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Central administration of motilin stimulates feeding in rats
Physiology & Behavior, Vol. 39, pp. 753-756. Copyright©Pergamon Journals Ltd., 1987. Printed in the U.S.A.
0031-9384/87 $3.00 + .00
Central Administration of Motilin Stimulates Feeding in R a t s I D A V I D J. R O S E N F E L D
AND THOMAS L. GARTHWAITE z
Department o f Medicine, Medical College o f Wisconsin, and VA Medical Center, Milwaukee, W I 53295 R e c e i v e d 30 O c t o b e r 1986 ROSENFELD, D. J., AND T. L. GARTHWAITE. Central administration ofmotilin stimulatesfeeding in rats. PHYSIOL BEHAV 39(6) 753-756, 1987.--Peripheral administration of motilin has been found to stimulate feeding behavior in rats. Since motilin immunoreactivity has been found in discrete brain sites, we tested the effect of motilin administered intracerebroventricularly on feeding in rats. Injection of 1 p.g of motilin significantly increased food consumption at 2 hours, 22 hours, and at 24 hours in animals tested either at or 2 hr prior to lights out. Motilin also significantly increased food consumption in animals maintained under continuous lights-on at 2 hours (488% of control), 22 hours (i 28% of control), and at 24 hours (140% of control). Motilin
Feeding
Gut-brain peptides
Appetite
Central Administration
M O T I L I N is a 22 amino acid peptide initially isolated from canine small intestinal mucosa [1]. Plasma concentrations of motilin are suppressed by feeding [9,17], although lipidcontaining meals may cause a brief initial increase [9]. Peripheral administration o f motilin has been found to stimulate feeding behavior in rats [6]. In view of the recent demonstration o f immunoreactive motilin in the hypothalamus [ 10], and the known central effects of other gut-brain peptides (e.g., cholecystokinin [7] and bombesin [12]), a study was undertaken to ascertain the effects of central administration of motilin on the feeding behavior of rats.
choloramphenicol dissolved in 0.2 ml of sterile water. Injection cannulae (29 gauge) were connected to a 10/zl Hamilton syringe by a 15 cm piece of polyethylene tubing. The injection cannulae was cut such that after insertion its end was flush with the end of the guide cannula. Four days after recovery, correct guide cannula placement was verified by the injection of 100/zg of angiotensin II. Placement was considered satisfactory if a previously nondrinking animal began to drink within 2 minutes after injection.
Experimental Procedures General. The first injection was made one day after cannula placement verification. All injections were given at 1400 hr with at least 48 hours between injections. Synthetic porcine motilin (Peninsula Laboratories, Belmont, CA) was dissolved in artificial cerebral spinal fluid (CSF), previously sterilized by passage through a 0.22/zm millipore filter, such that the final injection volume was always 10/zl. The composition of the artificial CSF: NaC1 126 mM, KCI 6 mM, Na2HPO4 1 mM, MgSO4.7H20 0.877 mM, NaHCO3 22 mM, CaCI~ 1.45 mM and D-glucose 11.1 mM; pH=7.4. Following injection, rats were returned to their cages and allowed access to a preweighed quantity o f pelleted lab chow. After 2 hours the remaining food was removed and weighed, and the amount consumed determined. A second preweighed quantity of food was provided and food consumption during the following 22 hours measured. Experiment I. Injection 2 hr before lights out. Animals were maintained on a 12 hour light/dark cycle with lights out at 1600 hr. Motilin was administered in two doses, 10 ng and 1/zg, with each of the 12 subjects receiving two injections at
METHOD
Subjects and Maintenance Adult male Sprague-Dawley rats (275-300 g, Sasco Laboratories Inc., Madison, WI) were maintained in individual wire bottom cages with free access to pelleted laboratory animal chow and tap water, and ambient temperature of 21°C. Rats were handled for 3 to 5 minutes the day prior to cannula implantation to accustom them to handling.
