaining an elevated body weight and eat appropriately to a number of regulatory challenges that induce anorexia in the intact rat (e.g., stomach and intravenous infusion of nutrients). Any theoretical account of the overeating and the attenuated amphetamine anorexia observed after DLT lesions cast in terms of an endogenous CNS satiety mechanism must, at this point, be accepted only as conjecture. 59
REFERENCE NOTE
1. Zacharko, R. University of Saskatchewan, Personal
communication, August 2, 1979. 60
REFERENCES
Ahlskog, J. E. Food intake and amphetamine anorexia after
selective brain norepinephrine loss. Brain Research,
1974, 82, 211-240.
Ahlskog, J. E. Feeding response to regulatory challenges after
6-hydroxydopamine injection into the brain noradrenergic
pathways. Physiology and Behavior, 1976, 11_, 407-411.
Ahlskog, J. E., & Hoebel, B. G. Overeating and obesity from
damage to a noradrenergic system in the brain. Science,
1973, m, 166-168.
Ahlskog, J. E., Hoebel, B. G., & Breisch, S. T. Hyperphagia
following lesions of the noradrenergic pathway is
prevented by hypophysectomy. Federation Proceedings,
1974, 33, 463.
Ahlskog, J. E., Randall, P. K., & Hoebel, B. G. Hypothalamic
hyperphagia: Dissociation from hyperphagia following
destruction of noradrenergic neurons. Science, 1975,
190, 399-401.
Aviado, D. M. Sympathomimetic drugs. Springfield, 111.;
Chas. Thomas, 1970.
Beatty, W. W. Operant responding in rats with dietary obesity;
A systematic replication. Physiology and Behavior, 1978,
21, 671-672.
Booth, D. A. Amphetamine-anorexia by direct action on the
adrenergic feeding system of rat hypothalamus. Nature,
1968, 217, 869-870. 61
Booth, D. A., D'Mello, G. D., Pilcher, C. W. T., & Stolerman,
I. P. Paradoxical aversive property of amphetamine.
British Journal of Pharmacology, 1976, ]^, 424-425.
Breisch, S. T., Zemlan, F. P., & Hoebel, B. G. Hyperphagia
and obesity following serotonin depletion by intra
ventricular p-chlorophenylalanine. Science, 1976, 192,
382-385.
Brobeck, J. R., Tepperman, T., & Long, C. M. H. Experimental
hypothalamic hyperphagia in the albino rat. Yale Journal
of Biology and Medicine, 1943, ]^, 831-853.
Campbell, C. S., & Davis, J. D. Peripheral control of food
intake: Interaction between test diet and postingestive
chemoreception. Physiology and Behavior, 1974, ]^, 377-
384.
Carey, R. J. Long-term aversion to a saccharin solution
induced by repeated amphetamine injections. Pharmacology
Biochemistry and Behavior, 1973, 1, 265-270.
Carey, R. J. Effects of selective forebrain depletions of
norephinephrine and serotonin on the activity and food
intake effects of amphetamine and fenfluramine.
Pharmacology Biochemistry and Behavior, 1976, 519-523.
Carey, R. J. Facilitation of responding for rewarding brain
stimulation by a high dose of amphetamine when hyper
thermia is prevented. Psychopharmacology, 1979, 61,
267-271. 62
Carlisle, H. J. Differential effects of amphetamine on food
and water intake in rats with lateral hypothalamic le
sions, Journal of Comparative and Physiological Psychol
ogy, 1964, 47-54.
Carlton, P. L. Cholinergic mechanisms in the control of
behavior. Psychological Review, 1963, 70.f 19-39.
Cole, S. 0. The relationship of amphetamine-induce anorexia
and freezing under free-feeding conditions. Pharmacolog
ical Research Communication, 1972, £, 71-76.
Costa, E., & Garattini, S. Amphetamines and related compounds.
New York: Raven Press, 197 0.
Ehrenfreund, D. The motivational effect of a continuous weight
loss schedule. Psychological Reports, 1960, 339-345.
Epstein, A. E. Suppression of eating and drinking by ampheta
mine and other drugs in normal and hyperphagic rats.
Journal of Comparative and Physiological Psychology, 1959,
37-45.
Friedman, M. I., & Strieker, E. M. The physiological psychol
ogy of hunger; A physiological perspective. Psycholog
ical Review, 1976, 409-431.
Garattini, S., Jori, A., & Samanin, R. Interactions of various
drugs with amphetamine. Annals of the New York Academy
of Sciences, 1976, 281, 409-425.
Gold, R. M. Hypothalamic obesity: The myth of the ventro
medial nucleus. Science, 1973, 18, 488-490. 63
Grossman, S. P., & Grossman, L. Food and water intake in rats
after transections of fibers en passage in the tegmentum.
Physiology and Behavior, 1977, 1^, 647-658.
Grossman, S. P., Grossman, L. & Halaris, A. Effects on hypo
thalamic and forebrain NE and 5-HT of tegmental knifecuts
that produce hyperphagia or hyperdipsia in the rat.
Pharmacology, Biochemistry and Behavior, 1977, 101-106.
Hetherington, A. W., & Ranson, S. W. Hypothalamic lesions
and obesity in the rat. Anatomical Record, 1940, 78,
149-172.
Hoebel, B. G. Satiety: Hypothalamic stimulation, anorectic
drugs, and neurochemical substrates. In D. Novin, W.
Wyrwicka, & G. Bray (Eds.), Hunger ; Basic mechanisms and
clinical implications. New York: Raven Press, 1976.
Hoebel, B.G. Hernandex, L., & Thompson, R. D. Phenyl
propanolamine inhibits feeding, but not drinking induced
by hypothalamic stimulation. Journal of Comparative and
Physiological Psychology, 1975, 8^, 1046-1052.
Irwin, D. Effects of ventromedial hypothalamic lesions on
passive avoidance behavior in rats. Unpublished doctoral
dissertation, Iowa State University, 1975.
Jesperson, S., & Scheel-Kruger, J. Evidence for a difference
in mechanism of action between fenfluramine- and
amphetamine-induced anorexia. Journal of Pharmacological
Pharmacology, 1973, 25, 49-54. 64
Kennedy, G. C., & Mitra, J. The effect of d-amphetamine on
energy balance in hypothalamic obese rats. British
Journal of Nutrition, 1963, 569-573.
Kent, M., & Peters, R. H. Effects of ventromedial hypothal
amic lesions on hunger motivated behavior in rats. Jour
nal of Comparative and Physiological Psychology, 1973,
92-97.
Kirk, R. E. Experimental design: Procedures for the behav
ioral sciences. Belmont, California: Brooks-Cole, 1968.
Konig, J. F. R., & Klippel, R. A. The rat brain. Baltimore:
Williams and Wilkins, Co., 1963.
Koob, G. F., Riley, S. J., Smith, S. C., & Robbins, T. W.
Effects of 6-hydroxydopamine lesions of the nucleus
accumbens septi and olfactory tubercle on feeding, loco
motor activity, and amphetamine anorexia in the rat.
Journal of Comparative and Physiological Psychology,
1978, 92, 917-927.
Kornblith, C. L., & Hoebel, B. G. A dose response study of
anorectic drug effects on food intake, self-stimulation,
and stimulation-escape. Pharmacology Biochemistry and
Behavior, 1976, 215-218.
Krinsky, R., Lotter, E. C., & Woods, S. C. Appetite suppres
sion caused by CCK is diet specific in VMH-lesioned rats.
Physiological Psychology, 1979, 1_, 67-69. 65
Leibowitz, S. F. Catecholaminergic adrenergic mechanisms of the
lateral hypothalamus: Their role in the mediation of
amphetamine anorexia. Brain Research, 1975, 9£, 529-545.
Luttmers, L. L. Comparisons of experimentally induced obesity
syndromes. Unpublished doctoral dissertation, Iowa State
University, 1978.
Lyon, M., & Bobbins, T. The action of central nervous system
stimulant drugs: A general theory concerning amphetamine
effects. In W. B. Essman & L. Valzelli (Eds.), Current
developments in psychopharmacology CVol. 2). New York;
Spectrum, 1975.
Mailer, 0. The effect of hypothalamic and dietary obesity on
taste preference in rats. Life Sciences, 1964, 1281-
1291.
Mantegazza, P., Muller, E. E., Naimzada, M. K., & Riva, M.
Studies on the lack of correlation between hyperthermia,
hyperactivity, and anorexia induced by amphetamine. In
E. Costa & S. Garattini (.Eds.), Amphetamine and related
compounds. New York: Raven Press, 1970.
Mayer, J. Some aspects of the problem of regulation of food
intake and obesity. New England Journal of Medicine,
1966, 274, 722-731.
Moruzzi, G., & Magoun, H. W. Brain stem reticular formation
and activation of the EEG. Electroencephalography and
Clinical Neurophysiology, 1949, 1, 455-473. 66
Oltmans, G., Lorden, J. F., & Margules, D. L. Food intakes and
body weights: Effects of specific and non-specific lesions
in the midbrain path of the ascending noradrenergic
neuron in the rat. Brain Research, 1977, 128, 293-308.
Panksepp, J., & Booth, D. A. Tolerance in the depression of
intake when amphetamine is added to the rats food.
Psychopharmacologia, 1973, 22, 45-54.
Peters, R. H., Gunion, M. W., & Wellman, P. J. Influence of
diet palatability on maintenance feeding behavior in
rats with dorsolateral tegmental damage. Physiology and
Behavior, in press, 1979.
Peters, R. H., Luttmers, L. L., Gunion, M. W., & Wellman, P. J.
VMH syndrome: Finickiness? Physiology and Behavior,
1978, 20, 279-285.
Peters, R. H., Wellman, P. J., & Gunion, M. W. Experimental
obesity syndromes in rats: Influence of diet palatability
on maintenance body weights. Physiology and Behavior,
in press, 1979.
Powley, T. L. The ventromedial hypothalamic syndrome, satiety,
and a cephalic phase hypothesis. Psychological Review,
1977, M, 89-126.
Reynolds, R. W. The effect of amphetamine on food intake in
normal and hypothalamic hyperphagic rats. Journal of
Comparative and Physiological Psychology, 1959, 52,
682-684. 67
Russek, M. Hepatic receptors and the neurophysiological
mechanisms controlling feeding behavior. In S. Ehrenpreis
(Ed.), Neuroscience Research (Vol. 4). New York:
Academic Press, 1971.
