Appetite-suppressing effects of urocortin, a CRF-related neuropeptide

Science

Volumn 273, Issue 5281, 1996, Pages 1561-1564

  Spina, Mariarosa ^a   Merlo Pich, Emilio ^a,c   Chan, Raymond K W ^b   Basso, Ana Maria ^a   Rivier, Jean ^b   Vale, Wylie ^b   Koob, George F ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b SALK INSTITUTE FOR BIOLOGICAL STUDIES   (United States)

^c GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CORTICOTROPIN RELEASING FACTOR; CORTICOTROPIN RELEASING FACTOR RECEPTOR; NEUROPEPTIDE;

APPETITE; ARTICLE; FEEDING; FOOD INTAKE; LOCOMOTION; PRIORITY JOURNAL; RECEPTOR AFFINITY; STRESS; SYMPATHETIC TONE;

EID: 0029741238     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.273.5281.1561     Document Type: Article

References (45)

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23. 2β receptors as determined in stable CHO-transfected cells were 0.16, 0.58, and 0.41 nM for UCN; 0.43, 3.4, and 3.00 nM for urotensin I; and 0.95, 13.00, and 17.00 nM for CRF, respectively.
24. 2β receptors as determined in stable CHO-transfected cells were 0.16, 0.58, and 0.41 nM for UCN; 0.43, 3.4, and 3.00 nM for urotensin I; and 0.95, 13.00, and 17.00 nM for CRF, respectively.
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32. For the deprivation-induced feeding experiment, rats (Wistar) were implanted with unilateral guide cannulas (7 mm long) 1 mm above the lateral ventricle while under halothane anesthesia. The side of the brain for implantations was alternated so as to eliminate hemispheric biases. After at least 7 days of recovery from surgery, the animals were food-deprived 24 hours before the experiment with free access to water. Six hours before the beginning of the experiment they were individually housed in cages without bedding. Animals were injected ICV with UCN (0.01, 0.1, 1, or 10 μg/2 μl) or vehicle. Injections were unilateral and performed over a 1 -min period by gravity, that is, the tubing containing the peptide was raised until flow began. No asymmetries, or untoward effects, were observed with these volumes and rate of injection. A few minutes after the injection, preweighed food (20g) was provided. The remaining food, including the spillage, was weighed 30, 60, and 120 min after the injection, and behavior was observed. Weight of the food at different times and cumulative amount of food eaten were calculated. For the water deprivation-induced drinking experiment, the animals were prepared as above and water-deprived for 24 hours. After the ICV injections, water was provided in Richter tubes, and water intake was measured at 30, 60, and 120 min after the injection. Food was not available during this period.
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34. Experiments were performed on individually housed conscious, freely moving Wistar rats 24 hours after implantation of femoral arterial catheters for monitoring blood pressure. Food and water were available ad libitum One hour before injection, the catheter was connected with a transducer. Arterial blood pressure was monitored on a pen recorder, and heart rate was computed from the blood pressure pulses with a biotachometer. The ICV injection unit was put in place 15 min before injection, and UCN (1 and 10 μg/2 μl) or vehicle were infused ICV in a randomized sequence. Depending on the dose, injections were spaced at 30-min to 1-hour intervals after the complete recovery of arterial blood pressure to the basal value. Subcutaneous injection of UCN (10 μg/ml) or vehicle at the scapular region was performed after the ICV injection session.
35. Rats were subjected to a two-bottle taste aversion test where UCN was injected ICV after exposure to a highly palatable saccharin ingestion session two times. Animals (vehicle n= 7; 0.1 μg of UCN, n= 8: 1.0 μg of UCN, n= 8) had 30-min access to water (days 1 through 6, 8, and 10) or saccharin solution (days 7 and 9) daily for the duration of an 11-day multiple-pairing test conditioning procedure. UCN was administered ICV on days 7 and 9 immediately after access to the saccharin. On day 11, all rats chose between two choices (water or saccharin). A significant taste aversion was observed only at 1.0 μg of UCN. Mean ± SEM milliliters of saccharin intake during the two-bottle test was as follows: vehicle. 16.4 ± 4.5 ml; 0.1 μg of UCN, 12.3 ± 3.5ml; and 1.0 of μg UCN, 1.1 ± 0.6 ml. Water intake during the same two-botlle test was as follows: vehicle, 8.1 ± 3.1 ml. 0.1 μg of UCN, 9.6 ± 2.3 ml; and 1.0 μg of UCN, 20.3 ± 1.2 ml. Water intake baseline on days 1 through 6, when the animals had access only to water, was 19.1 ± 1.3 (vehicle), 21.2 ± 1.5ml (0.1 μg of UCN), and 22.2 ± 1.8 ml (1.0 μg of UCN).