Cannula Implantation The rats were anesthetized with pentobarbitol (55 mg/kg IP) and placed in a stereotaxic apparatus. Stainless steel guide cannulas (length 15 ram, 24 gauge) were implanted unilaterally into the lateral ventricle and closed with a stainless steel plug (length 15 mm, 29 gauge). Coordinates for the tips of the cannulas, according to Pellegrino [16] were: A. 0.2, L. 1.5, V. - 3 . 0 . Immediately following cannula implantation rats were given an intraperitoneal injection of 20 mg of
~Supported by TOPS Club, Inc., Obesity and Metabolic Research Program, Milwaukee, WI, and The Veterans Administration. ~'Requests for reprints should be addressed to Thomas L. Garthwaite, M.D., Associate Chief of Staff for Research/151, Milwaukee, WI 53295.
753
754
R O S E N F E L D AND GARTHWAITE
~
4o
4-
J~ ¢N "~
--T-
[]
22HR [ ] 24 HR
NS 3O
3
o co
"1-
O
"62
O
i o
0 Vehicle
I0 ng
20
10
0 Vehicle
1 I~g
Dose of motilin
FIG. 2. Food intake (mean and mean+SE) at 22 and 24 hours in animals injected 2 hours prior to lights out. F(2,57)=4.21, p<0.02 and F(2,57)=7.43, p<0.002, for 22 and 24 hours, respectively; *p<0.05, **p<0.01, ***p<0.001 vs. vehicle.
~,
8
--v-
~"
40
3o
[ ] 22 HR VA 24 HR
** ~ "1-
"~ ~
4
1 gg
Dose of motilin
FIG. 1. Food intake (mean and mean+ SE) during the 2 hours following injection in animals injected 2 hours prior to lights out. F(2,57)=4.06, p<0.05; ***p<0.001 vs. vehicle.
** -'T-
10 ng
_*** *** --i-
o
--r-
"6
2O
i
~
2
0 Vehicle
10 ng
Vehicle
1 ~tg
Dose of motilin
10 ng
1 gg
Dose of motilin
FIG. 3. Food intake (mean and mean+SE) during the 2 hours following injection in animals injected at lights out. F(2,41)= 4.70, p <0.02; **p<0.01 vs. vehicle.
FIG. 4. Food intake (mean and mean+SE) at 22 and 24 hours in animals injected at lights out. F(2,41)=6.00, p<0.01 and F(2,41)=9.20, p<0.001, for 22 and 24 hours, respectively; *p<0.05, **p<0.01, ***p<0.001 vs. vehicle.
each dosage, as well as a sham injection of only artificial CSF, in the following order: sham, 10 ng, 1/zg, 1/zg, 10 ng. Experiment H. Injection at lights out. Animals were maintained on a 12 hour light/dark cycle with lights out at 1400 hr. Motilin was administered as in experiment I to each of the 9 subjects at 1400 hr. Experiment 111. Rats maintained on a 24 hour lights-on cycle. Injections were made as in Experiment I to 4 animals maintained under continuous lights-on. Results are expressed as m e a n - S E . One way analysis of variance (ANOVA) in combination with non-paired Student's t-test was used to assess significant differences in food intake among groups for the various doses of motilin tested. p~<0.05 was considered to be significant.
RESULTS
Experiment I As shown in Figs. 1 and 2, injection of 1 /xg of motilin significantly increased food consumption at 2 hours (162% of control), 22 hours (112% of control), and at 24 hours (116% of control). The 10 ng dose had no significant effect.
Experiment H As illustrated in Figs. 3 and 4, food consumption was significantly increased by a 10 lag dose of motilin at 2 hr and 24 hr, and by a 1/xg dose at all levels (2, 22, 24 hr).
CENTRAL MOTILIN STIMULATES FEEDING
755
4
40
~"
i3
~"
[ ] 22HR [ ] 24HR
***
a0
t
2
"6
t
['
-r o Vehicle
10 ng
1 p.g
Dose of motilin FIG. 5. Food intake (mean and mean + SE) during the 2 hours following injection in animals injected at 1400 hr and maintained under continuous lights-on. F(2,17)= 100.13, p <0.001 ; ***p<0.001 vs. vehicle.