Sailer, C. F., & Strieker, E. M. Hyperphagia and increased
growth in rats after interventricular injection of 5,7-
dihydroxytryptamine. Science, 1976, 192, 385-387.
Sclafani, A. Food motivation in hypothalamic hyperphagic rats
reexamined. Neuroscience and Biobehavioral Reviews,
1978, 2, 339-355. Sclafani, A., Belluzzi, J. D., & Grossman, S. P. Effects of
lesions in the hypothalamus and amygdala on feeding
behavior in the rat. Journal of Comparative and
Physiological Psychology, 1970, 12^, 394-403.
Sclafani, A., & Berner, C. H. Hyperphagia and obesity
produced by parasaggittal and coronal hypothalamic
knife cuts: Further evidence for a longitudinal feeding
inhibitory pathway. Journal of Comparative and Physio
logical Psychology, 1977, 1000-1018. Stolerman, I. P., & D'Mello, G. D. Amphetamine-induced taste
aversion demonstrated with operant behavior. Pharma
cology Biochemistry and Behavior, 1978, IB, 107-111.
Stowe, F. R., & Miller, A. T. The effect of amphetamine on
food intake in rats with hypothalamic hyperphagia.
Experientia, 1957, 114-115. 68
Teitelbaum, P. Random and food-directed activity in hyper-
phagic and normal rats. Journal of Comparative and
Physiological Psychology, 1957, 486-490.
Thorpe, G. Treating overweight patients. Journal of the
American Medical Association, 1967, 165, 1361-1365.
Ungerstedt, U. Stereotaxic mapping of monoamine pathways in
the rat brain. Acta Physiologica Scandinavia (Supplement
367), 1971, 82, 1-48.
Wise, R. A, Yokel, R. A., & DeWit, H. Both positive rein
forcement and conditioned aversion from amphetamine and
from apomorphine in rats. Science, 1976, 191, 1273-1275.
Wishart, T. B., & Walls, E. K. The effects of anorexic doses
of dextraamphetamine on the ventromedial-hypothalamic
hyperphagic rat. Canadian Journal of Physiology and
Pharmacology, 1973, 354-359.
Zacharko, R., & Wishart, T. B. A comparison of ventral
noradrenergic bundle and ventromedial hypothalamic
lesion-induced hyperphagia and obesity. Neuroscience
Abstracts, 1978, 4, 183. 69
FOOTNOTES
^Ahlskog and Hoebel (1973) and Ahlskog (1974) demonstra
ted that destruction of the VNB by either electrolytic lesions
or injections of 6-hydroxydopainine (a neurotoxin that prefer
entially destroys catecholamineric neurons) induced hyperpha-
gia and a corresponding depletion of hypothalamic levels of
the neurotransmitter norepinephrine (NE), thereby implicating
NE as asatiety neurotransmitter. More recent experiments,
however, question the role of NE depletion in the production of hyperphagia since rats often fail to overeat and become
obese after substantial depletions of NE (Grossman & Grossman,
1977; Grossman, Grossman, & Halaris, 1977; Oltmans, Lorden,
& Margules, 1977; Peters, Gunion, & Wellman, 1979; Peters,
Wellman, & Gunion, 1979). The terminology, DLT, is currently used to avoid the implication that the syndrome results from interruption of VNB fibers. 2 These syndromes are also dissimilar in that DLT lesions, unlike VMH lesions,
a. induce a moderate hyperphagia with a high-fat diet (Ahlskog, Randall, & Hoebel, 1975; see, however, Peters, Wellman, & Gunion, 1979),
b. induce hyperphagia only during the night (Ahlskog, et al., 1975; Luttmers, 1978),
c. may not produce hyperphagia and obesity in hypophy- sectomized rats (Ahlskog, Hoebel, & Breisch, 1974) and finally. 70
d. do not induce both overeating of palatable diets and undereating of unpalatable diets CPeters, Gunion, & Wellman, 1979; Peters, Wellman, & Gunion, 1979; Ahlskog, 19761.
^Current literature implicates catecholaminergic mechanisms within the lateral hypothalamus (LH) as mediating the anorexic effects of amphetamine. Cole C1972) and others have suggested that amphetamine may suppress feeding by blocking the activity of a putative LH feeding center. In congruence with such an interpretation, LH lesions attenuate amphetamine anorexia (Carlisle, 1964; Panksepp &
Booth, 1973) while direct cannulation of amphetamine into the LH suppresses feeding in fasted rats (Booth, 1968;
Leibowitz, 1975). The anorexic effect of amphetamine within the LH may be mediated by catecholaminergic mechanisms as
Leibowitz (1975) demonstrated that the beta-adrenergic blocker propanolol and the dopaminergic blocker haloperidol blocked the anorexic effect of amphetamine injections into the LH. 71
ACKNOWLEDGEMENTS
I would like to dedicate this work to those who aided
me throughout my graduate career at Iowa State University.
These include, but are not limited to, my parents, Paul and
Mary Ellen; my wife, Bonita; and my daughter, Kristen. The
assistance of Micheal T. Bardo and Mark W. Gunion during the
surgical procedure and of Bonnie Blythe during the course of
the experiments is gratefully acknowledged. I am especially indebted to Dr. Ronald H. Peters for his guidance and for
providing me with the appropriate model in my studies. 72
APPENDIX A; THE PERIPHERAL REGULATION OF FEEDING 73
INTRODUCTION AND OVERVIEW
Animals maintained on a single, moderately palatable,
diet exhibit relatively precise regulation of food intake and
body weight on a day-to-day basis. As the energy require
ments of an animal are varied (e.g., increased physical activ ity or changes in ambient temperature, Brobeck, 1948), appro
priate adjustments of food intake are observed. These ad
justments suggest that one (or more) physiological mechanisms
monitor nutritional state and either initiates or terminates
feeding as is required to maintain some optimal level of
caloric balance.
Historically, theoretical notions of the regulation of
feeding have oscillated between peripheral and central nervous
system (CNS) satiety mechanisms. Early workers emphasized the
primacy of peripheral mechanisms such as gastric contractions
(Cannon & Washburn, 1912; Carlson, 1916). With the advent of the Horsley-Clark stereotaxic apparatus, a device that allowed investigators to either destroy or stimulate discrete
brain regions, attention was soon shifted to CNS satiety
mechanisms. In particular, the ventromedial hypothalamus
(VMH) was implicated as a satiety center in the regulation of feeding. Lesions of the VMH produced rampant hyperphagia and subsequent obesity (Hetherington & Ranson, 1940; Brobeck,
Tepperman, & Long, 1943) while electrical stimulation 74
of the VMH via implanted electrodes suppressed feeding in
fasted rats (Krasne, 1962). The VMH was thought to inhibit
the activity of the more lateral hypothalamus CLH), a region
that was thought to initiate feeding since destruction of the
LH produced aphagia and adipsia CAnand & Brobeck, 1951) while
low-level LH stimulation induced stimulation-dependent feeding
CDelgado & Anand, 1953).
The notion that the VMH and LH reciprocally regulate food intake has recently been challenged. Several reports suggest that the VMH and the LH may not be centers for the regulation of feeding, but rather are simply prominent landmarks for destruction or stimulation that influence fiber systems that course through or near these regions. Gold C1973), for example, suggested that the ventral noradrenergic bundle (VNB), a diffuse fiber system that arises from brainstem nuclei to course through the ventral hypothalamus, may mediate the obesity syndrome produced by VMH lesions. Similarly, the aphagia syndrome observed after LH destruction has been linked to damage of the nigro-striatal bundle as it courses through the
LH CUngerstedt, 1971).
Finally, hypothalamic lesions produce marked alterations in peripheral energy metabolism that precede, and may even predict, subsequent changes in feeding behavior (Hustvedt &
L^v^, 1972). Thus, attention has again shifted to the periphery 75
in the regulation of food intake CNovin, 1976; Friedman &
Strieker, 1976; Powley, 1977; Russek, 1971). The present
review delineates the various satiety mechanisms that have
been described in the periphery and where possible, relates
the functioning of these peripheral mechanisms to putative
CNS satiety mechanisms.
In general, two distinct classes of satiety signals can
be distinguished. Preabosrptive satiety (PRE-SAT) refers to
those signals that terminate feeding prior to significant
absorption of nutrients by the gastrointestinal tract.
PRE-SAT signals are presumably neural and are thought to
arise following mechanical and/or chemical stimulation of
the oropharynx and the stomach. In contrast, postabsorptive
satiety (POS-SAT) refers to those signals that suppress feeding
during the interval following absorption of nutrients and
prior to ingestion of the next meal. POS-SAT signals may be
either neural and/or humoral and presumably arise from the
duodenum, intestine and the liver.
Preabsorptive Satiety
Neural signals from the pregastric (oropharynx) and
gastric (stomach) portions of the gastrointestinal tract have
been advanced as satiety signals triggered by ingested food.
Oropharyngeal Mechanisms
Ingestion of food is accompanied by considerable mechanical stimulation of the oropharynx during chewing and swallowing. Such stimulation might generate neural signals to 76
the brain, hereby serving a metering function. The available
literature, however, suggests that simple mechanical stimula
tion of the oropharynx, when isolated from the remainder of the
gastrointestinal tract, is not sufficient to suppress food in
take. Such isolation can be accomplished by allowing the
ingested food to drain out through an esophageal fistula (sham-
feeding). Numerous reports, using dogs, rats, monkeys and
humans, have demonstrated that sham-feeding subjects consume
considerable amounts of food that are far in excess of what
would be consumed during a normal meal (Gibbs & Falasco, 1978;
Mook, 1963; James, 1963; Busch, cited in Carlson, 1916). Hull,
Livingston, Rouse and Barker (1951), for example, reported that
a dog fitted with an open esophageal fistula are an amount of food equivalent to its body weight (approximately 8000 grams)
having a single bout of shamfeeding. Such exaggerated meals suggest that whatever termination of feeding that occurs during sham-feeding is likely due to sheer exhaustion.
It should be noted, however, that demonstrating that stimulation of the oropharynx per se is not sufficient to terminate feeding does not imply that the oropharynx does not participate in the regulation of feeding. As will be shown below, signals from the oropharynx may summate with signals from structure further down the gastrointestinal tract to produce potentiated suppressions of feeding. 77
Stomach Mechanisms
Since the time of the physician Galen, attention has been
focused on the stomach as the site for satiation. The follow
ing section briefly describes the various mechanisms (disten
sion, osmotic and chemical) in the stomach that purportedly
signal satiety to the CNS. The section will also introduce
several problems of interpretation of early data and presents
more recent data suggesting that the stomach, in conjunction
with the oropharynx, is sufficient to regulate feeding.