36. The nose-poke apparatus consists of an acrylic plastic chamber and wire mesh floor (25 cm by 25 cm by 25 cm) enclosed within a sound- and light-attenuating box. Two holes, one for food and one for water, were made (2 cm above the floor) in two opposite side walls of the chamber. Each nose poke in either the food or water hole activated the delivery of a 45-mg pellet or 100 μl of water, respectively, into a food or water tray situated next to each hole. Nose pokes were recorded by photocell beam interruptions and a microcomputer. Rats (Wistar) were exposed to one session daily for 20 hours and trained during several days to obtain an appropriate baseline level (±20% total food intake from day to day). Six animals were injected ICV with UCN in a within-subjects design; for example, each rat received each dose (0.01, 0.1, and 1.0 μg/2 μl) and vehicle according to a Latin-square design with a minimum of 3 days between injections. Injections were made at 19:30 hours, 90 min after the onset of the dark cycle (12 hours, 6 p.m. to 6 a.m.). Water intake followed food intake on a prandial basis. Results showed that nose pokes for water showed the same decrease as food intake at the same doses of UCN. The data were analyzed at 3, 6, and 12 hours after the injections. Meals or bouts of feeding were defined as continuous sequences of nose-poking for 45-mg food pellets with no inter-poke interval greater than 60 s and a minimum inter-bout interval of 15 min. This analysis is similar to that reported by others, and meals or bouts corresponded to those of visual inspection of the event recorded. J. A. Grinker, A. Drewnowski, M. Enns, H. Kissileff. Pharmacol. Biochem. Behav. 12, 265 (1980).
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39. S. Pellow, P. Chopin, S. E. File, M. Briley, J. Neurosci. Methods 14, 149 (1985); S. Heinrichs, E. M. Pich, K. A. Miczec, K. T. Britton, G. F. Koob, Brain Res. 581, 190 (1992). The plus-maze apparatus consisted of two open arms (50 cm long by 10 cm wide) and two enclosed arms of trie same size with walls 40 cm high. It was elevated 50 cm above the ground. The two open arms were exposed to the same amount of light (1.5 to 2.0 lux). Rats were acclimated for 2 hours to the anteroom adjoining the quiet room where the plus-maze was placed. Each animal was injected ICV with one of the doses of UCN (0.01, 0.1, or 1 μg/2 μl) or vehicle and placed back in its cage. After 5 min. it was placed onto the center of the plus-maze for the 5-min test. Time spent on each arm was recorded automatically by photocell beams and a computer program. The maze was carefully wiped with water with a damp sponge after each trial. Each animal was exposed only once to the maze. The experimental design for all of the studies was an independent group (between-subjects) design where each observation was made for a separate animal. All rats used in the plus-maze test were naïve and had not received any behavioral testing before being tested with the plus-maze because activity on the plus-maze is very sensitive to prior handling. However, to save on animal use, rats received additional tests and treatments after exposure to the plus-maze. For the locomotor activity and food intake studies, separate animals were assigned to each dose and peptide within that dependent variable, but most of the animals had been tested previously with one of the peptides on another behavioral test. No animals received more than a total of three peptide injections, and at least 1 week separated each peptide administration. Previous work has shown no interaction of prior plus-maze testing on locomotor activity or the feeding response.
40. The locomotor apparatus consisted of 16 wire mesh cages (20 cm by 25 cm by 36 cm) with two horizontal infrared photocell beams located across the long axis of the cage 2 cm above the floor and 16 cm from one another. Beam interruptions and crossovers were recorded (beam 1 broken followed by beam 2 and vice versa) by computer and printed out every 10 min. Activity was recorded over 3 hours, and behavior was observed every 30 min. The day before the experiment, rats were habituated for 1 hour to the room and then for 5 hours to the testing cages. On the testing day, after a 90-min habituation period, rats were injected ICV with UCN (0.1, 1, and 10 μg/2 μl) or vehicle, and the locomotor activity was monitored for the next 3 hours.
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44. M. Spina et al., data not shown.
45. We thank P. Sawchenko, O. Coscina, E. De Souza, D. Grigoriadis, and G. Schulteis for their helpful comments on the manuscript. E.M.P. is currently a research scientist at Geneva Biomedical Research Institute, Glaxo-Wellcome R&D, Geneva, Switzerland. A.M.B. is supported by grant 1 F05 TW05262 from the Fogarty International Center (NIH). We also gratefully thank the Molecular and Experimental Medicine Word Processing Center for manuscript preparation. We thank R. Lintz and P. Griffin for their technical assistance. Supported by NIH Program Project grant DK 26741 to W.V. and project component Behavioral Significance of Neuroendocrine Peptides to G,K. The experimental protocols for animals and their care were approved by the Institutional Review Committee for the Use of Animal Subjects.