Experiment III As shown in Figs. 5 and 6, injection of 1 /~g of motilin significantly increased food consumption in animals maintained under continuous lights-on at 2 hours (488% of control), 22 hours (128% of control), and at 24 hours (140% of control). The 10 ng dose did not significantly increase food consumption. DISCUSSION These experiments demonstrate an increase in food intake in response to central administration of motilin in nonfasted rats. Injection of 1 /zg of motilin significantly increased food consumption at 2 hr, 22 hr and 24 hr, regardless of light conditions. This increase in food consumption is in contrast to the suppressive effects after central administration of many other brain-gut peptides (e.g., cholecystokinin [5, 11, 21], bombesin [8], and caerulin [15]). The only other peptides which have been shown to stimulate feeding when injected centrally are some of the endorphins [13,20] and neuropeptide Y [4]. The f'mdings described here differ in part from the effects of peripheral motilin administration [6], in which food consumption was increased only if rats were fasted prior to injection. This difference in effect on feeding between central and peripheral administration may reflect a difference in the final concentration of motilin delivered to one central site or alternatively could suggest two sites of action, one peripheral and one central. The animals in this study were tested either just before or at lights out. Since rats eat very little during lights on, the rats in this study might be considered to be in a semi-fasted state (similar to man before breakfast). The response o f fasted animals to centrally administered motilin was not determined in this study. The greatest stimulation o f feeding in this study was at 2 hr in rats subjected to
Vehicle
10 ng
1 gg
Dose of motilin FIG. 6. Food intake (mean and mean+SE) at 22 and 24 hours in
animals injected at 1400 hr and maintained under continuous lightson. F(2,17)=3.74, p<0.05 and F(2,17)=8.55, p<0.01, for 22 and 24 hours, respectively; **p<0.01, ***p<0.001 vs. vehicle.
continuous lights-on. These animals may have lost some of the normal suppressive effect of light on feeding behavior. The finding that vehicle injected animals ate during lights on during this study is also different than in our previous study [6] in which fed animals did not eat after motilin or vehicle between 0900 and 1100 hr. This difference may be due to a nonspecific feeding stimulation related to the stress of central injection [14]. Additionally, animals may be hungrier at 2 hours prior to lights on (this study) than at 9 hours prior to lights on (previous study). The peripherally administered dose of motilin necessary to stimulate feeding in fasted rats was 5/~g/kg IP [6]. In this study, 1 /zg ICV was necessary to stimulate feeding in the non-fasted state. This relative insensitivity to centrally administered motilin may be explained by the non-fasted state of the animals in this study and/or the diffusion necessary for motilin to traverse the distance from the ventricular system to the brain site of action of motilin. The specific site of action of motilin within the central nervous system to stimulate feeding and the physiologic significance of motilin in feeding remain unknown. Since immunoreactive motilin has been found in a number of forebrain structures [3, 10, 15], it is likely that the rostral, rather than the caudal periventricular brain areas are involved in motilin induced feeding. Based on the relationship between motilin and interdigestive migrating myoelectric complexes in the gut, motilin may mediate the hunger associated with gastric contractions as observed by Cannon and Washburn [2].
ACKNOWLEDGEMENTS We gratefully acknowledge the technical assistance of Donald R. Martinson and the editorial assistance of Paul S. Rosenfeld.