The stimulus for hunger was initially thought to be the
rhythmic contraction of the stomach during fasting. The hun
ger pang reported during gasting was initially thought to re
sult from irritation as the stomach lining rubbed together
during contractions. Carlson (1916) and Cannon and Washburn
(1912) implicated stomach (gastric) contractions as the stimulus
for hunger. These investigators noted that subjective reports
of hunger pangs during a fast were associated with violent
contractions of the stomach, as measured by pressure changes in
an inflated balloon placed into the stomach. Afferents within
the vagus were thought to carry signals regarding somach
contraction to the CNS.
Gastric contractions, however, are not likely the signal for hunger. Sherrington (1900) noted that feeding and also sub jective reports of hunger persist even after complete removal 78
of the stomach while Mayer (1956) noted that feeding often
occurs prior to gastric contraction. Further, introduction of
an inflated balloon into the stomach to measure gastric
contractions may,in part, produce those contractions.
Although the notion that gastric contractions mediate the
sensation of hunger has not been supported, the converse (i.e.,
that gastric distension signals satiety) has received moderate
support. Sharma (1967) recently noted that afferent fibers,
carrying information regarding distension, osmotic pressure and
the presence of various chemicals within the lumen arise from all levels of the gastrointestinal tract. One class of receptors that have been described within the stomach is sensitive to distension of the stomach lining, as might occur during feeding. Paintal (1954) and also Niijima (1967) have described fibers within the pyloric and antral portions of the stomach that project via the vagus to brain. These fibers carry information regarding distension in that their firing rate is proportional to the amount of distension of the stomach wall. These results presumably reflect distension, rather than chemical or osmotic stimulation, since these investigators used inert substances such as balloons or wax balls to induce stomach distension.
Two paradigms have been used to examine the influence of bulk, or distension, in satiety. In one paradigm, animals are prepared with esophageal fistulas that allow ingested food to 79
drain from the throat. Such preparations consume large
amounts of food when the fistula is open but display normal
meals when the fistula is closed. Janowitz (1967), demon
strated that placement of non-nutritive bulk into the stomach
was sufficient to suppress subsequent sham-feeding. Suppres
sion of sham-feeding was time-dependent in that bulk loads
were effective When given shortly prior to sham-feeding, but
not 4 hours before sham-feeding. Share, Martyiuk, and
Grossman (1952) also noted that distension of the stomach,
using inflatable balloons, suppressed sham-feeding in dogs only when such stimulation shortly preceded sham-feeding.
Oropharyngeal stimulation is known to interact with gastric signals to induce satiety. Janowitz and Grossman
(1949) reported that prefeeding dogs with a small portion of their daily food, thereby stimulating both oropharyngeal and gastric mechanisms, produced larger suppressions of subse quent food intake than only placing the same load into the stomach via a tube. More recently, Kraly and others (Kraly,
Carty, & Smith, 1978; Kraly & Smith, 1978) have suggested that an interaction between oropharyngeal and gastric mecha nisms may be sufficient to regulate feeding. Three indices of satiety were used: Meal size (MS), the interval separating each meal (IMI), and the latency to rest after meal termina tion (LR). These workers used two types of fistulas: an esophageal fistula and a gastric fistula that allows ingested 80
food to drain from the stomach. When the stomach fistula was
open, rats displayed larger MS and smaller IMI than when the
fistula was closed. These rats, however, also displayed
smaller MS and larger IMI (suggestive of satiety) relative to
those parameters observed with an open esophageal fistula.
Gastric and oropharyngeal stimulation are apparently suffi
cient to induce satiety, at least in the sham-feeding prepara
tion.
A second paradigm involves preparing an otherwise intact
animal with a gastric tube through which various nutritive
and non-nutritive substances can be placed directly into the
stomach. The literature suggests that non-nutritive bulk
loads (cellulose, kaolin, or wax) suppress subsequent feeding
(Smith & Duffy, 1955; Smith, Pool, & Weinberg, 1962; Smith &
Duffy, 1957). Moreover, the magnitude of intake suppression
is directly related to the size of the bulk load.
Although stomach distension may partially result in
satiety and may, in conjunction with oropharyngeal stimula
tion, be sufficient to produce satiety in the sham-feeding
rat, stomach distension per se is not likely to be a primary
mechanism of satiety. Rats display appropriate adjustment of their food intake volume when the caloric density of their maintenance diet is altered. For example, when caloric content is diluted by such inert substances as cellulose or kaolin, rats display appropriate increases 81
in their total food intake volume to maintain some level of
caloric intake (Adolph, 1947; Teitelbaum, 1955; Wellman &
Peters, 1978). If distension per se controlled food intake,
such overeating of diluted diets would not be observed.
A number of investigators have noted that the stomach and
the intestines contain receptors that respond to various
chemical stimuli. Sharma and Nassett (1962) described three
classes of afferent fibers within the gastric lumen. Record
ings of electrical potentials from various fibers in response
to perfusion of the lumen revealed classes of fibers that
respond preferentially to amino acids, hydrochloric acid and
to glucose. In short, there are fibers within the stomach and
the intestines that carry information to the CNS regarding the
chemical composition of ingested foods.
Feeding is often substantially suppressed after various
nutritional substances are placed directly into the stomach.
Amino acid (Scharrer, Baile, & Mayer, 1970; Krauss & Mayer,
1965; Anika, Houpt, & Houpt, 1977), hydrochloric acid (Anika,
et al., 1977) and glucose solutions (Smith & Duffy, 1955;
Baile, et al., 1971; Yin & Tsai, 1973) are known to suppress
feeding when placed into the stomach. Such suppressions are
generally thought to reflect an influence of these substances
on mechanisms within the stomach. Such an interpretation,
however, is unwarranted in view of the recent demonstrations
by Balagura and Fibiger (1968) and also by Balagura and Coscina
(1969) that stomach loads larger than 5 milliliters rapidly 82
leave the stomach and penetrate for some distance into the in
testines. These findings are significant since stomach loads
(nutritive and non-nutritive alike) smaller than 5 mis are not effective in suppressing food intake (Smith & Duffy, 1955;
Kohn, 1951; Balagura & Fibiger, 1968). Thus, unless very small volumes are used, or unless the load is experimentally restricted to the stomach, any suppression of food intake ob served after stomach infusion cannot be solely attributed to activation of stomach satiety mechanisms.
Kraly and Smith (1978) , however, suggest that stimula tion of the intestines by ingested nutrients is not neces- say for satiety. Rats were prepared with pyloric nooses, that when drawn tight, prevented ingested nutrients from entering the intestines. An examination of meal size and intermeal interval when these rats were fed a liquid diet revealed that both parameters were similar when the noose was open or when it was closed with no differences between the conditions. Thus, intestinal stimulation per se is not required for the appearance of satiety.
An additional interpretative problem is that any anorexia observed after stomach preloads may be attributable to mal aise rather than satiation. Deutsch, Molina, and Puerto
(1976) reported that when a small volume of sesame oil, a nutrient that the rat will freely drink, is infused into 83
the stomach and this injection is paired with a novel flavor,
the rat will not consume that flavor. Thus, injection of
nutrients such as enriched milk CKohn, 1951) or glucose
(Jacobs, 1962) into the stomach may be aversive. Deutsch
Cet al., 1976) have argued that placement of such nutrients
into the stomach represents a non-physiological treatment in
that ingested foods are partially digested by salivary
secretions at the time of entry into the stomach whereas
typical loads are not. Predigested milk (.passed through the
gastrointestinal tract of a donor rat) injected into the
stomach produced satiety but no aversion was found when
such injections were paired with a novel flavor (Deutsch,
et al., 1976; Maddison, 1978).
Anorexia observed after intragastric injections cannot,
however, be solely attributed to malaise. Miller and Kessen
(1952), Berkun, Kessen, and Miller (1952), and more recently,
Holman (1968) demonstrated that rats would learn a response
upon which intragastric injections were made contingent. Such
injections are presumably rewarding because they reduce drive
or need and produce satiation. Moreover, rats are able to
rapidly detect the presence of nutritive and non-nutritive
solutions. Snowdon (1969) demonstrated that rats trained to
perform an operant response that delivered a liquid diet into the stomach made appropriate adjustments of performance to maintain their caloric intake. Snowdon (1970) reported that 84
wfien rats were allowed to feed to satiation and then had a
portion of the meal drained from the stomach, ate much sooner
than they ordinarily would have. Deutsch and Wang C1977), and
Puerto, Deutsch, Molina, & Roll (1976), using a pyloric cuff
to prevent stomach contents from entering the intestines,
allowed rats to consume one of two solutions. Consumption of
one solution was paired with an injection of saline into the
stomach while consumption of the other solution was paired
with an injection of predigested milk. Over trials, the rats
rapidly came to prefer the solution that was paired with the
nutrient solution. A subsequent experiment CDeutsch, Young, &
Kalogeris, 1978) ruled out excessive gastric pressure and also
demonstrated that if milk was withdrawn from the stomach while
the cuff is inflated, compensatory drinking, as was the case
in Snowdon C1970), was observed.
One argument that frequently is used to suggest that
stomach satiety signals are not of paramount importance in the
regulation of food intake is that visceral deafferentiation
via vagotomy does not appreciably alter patterns of feeding in
rats, dogs, and humans (Bash, 1939; Ingelfinger, 1944; Snowdon,
1970; Grossman & Stein, 1948; Kraly & Gibbs, 1978). It should
be noted, however, that the vagus is not the only pathway for afferent information to reach the CNS. Visceral information is also relayed to the CNS via the sympathetic splanchnics 85
CNiijima, 1967; Paintal, 1954). The observation that partial
deafferentiation of the viscera via vagotomy does not markedly
alter feeding pattern is not surprising given the dual
representation of visceral information within the vagal and
the splanchnic systems.
Postabsorpti-ve Satiety
Intestinal Mechanisms
Only recently have the intestines been considered
as participating in the regulation of feeding. Intestinal
satiety mechanisms were implicated from several lines of
research. Balagura and Fibiger C1968) and also Balagura and
Coscina C19691 demonstrated that intragastric infusions of
liquid diets suppressed food intake but also rapidly entered the intestines. Thus, anorexia observed after a stomach
infusion could not be attributed solely to activation of
stomach satiety mechanisms. Snowdon and Epstein (1970) noted that vagotomized rats ate smaller yet more frequent meals
(hence there was no change in overall intake) while Snowdon
(1970), also using vagotomized rats, demonstrated that liquid diets were rapidly "dumped" from the stomach into the duodenum.