756
ROSENFELD
AND GARTHWAITE
REFERENCES
1. Brown, J. C., V. Mutt and J. R. Dryburgh. The further purification of motilin, a gastric motor activity from the mucosa of the small intestine of dogs. Can J Physiol Pharmacol 48: 39%405. 1971. 2. Cannon, W. B. and A. L. Washburn. An explanation of hunger. Am J Physiol 29: 441-454, 1912. 3. Chan-Palay, V., G. Nilaver, S. L. Palay, M. C. Beinfeld, E. A. Zimmerman, J. Y. Wu and T. L. O'Donohue. Chemical heterogeneity in the cerebellar Purkinje cells: Existence and coexistence of glutamic acid and decarboxylase-like and motilin-like immunoreactives. Proc Natl Acad Sci USA 78: 7787-7791, 1981. 4. Clark, J., P. Kalra, W. Crowley and S. Kalra. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115: 427-429, 1984. 5. Feris, P. L., A. C. Scallet, J. W. Olney, M. A. Della-Fera and C. A. Baile. Behavioral and immunohistochemical analysis of the function of cholecystokinin in the hypothalamic paraventricular nucleus. Soc Neurosci Abstr 9: 184, 1983. 6. Garthwaite, T. L. Peripheral motilin administration stimulates feeding in fasted rats. Peptides 6: 41-44, 1985. 7. Gibbs, J., R. C. Young and G. P. Smith. Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245: 323-325, 1973. 8. Gibbs, J., D. J. Fauser, E. A. Rowe, B. J. Rolls, E. T. Rolls and S. P. Maddison. Bombesin suppresses feeding in rats. Nature 282: 208-210, 1979. 9. Imura, H., Y. Seino, K. Mori, Z. ltoh and N. Yanaihara. Plasma motilin levels in normal subjects and patients with diabetes mellitus and certain other diseases. Fasting levels and responses to food and glucose. EndocrinolJpn 1: 151-155, 1980. 10. Jacobowitz, D. M., T. L. O'Donohue, W. Y. Chey and T. M. Chang. Mapping of motilin-immunoreactive neurons of the rat brain. Peptides 2: 479-487, 1981.
11. McCaleb, M. L. and R. D. Meyers. Cholecystokinin acts on the hypothalamic "noradrenergic system" involved in feeding. Peptides i: 47-49, 1980. 12. Martin, C. F. and J. Gibbs. Bombesin elicits satiety in sham feeding rats. Peptides 1: 131-134, 1980. 13. Morley, J. E. and A. S. Levine. Dynorphin-(l-13) induces spontaneous feeding in rats. Lift, Sci 29: 1901-1903, 1981. 14. Morley, J. E. and A. S. Levine. Stress induced eating is mediated through endogenous opiates. Science 209: 1259-1261, 1980. 15. Nilaver, G., R. Defendini, E. A. Zimmerman, M. C. Beinfeld and T. L. O'Donohue. Motilin in the Purkinje cell of the cerebellum. Nature 295: 597-598, 1982. 16. Pellegrino, L. J. and A. J. Cushman. A stereotaxic atlas of the rat brain. New York: Appleton-Century-Crofts, 1967. 17. Ruckebusch, M. and J. Fioramonti. Electrical spiking activity and propulsion in small intestine in fed and fasted rats. Gastroenterology 68: 1500-1508, 1975. 18. Smith, G. P. and J. Gibbs. Brain-gut peptides and the control of food intake. In: Advances in Biochemical Psychopharmacology: Neurosecretion and Brain Peptides, edited J. B. Martin, S. Reichlin and K. L. Bick. New York: Raven Press, 1982, pp. 38%395. 19. Stern, J. J., C. A. Cudillo and J. Krupper. Ventromedial hypothalamus and short-term feeding suppression by caerulein in male rats. J Comp Physiol Psychol 90: 484-490, 1976. 20. Tseng, L.-F. and D. S. Cheng. Acute and chronic administration of/3-endorphin and naltrexone on food and water intake in rats. Fed Proc 39: 606, 1980. 21. Willis, G. L., J. Hansky and G. C. Smith. The role of some central catecholamine systems in the cholecystokinin induced satiety. Peptides 5: 41-46, 1984.
0031-9384/87 $3.00 + .00
Central Administration of Motilin Stimulates Feeding in R a t s I D A V I D J. R O S E N F E L D
AND THOMAS L. GARTHWAITE z
Department o f Medicine, Medical College o f Wisconsin, and VA Medical Center, Milwaukee, W I 53295 R e c e i v e d 30 O c t o b e r 1986 ROSENFELD, D. J., AND T. L. GARTHWAITE. Central administration ofmotilin stimulatesfeeding in rats. PHYSIOL BEHAV 39(6) 753-756, 1987.--Peripheral administration of motilin has been found to stimulate feeding behavior in rats. Since motilin immunoreactivity has been found in discrete brain sites, we tested the effect of motilin administered intracerebroventricularly on feeding in rats. Injection of 1 p.g of motilin significantly increased food consumption at 2 hours, 22 hours, and at 24 hours in animals tested either at or 2 hr prior to lights out. Motilin also significantly increased food consumption in animals maintained under continuous lights-on at 2 hours (488% of control), 22 hours (i 28% of control), and at 24 hours (140% of control). Motilin
Feeding
Gut-brain peptides
Appetite
Central Administration
M O T I L I N is a 22 amino acid peptide initially isolated from canine small intestinal mucosa [1]. Plasma concentrations of motilin are suppressed by feeding [9,17], although lipidcontaining meals may cause a brief initial increase [9]. Peripheral administration o f motilin has been found to stimulate feeding behavior in rats [6]. In view of the recent demonstration o f immunoreactive motilin in the hypothalamus [ 10], and the known central effects of other gut-brain peptides (e.g., cholecystokinin [7] and bombesin [12]), a study was undertaken to ascertain the effects of central administration of motilin on the feeding behavior of rats.