Snowdon (1970) argued that rapid emptying of stomach contents into the duodenum in the vagotomized preparation may have activated a duodenal satiety mechanism that was not dependent on the integrity of the vagus. The following sections will describe the data regarding the presence of osmotic or nutritive satiety mechanisms within the intestines. 86
Ehman, Albert, and Jamieson (1971) prepared fasted
rats with chronic intraduodenal cannulas through which various
solutions could be delivered. Their findings implicated an
osmotic satiety mechanism within the duodenum in that hyper
tonic sodium chloride and also hypertonic glucose solutions
injected into the duodenum suppressed subsequent food tintake.
Snowdon (1975) , using both gastric and intraduodenal infusions of hyperosmotic nutritive (glucose) and non-nutritive (urea, sodium chloride) solutions in the free-feeding rat, demon strated that hypertonic solutions decreased meal size, but also increased meal frequency; thus, there were no changes in overall food intake. Others (Smith & Duffy, 1957) have noted that large infusions of hypertonic salt solutions into the stomach suppress food intake; presumably this suppression reflects the activation of both gastric and duodenal osmotic mechanisms.
Two lines of data, however, suggest it is premature to conclude that the intestines contain an osmotic satiety mecha nism. Click and Modan (1977), using continuous infusions into the duodenum, failed to find any effect of either iso tonic or hypertonic sodium chloride solutions on meal pat terns in free-feeding rats. Secondly, Deutsch, Molina, and
Puerto (1976) demonstrated that hypertonic infusions of glu cose into the duodenum induced a conditioned taste aversion. 87
As was the case above, examination of intestinal mecha
nisms of satiety have used either sham-feeding preparations
or allowed animals to free-feed after infusion of various
nutrients into the intestines. Liebling, Eisner, Gibbs, and
Smith (1975), using a gastric sham-feeding preparation, noted that duodenal infusions of a liquid diet suppressed subse quent sham-feeding. This suppression was not due to malaise
associated with the infusions because such infusions did not
support a conditioned taste aversion. Liebling (et al.,
1975) proposed that receptors within the intestinal wall reflexly induce the release of the putative satiety hormone cholecystokinin. Early objections that ingested foods re quire considerable time to reach the intestines (thereby pre cluding a role for the intestines in short-term satiety) are less compelling in view of the recent demonstration by
Wiepkima, Alingh Prins, and Steffens (1972) that solid food consumed after 2 hours of food deprivation reaches some 10-
50 cm into the intestines within 10 minutes of the start of a meal. This occurs because as ingested foods enter the stomach, older ingesta is stored within the fundus while the latest ingesta rapidly enters the duodenum.
As was the case for activation of stomach satiety mecha nisms, oropharyngeal stimulation potentiates the effects of stimulation of the duodenum. Antin, Gibbs, and Smith (1977), 88
using a gastric sham-feeding preparation, allowed rats to sham
feed and infused liquid diet into the duodenum either -12, -6,
OL, +6, or +12 minutes before and after the initiation of sham-
feeding. When duodenal infusions were given 12 min prior to
sham-feeding, little suppression of intake was observed while
larger suppressions were found as the interval between feeding
and infusion was decreased.
Click and Modan C19771 observed that free-feeding rats
performed rather precise compensations of food intake when a
30% glucose solution was infused into either the duodenum or
terminal ileum over a 24-hour period. Oral intake decreases
were in the form of smaller meal sizes with no change in the
number of meals. Interestingly, a control infusion of 5.4%
sodium chloride which is equiosmotic to the 30% glucose solution
did not influence feeding. Further, their results indicate no
difference between duodenal or ileal infusions and the ileal
infusions were not found to backflow into the duodenum.
Infusions of glucose into the duodenum are known to
suppress feeding but such effects may not reflect the sole
activation of intestinal satiety mechanisms. Campbell and Davis
C1974), for example, infused glucose into either the duodenum
or the hepatic-portal system and observed that both procedures
induced similar suppressions of licking for a glucose solution.
They argued that hepatic-portal infusions suppress intake via a liver satiety mechanism described by Russek (1971). Further, 89
duodenal infusions also activate this mechanism since both
infusions produced intake changes of a similar magnitude and
latency. Such a notion suggests that although glucose
infusions are nominally restricted to the duodenum, the site
of anorexia may be the liver via the hepatic-portal system.
Although the notion advanced by Campbell and Davis (1974)
is conceptually appealing, others have demonstrated the
independence of the duodenal, and liver satiety mechanisms.
Vanderweele, Novin, Rezek, and Sanderson (1974), using rabbits,
observed that duodenal and hepatic-portal infusions of either
hypertonic or isotonic glucose differentially altered feeding
depending on the current nutritional status of the rabbit.
Duodenal glucose, but not hepatic-portal glucose, suppressed
feeding when the rabbits were allowed to free-feed. When the
rabbits were 22 hours food deprived, however, only hepatic-
portal glucose infusions suppressed intake. These findings suggest that these satiety mechanisms are independent and that the primacy of each mechanism shifts with the deprivation state of the animal. Duodenal satiety apparently is operative only when the animal is minimally food deprived, that is, under normal feeding conditions (in the rabbit the intermeal inter val is approximately 2 hours). With longer periods of food deprivation, the duodenal mechanism is inoperative since acti vation of the duodenal mechanism after a long fast would term inate feeding long before the nutritional balance of the 90
animal was restored. Termination of feeding after a fast of
longer than 4 hours requires activation of the liver satiety
mechanism. Finally, both duodenal and hepatic-portal glucose
infusions require an intact vagus to suppress food intake
(Novin, Sanderson, & Vanderweele, 1974).
Intestinal distension, per se, may induce activity in
stretch receptors within the intestinal lumen (Iggo, 1957) and
signal satiety. Ehman et al. (1971), for example, demonstra
ted that infusions of a cellulose solution into the duodenum
suppressed food intake. Collins and Davis (1978) placed
solutions of mannitol, a carbohydrate that retards absorption,
into the intestine, resulting in the filling of the intestines
with fluid. Such treatments also suppressed the intake of a glucosesolution. Although these authors note (rather honestly) that mannitol induces cramps in humans, they were unable to obtain a conditioned taste aversion using mannitol in the intestine. Davis, Collins and Levine (1975) argue that a negative feedback signal initiated by tension receptors within the intestine terminates feeding whenever the rate of feeding and the rate of gastric emptying into the duodenum exceeds the clearance of ingesta from the intestines.
Humoral Mechanisms
Several recent reports demonstrate that some unknown fac tor in blood may produce satiety and terminate feeding. Davis,
Gallagher, and LaDove (1967) observed that the food intake of fasted rats was suppressed by nearly 50% after their 91
Blood was thoroughly mixed with the blood of satiated rats.
Seoane, Bailey and Martin C19721 demonstrated that the cross-
perfusion of blood from satiated to hungry sheep decreased
the food intake of the latter by 17% but also increased the
food intake of the former group by 48%. Recordings from the
cortex during blood-mixing reveal that the characteristic EEG
pattern of fasted rats shifts to a satiation pattern following
the cross-perfusion of blood from satiated to fasted rats
(Rosen, Davis, & LaDove, 1971). These observations strongly
suggest that some humoral substance produces satiety in
response to ingested foods and as the interval following a
meal increases, blood concentrations of this substance decrease
until at some threshold, feeding is again initiated. Such an
analysis accounts for the observation by LeMagnen & Talion
(1966) that the size of a particular meal is correlated with
the interval of satiety following that meal and is not
correlated with the interval preceding the meal.
Enterogastrone, a putative gastrointestinal hopmone that is
thought to inhibit gastric emptying, has been implicated as a
possible humoral satiety signal. MacLagan (1937) demonstrated that intraperitoneal injections of enterogastrone extracts obtained from canine intestine suppressed the feeding of fasted rabbits. More recently, intestinal extracts that purportedly contain enterogastrone have been shown to produce satiety in 92
fasted rats and fasted mice (Ugolev, 1960; Schally, Redding,
Lucien, & Mayer, 1967; Click & Mayer, 1968). The failure to
subsequently isolate and identify enterogastrone's structure,
however, has prevented delineation of its possible role in
satiety.
Cholecystokinin CCCK) is an intestinal polypeptide that
has been implicated as a humoral satiety factor. CCK release is
from the duodenum, jejunem and ileum (Polak, Pearse. Bloom,
Buchan, Rayford, and Thompson, 1975) in response to entry of
fats, partially digested proteins and into the duodenum
[Grossman, 1973). CCK rapidly enters the bloodstream and can
be detected in the portal venous blood of dogs within 1-3 minutes after perfusion of the duodenum with hydrochloric acid
(Berry & Flower, 1971), The known physiological actions of
CCK include the stimulation of pancreatic ecbolic secretion, the release of glucagon and insulin, contraction of the resting stomach and pyloric sphincter, inhibition of the sphincter of
Oddi Can action that results in the release of bile from the gallbladder) and lastly, acceleration of small intestinal transit time (.Grossman, 1973; Mueller & Hsiao, 1978; Levant,
Kun, Jachna, Sturdevant, & Isenberg, 1974).
Initial investigations into the effects of CCK on food intake were largely negative. Glick, Thomas and Mayer (1971) reported that neither rntraortal nor intraperitoneal infusions of CCK altered bar-pressing for food in fasted rats. It should 93
be noted, however, that these investigators used both impure
extracts of CCK and very slow infusion rates. Data obtained
by Berry and Flower C1971) indicate that CCK is rapidly
removed from the blood stream and has a half-life of
approximately 15 minutes. It is unlikely that any significant
levels of CCK in the blood could be attained using the
infusion rates of Click et al. (1971).
More recent research has provided mixed support for the
notion that CCK is a humoral gut satiety factor. The following
section will only briefly describe some of these studies as
Mueller and Hsiao (1978) have compiled, in great detail, data relating CCK to satiety. Many of these experiments were either not considered by Mueller & Hsiao in their review or appeared in print after the review.