choloramphenicol dissolved in 0.2 ml of sterile water. Injection cannulae (29 gauge) were connected to a 10/zl Hamilton syringe by a 15 cm piece of polyethylene tubing. The injection cannulae was cut such that after insertion its end was flush with the end of the guide cannula. Four days after recovery, correct guide cannula placement was verified by the injection of 100/zg of angiotensin II. Placement was considered satisfactory if a previously nondrinking animal began to drink within 2 minutes after injection.
Experimental Procedures General. The first injection was made one day after cannula placement verification. All injections were given at 1400 hr with at least 48 hours between injections. Synthetic porcine motilin (Peninsula Laboratories, Belmont, CA) was dissolved in artificial cerebral spinal fluid (CSF), previously sterilized by passage through a 0.22/zm millipore filter, such that the final injection volume was always 10/zl. The composition of the artificial CSF: NaC1 126 mM, KCI 6 mM, Na2HPO4 1 mM, MgSO4.7H20 0.877 mM, NaHCO3 22 mM, CaCI~ 1.45 mM and D-glucose 11.1 mM; pH=7.4. Following injection, rats were returned to their cages and allowed access to a preweighed quantity o f pelleted lab chow. After 2 hours the remaining food was removed and weighed, and the amount consumed determined. A second preweighed quantity of food was provided and food consumption during the following 22 hours measured. Experiment I. Injection 2 hr before lights out. Animals were maintained on a 12 hour light/dark cycle with lights out at 1600 hr. Motilin was administered in two doses, 10 ng and 1/zg, with each of the 12 subjects receiving two injections at
METHOD
Subjects and Maintenance Adult male Sprague-Dawley rats (275-300 g, Sasco Laboratories Inc., Madison, WI) were maintained in individual wire bottom cages with free access to pelleted laboratory animal chow and tap water, and ambient temperature of 21°C. Rats were handled for 3 to 5 minutes the day prior to cannula implantation to accustom them to handling.
Cannula Implantation The rats were anesthetized with pentobarbitol (55 mg/kg IP) and placed in a stereotaxic apparatus. Stainless steel guide cannulas (length 15 ram, 24 gauge) were implanted unilaterally into the lateral ventricle and closed with a stainless steel plug (length 15 mm, 29 gauge). Coordinates for the tips of the cannulas, according to Pellegrino [16] were: A. 0.2, L. 1.5, V. - 3 . 0 . Immediately following cannula implantation rats were given an intraperitoneal injection of 20 mg of
~Supported by TOPS Club, Inc., Obesity and Metabolic Research Program, Milwaukee, WI, and The Veterans Administration. ~'Requests for reprints should be addressed to Thomas L. Garthwaite, M.D., Associate Chief of Staff for Research/151, Milwaukee, WI 53295.
753
754
R O S E N F E L D AND GARTHWAITE
~
4o
4-
J~ ¢N "~
--T-
[]
22HR [ ] 24 HR
NS 3O
3
o co
"1-
O
"62
O
i o
0 Vehicle
I0 ng
20
10
0 Vehicle
1 I~g
Dose of motilin
FIG. 2. Food intake (mean and mean+SE) at 22 and 24 hours in animals injected 2 hours prior to lights out. F(2,57)=4.21, p<0.02 and F(2,57)=7.43, p<0.002, for 22 and 24 hours, respectively; *p<0.05, **p<0.01, ***p<0.001 vs. vehicle.