A number of experiments have demonstrated that either intraperitoneal or intravenous injection of CCK suppresses subsequent food intake in fasted rats, cats, mice, monkeys and humans (Gibbs, Young, & Smith, 1974; Bernstein, Lotter &
Zimmerman, 1976; Goetz & Sturdevant, 1975; Gibbs, Falasco, &
McHugh, 1976). In animals, the shape of the dose-response curve for CCK is U-shaped; feeding is suppressed more as dosage increases from 5 Ivy Dog Units ClDU)/kg to approximately
40 IDU/kg with even higher dosages being ineffective
(Kulkosky, Breckenridge, Krinsky, & Woods, 1976). In humans. 94
CCK produces variable and paradoxical anorexia in that
infusions (iv) of 0.5 IDU/kg reliably suppresses intake while
slightly higher dosages either do not influence or actually
increase food intake CSturdevant & Goetz, 1976).
If CCK is a humoral satiety signal, the suppression should be specific to feeding. Gibbs, Young and Smith (1973) noted that CCK did not alter water consumption in 12-hour water deprived rats at dosages that reliably suppressed food intake. Other investigators, however, have noted that CCK suppresses non-specifically both water and food intake
(Koopmans, Deutsch, & Branson, 1972). In the latter report, however, mice served as subjects and the CCK used was the impure extract. More recent reports have generally confirmed the failure of CCK to alter water intake CBernstein, Lotter, &
Zimmerman, 1976; Kraly, Carty, Resnick, & Smith, 1978).
In an elegant experiment, Mueller and Hsiao C1977) trained rats to consume either a milk diet or water after 23.5 hours water deprivation. When treated with various dosages of CCK, the rats consumed normal amounts of water while their milk intake was suppressed in a dose-dependent fashion.
A related issue is that CCK should not suppress food intake because it produces malaise in the animal. A paradigm that is sensitive to sickness induced by drugs is that of learned taste aversion (LTA). Garcia and his colleagues 95
(Garcia, Ervin, & Koelling, 1966) allowed rats access to a
novel flavor and then injected the rats with lithium chloride,
a substance that rapidly produces gastric malaise. When again
presented with the flavor, the rats avoided consuming it, even
when the interval between flavor presentation and the onset of illness was on the order of 6-8 hours. These data suggested that rats (and other animals) come to rapidly associate consumption of a novel food with illness.
The available literature almost uniformly demonstrates that even very large dosages of CCK will not support a learned taste aversion (.Gibbs, Young, & Smith, 1973; Houpt,
Anika, & Wolff, 1978; Holt, Antin, Gibbs, Young, & Smith, 1974;
Kraly, Oarty, Resnick, & Smith, 1978). The only report to date that has demonstrated conditioned aversion to CCK has used very different procedures and an excessively large dosage of CCK CDeutsch & Hardy, 1977). Gibbs and Smith (1977) have cogently argued that production of a conditioned taste aversion using a large dosage of CCK does not invalidate its putative role as a satiety signal since Deutsch and Hardy
C1977) did not compare the dose-response curves for anorexia and aversion to CCK. It may be the case that very low dosages of CCK are sufficient to produce anorexia but not aversion.
The aversion to CCK noted by Deutsch and Hardy (1977) may simply reflect a non-physiological response (e.g., hyperthermia, rapid gastric emptying) to a non-physiological dosage. 96
A number of behaviors are known to be roughly correlated
with changes in food motivation. Activity, for example,
typically increases as the number of hours of food deprivation
increases, although this relationship may not always be
obtained. Another behavior correlated with motivation for
food is self-stimulation rate of the lateral hypothalamus.
Olds and Milner (1954), in their pioneer work, noted that rats would work to obtain low-level stimulation of various portions of their brain. One site from which high response rates are obtained is that of the medial forebrain bundle at the level of the lateral hypothalamus. This region is intricately involved with feeding as demonstrated by the observation that self-stimulation (SS) placements in the LH will also induce stimulation-bound feeding (Margules & Olds,
1962).
Hoebel (1976) has argued that SS rate from the LH is sensitive to manipulations of hunger motivation. When a rat's hunger motivation is increased by food deprivation, SS rate increases and when hunger motivation is decreased by manipulations such as forced feeding, SS rate is decreased.
Moreover, Hoebel has further shown that rats will respond to turn off continuous trains of LH stimulation (Stimulation- escape, SE). SE and SS are inversely related to each other.
When SS and SE responding is alternated during a test session, manipulations that increase hunger motivation increase SS rate 97
but decrease SE rate. The reverse holds true for manipulations that decrease hunger. The point to all of this is that SS and SE rate from LH sites can serve as an index of the motivational state of the animal.
Hoebel's SS/SE paradigm may provide direct examination of the notion that CCK produces satiety rather than malaise.
If CCK produces satiety, then SS rate from the LH should decrease while SE rate from the LH should correspondingly increase, whereas if CCK produces malaise, then both SS and
SE should decrease. Kornblith, Ervin, and King (1978) examined this question by assessing the effects of CCK on SS rates from two areas of the brain. One region, the LH, is known to be involved in feeding and is sensitive to changes of hunger motivation, while the other area, the locus coeruleus supports SS but has not been shown to support stimulation-bound feeding. Their results indicate that CCK suppressed SS of the lateral hypothalamus, as predicted.
Unfortunately, CCK also suppressed SS from the locus coeruleus, an outcome that suggests the suppressive effect of CCK may not be specific to feeding. The problem might have been resolved had these researchers examined both SS and SE rates from these two regions to determine if CCK suppressed both indices. 98
Overeating to obesity may, at lease in part, be
transmitted genetically from generation to generation. There
are currently several forms of genetically determined
obesity in mice (ob/ob) and in rats (Zucker). These animals
are somewhat similar to VMH lesioned rats in their overeating
and their ability to accumulate tremendous amounts of body
fat.
Although genetic obesity may result from inborn aber
rations of peripheral energy metabolism, at lease one report
has implicated CCK as being involved in these syndromes.
Straus and Yalow (1979) demonstrated that genetically obese
mice have significantly lower concentrations of CCK in their
cerebral cortex than do their non-obese littermates. The
overeating of these mice is presumably the result of less of
a satiety signal such that these mice do not stop feeding to
ingested food. It is not presently known, however, that
cortical CCK concentrations are an index of CCK levels in
the periphery; hence these data are only speculative.
Antelman and coworkers (Antelman, Rowland, & Fischer,
1976) have demonstrated that a mild stressor, such as a non-
painful pinch applied to the tail, will produce motivated be haviors. If a rat is in the presence of food during the tail- pinch, it will vigorously consume that food and if these treatments are continued for some period of time, will become obese. The effect of this stressor is not specific to feeding 99
per se, since a tail-pinch will also induce drinking if water
is present or copulation if a receptive female is present
during the pinch. The overeating produced by a mild stressor
has been likened to the overeating frequently observed in
humans during prolonged stressful situations.
Nemeroff, Osbahr, Bissette, Jahnke, Lipton, and Prange
(1978) reported that either intraperitoneal or intraventricular injection of CCK reliably antagonized tail-pinch induced feeding in rats. The blockade of feeding was dose-dependent and was apparently specific for feeding since CCK did not influence tail-pinch induced wood gnawing. The intriguing aspect of their data is that the dose of CCK necessary to produce a minimal blockade of tail-pinch induced feeding was significantly larger for ventricular infusions than for intra peritoneal injections, an outcome that suggests CCK receptors may be located in the periphery. It should be noted, however, that just the reverse has been obtained by Maddison (1977), using bar-pressing for liquid diets as a measure of food motivation.
The data obtained by Maddison (1978) and by Nemeroff et al. (1878) serve to introduce the question of where the receptors for CCK are located. Since it is unlikely that a protein the size of CCK would pass the blood-brain-barrier
(although a biologically active fragment might pass this barrier), it would seem that the receptors for CCK are in the 100
periphery. One structure that is a likely candidate to contain
CCK receptors is the liver. Russek and others have demonstra
ted the existence of glucoaitimonium receptors within the liver
that signal satiety to the CNS via the vagus (Russek, 1971;
Niijima, 1969). CCK, or an active fragment of CCK might
attach to these glucoammonium receptors and signal satiety.
Section of the vagus might reasonably be expected to
block the anorexic activity of CCK, if vagal afferents from
liver CCK receptors signal satiety to the CNS. Early reports,
using a variety of species (Houpt, Anika, & Wolff, 1978; Anika,
Houpt, & Houpt, 1977), failed to demonstrate any influence of
vagotomy on CCK anorexia. More recently, however, Lorenz and
Goldman (1978) reported that "complete" subdiaphragmatic vagotomy, including the hepatic branches, abolished the anorexia induced by a wide range (20-640 IDU/kg) of CCK dosages. These findings, although they do not specifically implicate the liver as containing CCK receptors, do imply that the receptors are in the periphery and that CCK satiety signals are carried to the brain via the vagus.
The vagus is known to project to various portions of the brain, the most notable of which is the lateral portion of the hypothalamus. Dafny, Jacob, and Jacobson (1975) reported that peripheral injects of CCK markedly influenced the average evoked acoustic response recorded from the lateral and ventro medial portions of the hypothalamus, but not from other regions 101 such as the septum, hippocampus or cortex. These findings are intriguing in that, as was discussed in the Introduction, both the VMH and the LK are involved in the regulation of feeding. Cole (1973) has argued that anorexic drugs, such as amphetamine, may induce anorexia via one of two mechanisms.
An anorexic drug may "mimick" the activity of the VMH or it may "block" the activity of the LH to produce anorexia. Since the vagus is known to carry information to the LH, it is reasonable to suggest that CCK may induce anorexia by blocking the activity of the LR. Lesions of the LH, however, do not block the anorexic activity of carulein, a decapeptide obtained from frog skin that is similar in structure and function to
CCK (Stern, Cudillo, & Kruper, 1976).
Vagotomy blocks or reverses VMH obesity (Powley &
Opsahl, 1974; see however. Carpenter, King, Stamoutsos, &
Grossman, 1978) as well as CCK-induced anorexia. If the VMH mediates the anorexia induced by CCK, VMH destruction (with out vagotomy) should diminish CCK-induced anorexia. Three reports that examine this question, however, have resulted in conflicting outcomes. While Kulkosky et al. (1976) noted that VMH rats display normal anorexia to CCK, Stern et al.
(1976) reported that VMH lesions attenuate anorexia to caerulein. A third study, by Krinsky, Lotter, and Woods
(1979), in which CCK did not produce reliable anorexia in VMH rats is uninterpretable because CCK also did not induce re liable anorexia in control rats. 102
Finally, recent reports suggest that the anorexia induced
by CCK is extremely variable and may habituate with repeated
administrations of a constant CCK dosage. Mineka and Snowdon
(1978), for example, demonstrated that rats given repeated
daily injections of CCK rapidly display rapid habituation of
anorexia. Others, including the present author, have failed
to obtain reliable suppressions of intake to CCK, even under
optimal testing conditions. Why such variable anorexia is
frequently obtained is presently not known, although individual
differences among animals may partly contribute. Houpt, Anika,
and Wolff (1978), using intravenous infusions of CCK in rabbits,
noted that considerable interanimal variability was associated
with CCK anorexia. Some animals consistently displayed
large suppressions of intake to CCK while others consistently
displayed no change in their feeding after CCK treatment.
These findings suggest, at least tentatively, that some
unspecified mechanism interacts with CCK and has a permissive
function such that CCK anorexia may be blocked. In conclusion, there is a considerable body of data implicating the release of CCK to ingested foods as a humoral signal for satiety. The details by which CCK induces short-term satiety, if indeed
CCK induces satiety, however, remain to be elucidated.
Early notions of hunger and satiety emphasized absolute levels of blood glucose as the signal for hunger and satiation.
Small decreases in blood sugar (hypoglycemia), as are produced 103
by fasting or by injection of insulin, are associated with
feeding (Morgan & Morgan, 1940; Mac^ay, Calloway, & Barnes,
1940; Janowitz & Ivy, 1949) while satiety is associated with
the return of blood glucose levels to normal (Mayer, 1953,
1956).
Diabetics, however, are chronically hungry even though
their blood glucose levels are elevated as a result of the
absence of insulin to transport glucose across cell membranes.
Mayer (1956) subsequently proposed that glucose utilization,
rather than absolute glucose level, determined hunger.
Glucose utilization was indexed by the difference between
arterial (A) and venous (V) glucose levels. Large A-V
differences, as is the case when peripheral tissues are taking
up glucose, were associated with satiety ; small differences,
as is the case when no glucose is available, were associated
with feeding.
Mayer and coworkers (Mayer & Marshall, 1956; Mayer &
Thomas, 1967) further proposed the existence of glucoreceptors
within the ventromedial hypothalamus (VMH). Brecher and Waxier
(1949), and more recently, Debons, Krinsky, and From (1970)
demonstrated that tissue within the VMH was destroyed after injection of golthioglucose (GTG), but not after injections of golthio- compounds that do not contain glucose. These results suggested that cells within the VMH take up glucose compounds. 104
Interestingly, Mayer (1955) proposed that these VMH neurons,
unlike other CNS neurons, require insulin for glucose
transport, just as cells in periphery also require insulin.
Further support for CNS glucoreceptors comes from a report by
Miselis and Epstein (1970) in which ventricular infusions of
2-deoxy-D-glucose (2-DG), a sugar that both inhibits glycolysis
and the secretion of insulin, thereby blocking glucose
utilization, produced feeding.
The Miselis and Epstein (1970) report withstanding, a
review of the remaining literature prompts the conclusion
that receptors for glucose utilization are not contained within
the VMH and further, are not likely to reside in the CNS.
Several recent reports have demonstrated that VMH destruction
produced by GTG is not a result of glucose uptake by neurons
within the VMH, but is likely the result of non-specific
destruction caused by capillary ischemia (Caffyn, 1972). The observation that insulin-induced hypoglycemia is an effective stimulus for feeding even in VMH lesioned rats is presumptive
evidence against VMH glucoreceptors.
Friedman, Rowland, Sailer, and Strieker (1976), in an elegant experiment, demonstrated that the mechanism(s) that mediate the feeding observed after a number of treatments
(insulin, 2-DG) which induce hypoglycemia are not likely to reside within the CNS. Rats were made hypoglycemic by insulin 105
injections and were allowed to feed after infusions of either
ketones or of fructose. Their results indicate that ketone,
a substance that can be used as an energy source by neurons,
did not produce satiety while fructose, a sugar that can be
utilized by the liver and does not cross the blood-brain-
barrier, readily induced satiety in hypoglycemic rats.
These data imply that the receptors for glucose reside within
the periphery.
Russek C1970, 1971) emphasized that the liver, a structure
largely ignored in previous conceptualizations of feeding and
satiety, contains glucoreceptors. A number of reports have
demonstrated that glucose infusions into the hepatic-portal
âysrem reliably produce satiety whereas similar infusions into
the jugular system were without influence on feeding (Russek,
1970, 1971; Yin & Tsai, 1973). Infusions of glucose into the hepatic-portal system pass immediately into the liver while jugular infusions do not. Russek suggested that glucose receptors within the liver signal satiety to the CNS via the
vagus. Niijima (1969) demonstrated that: the firing rate of fibers within the vagus is inversely proportional to the glucose concentration of the perfusate bathing these isolated vagal fibers. Thus, low rates of vagal firing signal high glucose concentrations within the liver and are presumably associated 106
with satiety. Indirect support for this notion was obtained
by Penaloza-Rojas and Russek (.1963) in that do blockade of the
vagus (a state that is functionally equivalent to high liver
concentrations of glucose) produced prolonged satiety in a
fasted cat.
The liver stores glucose as glycogen and this is readily
converted to glucose upon demand or when hormones such as
adrenaline, glucagon or growth hormone enter the liver.
Adrenaline (Russek, 1971) and glucagon (Martin & Novin, 1977)
infusions either intraperitoneally or into the hepatic-portal
system induce satiety in fasted rats and dogs. These substances
presumably induce satiety by effecting the conversion of stored
liver glycogen to glucose, resulting in suppression of neural
activity in liver glucoreceptors. Several lines of evidence
implicate the liver as mediating the influence of glucagon
on food intake. Glucagon does not suppress intake in the
vagotomized preparation and is less effective in severely food
deprived mice (Martin, Novin, & Vanderweele, 1978; Schally,
Redding, Lucien, & Mayer, 1967). The latter outcome is
presumably the result of an absence of liver glycogen stores,
following extended food deprivation.
In summary, there is presently a large body of literature describing numerous satiety mechanisms residing within the periphery and within the central nervous system. It is 107
readily apparent that future conceptualizations of the regula tion of feeding will emphasize the interactions between periph eral and CNS mechanisms rather than overemphasizing mechanisms within one region. It also is apparent that no unitary satiety mechanism can be found, as Russek (1971) has suggested. Rather, there is considerable redundancy within the system, both peripherally and centrally. 108
REFERENCES
Adolph, E. Urges to eat and drink in rats. American Journal
of Physiology, 1947, 151, 110-125.
Anand, B. K., & Brobeck, J. R. Hypothalamic control of food
intake in rats and cats. Yale Journal of Biology and
Medicine, 1951, 24, 123-140.
Anika, S. M., Houpt, T. R., & Houpt, K. A. Satiety elicited
by CCK in intact and vagotomized rats. Physiology and
Behavior, 1977, 761-766.
Antelman, S. M., Rowland, N. E., & Fischer, A. E. Stimulation
bound ingestive behavior; A view from the tail.
Physiology and Behavior, 1976, ]^, 743-748.
Antin, J., Gibbs, J., & Smith, G. P. Intestinal satiety
requires pregastric food stimulation. Physiology and
Behavior, 1977, 421-425.
Baile, C. A., Zinn, W., & Mayer, J. Feeding behavior of
monkeys: Glucose utilization rate and site of glucose
entry. Physiology and Behavior, 1971, 6, 537-541.
Balagura, S., & Coscina, D. V. Influence of gastro-intestinal
loads on meal eating pattern. Journal of Comparative and
Physiological Psychology, 1969, £9, 101-106.
Balagrua, S., & Fibiger, H. C. Tube feeding: Intestinal
factors in gastric loading. Psychonomic Science, 1968,
10, 373-374. 109
Bash, K. W. An investigation into a possible organic basis
for the hunger drive. Journal of Comparative Psychology,
1939, 109-13,4.
Berkun, M. M., Kessen, M. L., & Miller, N. E. Hunger-reducing
effects of food by stomach fistula versus food by mouth,
measured by a consummatory response. Journal of Compar
ative and Physiological Psychology, 1952, £5, 550-554.
Bernstein, I. L., Letter, E. C., & Zimmerman, J. C.
Cholecystokinin-induced satiety in weanling rats.
Physiology and Behavior, 1976, 1^, 541-543.
Berry, H., & Flower, R. J. The assay of endogenous
cholecystokinin and factors influencing its release in
the dog and cat. Gastroenterology, 1971, 409-420.
Brecher, G., & Waxier, S. Obesity in albino mice due to
single injections of golthioglucose. Proceedings of the
Society for Experimental Biology and Medicine, 1949, 70,
498.
Brobeck, J. R. Food intake as a mechanism of temperature
regulation. Yale Journal of Biology and Medicine, 1948,
20^, 545-552.
Brobeck, J. R., Tepperman, J., & Long, C. N. H. Experimental
hypothalamic hyperphagia in the albino rat. Yale
Journal of Biology and Medicine, 1943, 831-853. 110
Caffyn, Z. E. Y. Early vascular changes in the brain of the
mouse after injections of goldthioglucose and biperidyl
mustard. Journal of Pathology, 1972, 106, 49-56.
Campbell, C. S., & Davis, J. D. Licking rate of rats is re
duced by intraduodenal and intraportal glucose infusion.
Physiology and Behavior, 1974, ]^, 357-365.
Cannon, W. B., & Washburn, A. L. An explanation of hunger.
American Journal of Physiology, 1912, £9, 444-454.
Carlson, A. J. The control of hunger in health and disease.
Chicago: University of Chicago Press, 1916.
Carpenter, R. G., King, B. M., Stamoutsos, B. A., & Grossman,
S. P. VMH lesions in vagotomized rats: A note of
caution. Physiology and Behavior, 1978, 1031-1036.
Cole, S. Hypothalamic feeding mechanisms and amphetamine
anorexia. Psychological Bulletin, 1973, 13-20.
Collins, B. J., & Davis, J. D. Long-term inhibition of intake
by mannitol. Physiology and Behavior, 1978, 21, 957-965.
Dafny, N., Jacob, R. H., & Jacobson, E. D. Gastrointestinal
hormones and neural interaction within the central nervous
system. Experientia, 1975, 655-660.