~,
8
--v-
~"
40
3o
[ ] 22 HR VA 24 HR
** ~ "1-
"~ ~
4
1 gg
Dose of motilin
FIG. 1. Food intake (mean and mean+ SE) during the 2 hours following injection in animals injected 2 hours prior to lights out. F(2,57)=4.06, p<0.05; ***p<0.001 vs. vehicle.
** -'T-
10 ng
_*** *** --i-
o
--r-
"6
2O
i
~
2
0 Vehicle
10 ng
Vehicle
1 ~tg
Dose of motilin
10 ng
1 gg
Dose of motilin
FIG. 3. Food intake (mean and mean+SE) during the 2 hours following injection in animals injected at lights out. F(2,41)= 4.70, p <0.02; **p<0.01 vs. vehicle.
FIG. 4. Food intake (mean and mean+SE) at 22 and 24 hours in animals injected at lights out. F(2,41)=6.00, p<0.01 and F(2,41)=9.20, p<0.001, for 22 and 24 hours, respectively; *p<0.05, **p<0.01, ***p<0.001 vs. vehicle.
each dosage, as well as a sham injection of only artificial CSF, in the following order: sham, 10 ng, 1/zg, 1/zg, 10 ng. Experiment H. Injection at lights out. Animals were maintained on a 12 hour light/dark cycle with lights out at 1400 hr. Motilin was administered as in experiment I to each of the 9 subjects at 1400 hr. Experiment 111. Rats maintained on a 24 hour lights-on cycle. Injections were made as in Experiment I to 4 animals maintained under continuous lights-on. Results are expressed as m e a n - S E . One way analysis of variance (ANOVA) in combination with non-paired Student's t-test was used to assess significant differences in food intake among groups for the various doses of motilin tested. p~<0.05 was considered to be significant.
RESULTS
Experiment I As shown in Figs. 1 and 2, injection of 1 /xg of motilin significantly increased food consumption at 2 hours (162% of control), 22 hours (112% of control), and at 24 hours (116% of control). The 10 ng dose had no significant effect.
Experiment H As illustrated in Figs. 3 and 4, food consumption was significantly increased by a 10 lag dose of motilin at 2 hr and 24 hr, and by a 1/xg dose at all levels (2, 22, 24 hr).
CENTRAL MOTILIN STIMULATES FEEDING
755
4
40
~"
i3
~"
[ ] 22HR [ ] 24HR
***
a0
t
2
"6
t
['
-r o Vehicle
10 ng
1 p.g
Dose of motilin FIG. 5. Food intake (mean and mean + SE) during the 2 hours following injection in animals injected at 1400 hr and maintained under continuous lights-on. F(2,17)= 100.13, p <0.001 ; ***p<0.001 vs. vehicle.
Experiment III As shown in Figs. 5 and 6, injection of 1 /~g of motilin significantly increased food consumption in animals maintained under continuous lights-on at 2 hours (488% of control), 22 hours (128% of control), and at 24 hours (140% of control). The 10 ng dose did not significantly increase food consumption. DISCUSSION These experiments demonstrate an increase in food intake in response to central administration of motilin in nonfasted rats. Injection of 1 /zg of motilin significantly increased food consumption at 2 hr, 22 hr and 24 hr, regardless of light conditions. This increase in food consumption is in contrast to the suppressive effects after central administration of many other brain-gut peptides (e.g., cholecystokinin [5, 11, 21], bombesin [8], and caerulin [15]). The only other peptides which have been shown to stimulate feeding when injected centrally are some of the endorphins [13,20] and neuropeptide Y [4]. The f'mdings described here differ in part from the effects of peripheral motilin administration [6], in which food consumption was increased only if rats were fasted prior to injection. This difference in effect on feeding between central and peripheral administration may reflect a difference in the final concentration of motilin delivered to one central site or alternatively could suggest two sites of action, one peripheral and one central. The animals in this study were tested either just before or at lights out. Since rats eat very little during lights on, the rats in this study might be considered to be in a semi-fasted state (similar to man before breakfast). The response o f fasted animals to centrally administered motilin was not determined in this study. The greatest stimulation o f feeding in this study was at 2 hr in rats subjected to
Vehicle
10 ng
1 gg
Dose of motilin FIG. 6. Food intake (mean and mean+SE) at 22 and 24 hours in
animals injected at 1400 hr and maintained under continuous lightson. F(2,17)=3.74, p<0.05 and F(2,17)=8.55, p<0.01, for 22 and 24 hours, respectively; **p<0.01, ***p<0.001 vs. vehicle.