David, J. D., Collins, B. J., & Levine, M. W. Peripheral
control of drinking: Gastrointestinal filling as a
negative feedback signal, a threshold and experimental
analysis. Journal of Comparative and Physiological
Psychology, 1975, 89, 985-1002. Ill
Davis, J. D., Gallagher, R. J., & LaDove, R. Food intake
controlled by a blood factor. Science, 1967, 156, 1247-
1248.
Debons, A., Krinsky, I., & From, A. A direct action of
insulin on the hypothalamic satiety center. American
Journal of Physiology, 1970, 219, 938-942.
Delgado, J. M. R., & Anand, B. K. Increased food intake
induced by electrical stimulation of the lateral hypo
thalamus. American Journal of Physiology, 1953, 172,
162-168.
Deutsch, J. A., & Hardy, W. T. Cholecystokinin produces bait-
shyness in rats. Nature, 1977, 266, 197.
Deutsch, J. A., Molina, F., & Puerto, A. Conditioned taste
aversion caused by palatable nontoxic nutrients.
Behavioral Biology, 1976, 161-174.
Deutsch, J. A., & Wang, M. L. The stomach as a site for
rapid nutrient reinforcement sçjnsors. Science, 1977,
195, 89-90.
Deutsch, J. A., Young, W. G., & Kalogeris, T. J. The stomach
signals satiety. Science, 1978, 201, 165-167.
Ehman, G. K., Albert, D. J., & Jamieson, J. L. Injectsion
into the duodenum and induction of satiety in the rat.
Canadian Journal of Psychology, 1971, 25, 147-166. 112
Friedman, M. I., Rowland, N., Sailer, C. F., & Strieker, E. M.
Homeostasis during hypoglycemia: Central control of
adrenal secretion and peripheral control of feeding.
Science, 1976, 1^, 215-219.
Friedman, M. I., & Strieker, E. M. The phsiological psychol
ogy of hunger: A physiological perspective. Psycholog
ical Review, 1976, 409-431.
Garcie, J., Ervin, P. R., & Koelling, R. A. Learning with a
prolonged delay of reinforcement. Psychonomic Science,
1966, 5, 121-122.
Gibbs, J., & Falasco, J. D. Sham feeding in the rhesus monkey.
Physiology and Behavior, 1978, 2^, 245-249.
Gibbs, J., Falasco, J. D., & McHugh, P. R. Cholecystokinin
decreased food intake in rhesus monkeys. American
Journal of Physiology, 1976, 230, 15-18.
Gibbs, J., & Smith, G. P. Gibbs and Smith reply. Nature,
1977, £66, 196.
Gibbs, J., Young, R. C., & Smith, G. P. Cholecystokinin
elicits satiety in rats with open gastric fistulas.
Nature, 1973, 24^, 323-325.
Gibbs, J., Young, R. C., & Smith, G. P. CCK decreases food
intake in rats. Journal of Comparative and Physiological
Psychology, 1974, 8£, 488-495.
Glick, Z., & Mayer, J. Preliminary observations on the effect
of intestinal mucosa on food intake of rats. Federation Proceedings, 1968, 21_, 485. 113
Click, Z,, & Modan, M. Behavioral compensatory responses to
continuous duodenal and upper ileal glucose infusion in
rats. Physiology and Behavior, 1977, l^, 703-706.
Click, Z., Thomas, D. W., & Mayer, J. Absence of effect of
injections of intestinal hormones secretin and CCK-
pancreozymin upon feeding behavior. Physiology and
Behavior, 1971, 6, 5-8.
Coetz, H., & Sturdevant, R. Effect of CCK on food intake in
man. Clinical Research, 1975, 98-100.
Gold, R. M. Hypothalamic obesity: The myth of the ventro
medial nucleus. Science, 1973, 1^, 488-490.
Crossman, M. I. Physiology: Hormonal effects. In S. A.
Berson, & R. S. Yalow (Eds.), Methods in investigative
and diagnostic endocrinology. New York: Elsevier, 1973.
Grossman, M. I., & Stein, I. F. Vagotomy and the hunger-
producing action of insulin in man. Journal of
Applied Physiology, 1948, 1, 263-269.
Hetherington, A. W., & Ranson, S. W. Hypothalamic lesions
and adiposity in the rat. Anatomical Record, 1940, 78,
149-172.
Hoebel, B. G. Satiety; Hypothalamic stimulation, anorectic
drugs, and neurochemical substrates. In D. Novin, W.
Wyrwicka, & G. Bray (Eds.), Hunger:Basic mechanism and
clinical implications. New York: Raven Press, 1976. 114
Holman, G. L. Intragastric reinforcement effect. Journal
of Comparative and Physiological Psychology, 1968, 69,
432-441.
Holt, J., Antin, J., Gibbs, J., Young, R. C., & Smith, G. P.
CCK does not produce baitshyness in rats. Physiology and
Behavior, 1974, 12, 497-498.
Houpt, T. R., Anika, S. M., & Wolff, N. C. Satiety effects
of cholecystokinin and caerulein in rabbits. American
Journal of Physiology, 1978, 235, 23-28.
Hull, C. L., Livingston, J. R., Rouse, J. R., & Barker, A. N.
True, sham, and esophageal feeding as reinforcements.
Journal of Comparative and Physiological Psychology,
1951, 44, 236-245.
Hustvedt, B. E., & Lç6v0, A. Correlation between hyperinsulin-
emia and hyperphagia in rats with ventromedial hypothalamic
lesions. Acta Physiologica Scandinavia, 1972, 8j4, 29-33.
Iggo, A. Gastro-intestinal tension receptors with
unmyelinated afferent fibers in the vagus of the cat.
Quarterly Journal of Experimental Physiology, 1957, 42,
130-143.
Ingelfinger, F. J. The late effects of total and subtotal
gastrectomy. New England Journal of Medicine, 1944, 231,
321-327.
Jacobs, H. Some physical, metabolic, and sensory components in
the appetite for glucose. American Journal of Physiology,
1962, 203, 1043-1054. 115
James, W. T. An analysis of esophageal fistula as a form of
operant reinforcement in the dog. Psychological Reports,
1963, ]^, 31-39.
Janowitz, H. D. Role of the gastrointestinal tract in regu
lation of food intake. In C. F. Code (Ed.), Alimentary
canal, handbook of physiology. Vol. 1. Baltimore:
Williams and Wilkins, 1967.
Janowitz, H. D., & Grossman, M. I. Some factors affecting the
food intake of normal dogs and dogs with esophagotomy
and gastric fistulas. American Journal of Physiology,
1949, 0^, 143-148.
Janowitz, H. D., & Ivy, A. C. Rate of blood-sugar levels in
spontaneous and insulin-induced hunger in man. Journal
of Applied Physiology, 1949, 643-647.
Kohn, M. Satiation of hunger from food injected directly into
the stomach versus food ingested by mouth. Journal of
Comparative and Physiological Psychology, 1951, 44,
412-422.
Koopmans, H. S., Deutsch, J. A., & Branson, P. J. The effect
of cholecystokinin-pancreozymin on hunger and thirst in
mice. Behavioral Biology, 1972, 7, 441-444.
Kornblith, C. L., Ervin, G. N., & King, R. A. Hypothalamic
and locus coeruleus self-stimulation are decreased by
cholecystokinin. Physiology and Behavior, 1978, 21,
1037-1042. 116
Kraly, F. S., Carty, W. J., Resnick, S,, & Smith, G. P. Effect
of cholecystokinin on meal size and intermeal interval in
the sham-feeding rat. Journal of Comparative and
Physiological Psychology, 1978, 9_2, 697-707.
Kraly, F. S., Carty, W. J., & Smith, G. P. Effect of pre-
gastric food stimuli on meal size and intermeal interval
in the rat. Physiology and Behavior, 1978, 20i, 779-784.
Kraly, F. S., & Gibbs, J. Vagotomy fails to block the sati
ating effect of food in the stomach. Neuroscience
Abstracts, 1978, 176.
Kraly, F. S., & Smith, G. P. Combined pregastric and gastric
stimulation by food is sufficient for normal meal size.
Physiology and Behavior, 1978, 21, 405-408.
Krasne, F. B. General disruption resulting from electrical
stimulation of ventromedial hypothalamus. Science, 1962,
138, 822-823.
Krauss, R. M., & Mayer, J. Influence of protein and amino
acids on food intake in the rat. American Journal of
Physiology, 1965, 209, 479-484.
Krinsky, R., Lotter, E. C., & Woods, S. C. Appetite suppres
sion caused by cholecystokinin in diet specific in VMH
lesioned rats. Physiological Psychology, 1979, 1_, 67-69. Kulkosky, P. E., Breckenridge, C., Krinsky, R., & Woods, S. C.
Satiety elicited by the C terminal octapeptide of CCK in normal and VMH lesioned rats. Behavioral Biology, 1976, 18, 227-234. 117
/ X LeMagnen, J., & Talion, S. La périodicité spontanee de la • prise daliments ad libitum du rat blanc. Journal de
Physiologie, (Paris), 1966, 323-349.
Levant, J. A., Kun, T. L., Jacna, J., Sturdevant, A. L., &
Isenberg, J. I. The effects of graded doses of C-ter-
minal octapeptide of CCK on small intestine transit time
in man. American Journal of Digestive Disease, 1974, 19,
207-209.
Liebling, D. J., Eisner, J. D., Gibbs, J., & Smith, G. P.
Intestinal satiety in rats. Journal of Comparative
and Physiological Psychology, 1975, 8£, 955-965.
Lorenz, D., & Goldman, S. A. Dependence of the cholecystokinin
satiety effect on vagal innervation. Neuroscience
Abstracts, 1978, £, 178.
MacKay, E. M., Calloway, J. W., & Barnes, R. H. Hyper
alimentation in normal animals produced by protamine
insulin. Journal of Nutrition, 1940, 2^, 59-66.
MacLagan, N. F. The role of appetite in the control of body
weight. Journal of Physiology, 1937, 385-394.
Maddison, S. Intraperitoneal and intracranial CCK depress
operant responding for food. Physiology and Behavior,
1977, 19, 812-824.
Maddison, S. Predigestion and suppression of food intake by
gastric loads. Physiology and Behavior, 1978, 21, 497-
502. 118
Margules, D. C., & Olds, J. Identical "feeding" and "reward
ing"systems in the lateral hypothalamus of rats. Science,
1962, 374-375.
Martin, J. R., & Novin, D. Decreased feeding in rats follow
ing hepatic-portal infusion of glucagon. Physiology and
Behavior, 1977, ]^, 461-466.
Martin, J. R., Novin, D., & Vanderweele, D. A. Loss of
glucagon suppression of feeding after vagotomy in rats.
American Journal of Physiology, 1978, 243, 313-318.
Mayer, J. Glucostatic mechanisms of regulation of food intake.
New England Journal of Medicine, 1953, 249, 13-16.
Mayer, J. Regulation of energy intake and the body weight:
The glucostatic theory and the lipostatic hypothesis.
Annals of the New York Academy of Science, 1955, 63,
15-43.
Mayer, J. Appetite and obesity. Scientific American, 1956,
195, 108-116.
Mayer, J., & Marshall, N. B. Specificity of gold-thioglucose
for ventromedial hypothalamic lesions and obesity.
Nature (London), 1956, 178, 1399-1400.
Mayer, J., & Thomas, D. W. Regulation of food intake and
obesity. Science, 1967, 156, 328-337.
Miller, N. E., & Kessen, M. L. Reward effects of food via stomach fistula compared with those of food via mouth. Journal of Comparative and Physiological Psychology,
1952, 45, 555-564. 119
Mineka, S., & Snowdon, C. T. Inconsistency and possible
habituation of CCK-induced satiety. Physiology and
Behavior, 1978, 21, 65-72.
Miselis, R., & Epstein, A. N. Feeding induced by 2-deoxy-
D-glucose injections into the lateral ventricle of the
rat. Physiologist, 1970, ]^, 262.
Mook, D. G. Oral and postingestional determinants of the in
take of various solutions in rats with esophageal fistulas.
Journal of Comparative and Physiological Psychology,
1963, 645-659.
Morgan, C. T., & Morgan, J. D. Studies in hunger II: The
relation of gastric denervation and dietary sugar to the
effect of insulin upon food intake in the rat. Journal
of General Psychology, 1940, b2_, 153-163.
Mueller, K., & Hsiao, S. Specificity of cholecystokinin
satiety effect: Reduction of food but not water intake.
Pharmacology Biochemistry and Behavior, 1977, £, 643-646.
Mueller, K., & Hsiao, S. Current status of cholecystokinin
as a short-term satiety hormone. Neuroscience and
Biobehavioral Reviews, 1978, £, 79-87.
Nemeroff, C. B., Osbahr, A. J., Bissette, G., Jahnke, G.,
Lipton, M. A., & Prange, A. J. Cholecystokinin
inhibits tail inch-induced eating in rats. Science,
1978, 200, 793-794. 120
Niijiraa, A. Afferent impulse in the gastric and oesaphageal
branch of the vagal nerve of toad. Physiology and
Behavior, 1967, 2^, 1-4.
Niijima, A. Afferent impulse discharges from the glucorecep-
tors in the liver of the guinea pig. Annals of the New
York Academy of Sciences, 1969, 157, 690-700.
Novin, D. Visceral mechanisms in the control of food intake.
In D. Novin, W. Wyrwicka, & G. Bray (Eds.), Hunger ;Basic
mechanisms and clinical implications. New York; Raven
Press, 1976.
Novin, D., Sanderson, J. D., & Vanderweele, D. A. The effect
of isotonic glucose on eating as a function of feeding
condition and infusion site. Physiology and Behavior,
1974, 13, 3-7.
Olds, J., & Milner, P. Positive reinforcement produced by
electrical stimulation of the septal area and other
regions of the rat brain. Journal of Comparative and
Physiological Psychology, 1954, 419-427.
Paintal, A. S. A study of gastric stretch receptors. Journal
of Physiology (London), 1954, 126, 255-270.
Penaloza-Rojas, J. H., & Russek, M. Anorexia produced by
direct-current blockade of the vagus nerve. Nature,
1963, 200, 176. 121
Polak, J. M., Pearse, A. G. E., Bloom, S. R., Buchan, A. M. J.,
Rayford, P. L., & Thompson, J. C. Identification of
cholecystokinin-secreting cells. Lancet, 1975, £,
1016-1018.
Powley, T.L. The ventromedial hypothalamic syndrome, satiety,
and a cephalic phase hypothesis. Psychological Review,
1977, 8_4, 89-126.
Powley, T. L., & Opsahl, C. A. Ventromedial hypothalamic
obesity abolished by subdiaphragmatic vagotomy. American
Journal of Physiology, 1974, 226, 25-33.
Puerto, A., Deutsch, J. A., Molina, F., & Roll, P. Rapid
discrimination of rewarding nutrient by the upper
gastrointestinal tract. Science, 1976, 192, 485-486.
Rosen, A. J., Davis, J. D., & LaDove, R. Electrocortical
activity; Modification by food ingestion and a humoral
satiety factor. Communications in Behavior and Biology,
1971, 6, 323-327.
Russek, M. Demonstration of the influence of an hepatic
glucosensitive mechanism on food intake. Physiology
and Behavior, 1970, 5, 1207-1210.
Russek, M. Hepatic receptors and the neurophysiological
mechanism controlling feeding behavior. In S.
Ehrenpreis (Ed,), Neuroscience Research, Vol. 4.
New York; Academic Press, 1971. 122
Schally, A. V., Redding, T. W., Lucien, H. W., & Mayer, J.
Enterogastrone inhibits eating by fasted mice. Science,
1967, 3^, 210-211.
Scharrer, E., Baile, C. A., & Mayer, J. Effects of amino acids
and protein on food intakes of hyperphagic and recovered
aphagic rats. American Journal of Physiology, 1970, 218,
400-404.
Seoane, J. R., Bailey, C. A., & Martin, G. Humoral factors
modifying feeding behavior of sheep. Physiology and
Behavior, 1972, 8, 993-995.
Share, I. E., Martyiuk, L., & Grossman, M. I. Effects of
prolonged intragastric feeding on oral food intake in
dogs. American Journal of Physiology, 1952, 169, 229-235.
Sharma, K.N. Receptor mechanisms in the alimentary tract;
Their excitation and functions. In C. F. Code (Ed.),
Alimentary canal, handbook of physiology. Vol. 1.
Baltimore: Williams and Wilkins, 1967.
Sherrington, C. S. Experiments on the value of vascular and
visceral factors for the genesis of emotion. Proceedings
of the Royal Society (London), 1900, £6, 390-403.
Smith, M., & Duffy, M. The effects of intragastric injection
of various substances on subsequent bar-pressing.
Journal of Comparative and Physiological Psychology,
1955, 48, 387-391. 123
Smith, M., & Duffy, M. Some physiological factors that regu
late eating behavior. Journal of Comparative and
Physiological Psychology, 1957, 50^, 601-608.
Smith, M., Pool, R., & Weinberg, H. The role of bulk in the
control of eating. Journal of Comparative and Physio
logical Psychology, 1962, 115-120.
Smith, M., Salisbury, R., & Weinberg, H. The reaction of
hypothalamic hyperphagic rats to stomach preloads.
Journal of Comparative and Physiological Psychology, 1961,
54, 660-664.
Snowdon, C. T. Motivation, regulation and control of meal
parameters with oral and intragastric feeding.
Journal of Comparative and Physiological Psychology,
1969, 91-100.
Snowdon, C. T. Gastrointestinal sensory and motor control of
food intake. Journal of Comparative and Physiological
Psychology, 1970, 11, 68-76.
Snowdon, C. T. Production of satiety with small intraduodenal
infusions in the rat. Journal of Comparative and
Physiological Psychology, 1975, 231-238.
Snowdon, C. T., & Epstein, A. N. Oral and intragastric
feeding in vagotomized rats. Journal of Comparative and
Physiological Psychology, 1970, T1, 59-67. 124a
Stern, J. J., Cudillo, C. A., & Kruper, J. Ventromedial
hypothalamus and short-term feeding suppression by
caerulein in male rats. Journal of Comparative and
Physiological Psychology, 1976, 90.' 484-490.
Straus, E., & Yalow, R. S. Cholecystokinin in the brains of
obese and nonobese mice. Science, 1979, 203, 68-69.
Sturdevant, R., & Goetz, H. CCK both stimulates and inhibits
food intake. Nature, 1976, 261, 713-714.
Teitelbaum, P. Sensory control of hypothalamic hyperphagia.
Journal of Comparative and Physiological Psychology,
1955, 156-163.
Ugolev, A. M. The influence of duodenal abstracts on general
appetite. Doklady Akademii Nauk SSSR, 1960, 133, 632-
634.
Ungerstedt, U. Stereotaxic mapping of monoamine pathways in
the rat brain. Acta Physiologica Scandinavia, (Suppl.
367) , 1971, 1-48.
Vanderweele, D. A., Novin, D., Rezek, M., & Sanderson, J. D.
Duodenal or hepatic-portal perfusion: Evidence for
duodenally-based satiety. Physiology and Behavior,
1974, r2, 467-473.
Wellman, P. J., & Peters, R. H. Effects of cellulose-
adulteration on maintenance feeding behavior in rats
with VMH lesions. Physiological Psychology, 1978, 6,
494-496. 124b
Wiepkema, P., Alingh Prins, A. J., & Steffens, A. B.
Gastrointestinal food transport in relation to meal
occurrence in rats. Physiology and Behavior, 1972,
759-763.
Yin, T. H., & Tsai, C. T. Effects of glucose on feeding in
relation to routes of entry in rats. Journal of
Comparative and Physiological Psychology, 1973, 85,
258-264. 125
APPENDIX B: HISTOLOGICAL ANALYSES
Representative unstained and unretouched photomicrographs
of tissue damage sustained by VMH and by DLT animals. Lesion
damage is indicated by a small arrow and an unlesioned section
through the same coronal plane is provided for comparison.
The figure to the right of the identification code is the cum
ulative body weight gain for that rat (grams/30 days access to the high-fat diet). Photomicrograph magnification is 14X for both figures. During sectioning, the brain was blocked and the right cerebral cortex notched to indicate the right side of the brain. Also, there were frequent losses of cortical tissue especially for the DLT rats during the mounting and photography of brain sections. ' , SM ,^fPVT/ A h
LAMI LAME
ffTtt
LSTH
1?IVTI\C \ \ CSDv \ ^ ,av CTH 127 CFD
FLDT S6CD
t-m % SGCV
FLOG v-ï-ee
PCM LT DPCS FPT YM TT5 129