continuous lights-on. These animals may have lost some of the normal suppressive effect of light on feeding behavior. The finding that vehicle injected animals ate during lights on during this study is also different than in our previous study [6] in which fed animals did not eat after motilin or vehicle between 0900 and 1100 hr. This difference may be due to a nonspecific feeding stimulation related to the stress of central injection [14]. Additionally, animals may be hungrier at 2 hours prior to lights on (this study) than at 9 hours prior to lights on (previous study). The peripherally administered dose of motilin necessary to stimulate feeding in fasted rats was 5/~g/kg IP [6]. In this study, 1 /zg ICV was necessary to stimulate feeding in the non-fasted state. This relative insensitivity to centrally administered motilin may be explained by the non-fasted state of the animals in this study and/or the diffusion necessary for motilin to traverse the distance from the ventricular system to the brain site of action of motilin. The specific site of action of motilin within the central nervous system to stimulate feeding and the physiologic significance of motilin in feeding remain unknown. Since immunoreactive motilin has been found in a number of forebrain structures [3, 10, 15], it is likely that the rostral, rather than the caudal periventricular brain areas are involved in motilin induced feeding. Based on the relationship between motilin and interdigestive migrating myoelectric complexes in the gut, motilin may mediate the hunger associated with gastric contractions as observed by Cannon and Washburn [2].
ACKNOWLEDGEMENTS We gratefully acknowledge the technical assistance of Donald R. Martinson and the editorial assistance of Paul S. Rosenfeld.
756
ROSENFELD
AND GARTHWAITE
REFERENCES
1. Brown, J. C., V. Mutt and J. R. Dryburgh. The further purification of motilin, a gastric motor activity from the mucosa of the small intestine of dogs. Can J Physiol Pharmacol 48: 39%405. 1971. 2. Cannon, W. B. and A. L. Washburn. An explanation of hunger. Am J Physiol 29: 441-454, 1912. 3. Chan-Palay, V., G. Nilaver, S. L. Palay, M. C. Beinfeld, E. A. Zimmerman, J. Y. Wu and T. L. O'Donohue. Chemical heterogeneity in the cerebellar Purkinje cells: Existence and coexistence of glutamic acid and decarboxylase-like and motilin-like immunoreactives. Proc Natl Acad Sci USA 78: 7787-7791, 1981. 4. Clark, J., P. Kalra, W. Crowley and S. Kalra. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115: 427-429, 1984. 5. Feris, P. L., A. C. Scallet, J. W. Olney, M. A. Della-Fera and C. A. Baile. Behavioral and immunohistochemical analysis of the function of cholecystokinin in the hypothalamic paraventricular nucleus. Soc Neurosci Abstr 9: 184, 1983. 6. Garthwaite, T. L. Peripheral motilin administration stimulates feeding in fasted rats. Peptides 6: 41-44, 1985. 7. Gibbs, J., R. C. Young and G. P. Smith. Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245: 323-325, 1973. 8. Gibbs, J., D. J. Fauser, E. A. Rowe, B. J. Rolls, E. T. Rolls and S. P. Maddison. Bombesin suppresses feeding in rats. Nature 282: 208-210, 1979. 9. Imura, H., Y. Seino, K. Mori, Z. ltoh and N. Yanaihara. Plasma motilin levels in normal subjects and patients with diabetes mellitus and certain other diseases. Fasting levels and responses to food and glucose. EndocrinolJpn 1: 151-155, 1980. 10. Jacobowitz, D. M., T. L. O'Donohue, W. Y. Chey and T. M. Chang. Mapping of motilin-immunoreactive neurons of the rat brain. Peptides 2: 479-487, 1981.
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