Cocaine-Amphetamine-Regulated Transcript Influences Energy Metabolism, Anxiety and Gastric Emptying in Mice

This study was designed to investigate the effects of cocaine-amphetamine-regulated transcript (CART), a recently discovered hypothalamic neuropeptide, on food intake, anxiety, oxygen consumption and gastric emptying in mice. Intracerebroventricular (i. c. v.) injection of CART (1 - 100 pmol) markedly reduced food intake in a dose-related manner. A significant decrease was observed 20 min after i. c. v. injection of CART and continued for four hours. In the elevated plus maze test, i. c. v. CART injection significantly raised the normal preference for the closed arms. Furthermore, the i. c. v. injection of CART significantly reduced oxygen consumption and gastric emptying rate. These results suggest that CART modulates feeding, emotion, and autonomic functions in mice.

Key words:

Anxiogenic - Cocaine-Amphetamine-Regulated Transcript - Feeding - Gastric Emptying - Intracerebroventricular - Mice - Oxygen Consumption

References

• 1 Douglass J, Mckinzie A A, Couceyro P. PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine.  J Neurosci. 1995;  15 2471-2481
• 2 Koylu E O, Couceyro P R, Lambert P D, Ling N C, DeSouza E B, Kuhar M J. Immunohistochemical localization of novel CART peptides in rat hypothalamus, pituitary and adrenal gland.  J Neuroendocrinol. 1997;  9 823-833
• 3 Vrang N, Larsen P J, Clausen J T, Kristensen P. Neurochemical characterization of hypothalamic cocaine- amphetamine-regulated transcript neurons.  J Neurosci. 1999;  19 1-8
• 4 Couceyro P R, Koylu E O, Kuhar M J. Further studies on the anatomical distribution of CART by in situ hybridization.  J Chem Neuroanat. 1997;  12 229-241
• 5 Koylu E O, Couceyro P R, Lambert P D, Kuhar M J. Cocaine- and amphetamine-regulated transcript peptide immunohistochemical localization in the rat brain.  J Comp Neurol. 1998;  391 115-132
• 6 Kristensen P, Judge M E, Thim L, Ribel U, Christjansen K N, Wulff B S, Clausen J T, Jensen P B, Madsen O D, Vrang N, Larsen P J, Hastrup S. Hypothalamic CART is a new anorectic peptide regulated by leptin.  Nature. 1998;  393 72-76
• 7 Lambert P D, Couceyro P R, McGirr K M, Dall Vechia S E, Smith Y, Kuhar M J. CART peptides in the central control of feeding and interactions with neuropeptide Y.  Synapse. 1998;  29 293-298
• 8 Elias C F, Lee C, Kelly J, Aschkenasi C, Ahima R S, Couceyro P R, Kuhar M J, Saper C B, Elmquist J K. Leptin activates hypothalamic CART neurons projecting to the spinal cord.  Neuron. 1998;  21 1375-1385
• 9 Phillips R J, Powley T L. Gastric volume rather than nutrient content inhibits food intake.  Am J Physiol. 1996;  271 R766-R779
• 10 Asakawa A, Inui A, Momose K, Ueno N, Fujino M A, Kasuga M. Endomorphins have orexigenic and anxiolytic activities in mice.  Neuroreport. 1998;  9 2265-2267
• 11 Hirosue Y, Inui A, Teranishi A, Miura M, Nakajima M, Okita M, Nakajima Y, Himori N, Baba S, Kasuga M. Cholecystokinin octapeptide analogues suppress food intake via central CCK-A receptors in mice.  Am J Physiol. 1993;  265 R481-R486
• 12 Nakajima M, Inui A, Teranishi A, Miura M, Hirosue Y, Okita M, Himori N, Baba S, Kasuga M. Effects of pancreatic polypeptide family peptides on feeding and learning behavior in mice.  J Pharmacol Exp Ther. 1994;  268 1010-1014
• 13 Inui A. Feeding and body-weight regulation by hypothalamic neuropeptides-mediation of the actions of leptin.  Trends Neurosci. 1999;  22 62-67
• 14 Inui A. Transgenic approach to the study of body weight regulation.  Pharamcol Rev. 2000;  52 35-62
• 15 Rolla M, Andreoni A, Bellitti D, Ferdeghini M, Ghigo E, Muller E E. Corticotrophin-releasing hormone dose not inhibit growth hormone-releasing hormone-induced release of growth hormone in control subjects but is effective in patients with eating disorders.  J Endocrinol. 1994;  140 327-332
• 16 Kaye W H. Neuropeptide abnormalities in anorexia nervosa.  Psychiatry Res. 1996;  62 65-74
• 17 Montgomery K C. The relation between fear induced by novel stimulation and exploratory behavior.  J Comp Physiol Psychol. 1958;  48 254-260
• 18 Momose K, Inui A, Asakawa A, Ueno N, Nakajima M, Fujimiya M, Kasuga M. Intracerebroventricularly administered corticotropin-releasing factor inhibits food intake and produces anxiety-like behaviour at very low doses in mice.  Diab Obes Metab. 1999;  1 281-284
• 19 Walker H C, Romsos D R. Similar effects of NPY on energy metabolism and on plasma insulin in adrenalectomized ob/ob and lean mice.  Am J Physiol. 1993;  264 E226-E230
• 20 Asakawa A, Inui A, Ueno N, Fujimiya M, Fujino M A, Kasuga M. Endomorphin-1, an endogenous mu-opioid receptor-selective agonist, stimulates oxygen consumption in mice.  Horm Metab Res. 2000;  32 51-52
• 21 Drescher V S, Chen H L, Romsos D R. Corticotropin-releasing hormone decreases feeding oxygen consumption and activity of genetically obese (ob/ob) and lean mice.  J Nutrition. 1994;  124 524-530
• 22 Vrang N, Tang C M, Larsen P J, Kristensen P. Recombinant CART peptide induces c-Fos expression in central areas involved in control of feeding behaviour.  Brain Res. 1999;  818 499-509
• 23 Phillips R J, Powley T L. Gastric volume rather than nutrient content inhibits food intake.  Am J Physiol. 1996;  271 R766-R779
• 24 Duggan J P, Booth D A. Obesity, overeating and rapid gastric emptying in rats with ventromedial hypothalamic lesions.  Science. 1986;  231 609-611
• 25 Asakawa A, Inui A, Ueno N, Makino S, Fujino M A, Kasuga M. Urocortin reduces food intake and gastric emptying in lean and ob/ob obese mice.  Gastroenterology. 1999;  116 1287-1292
• 26 Okumura T, Yamada H, Motomura W, Kohgo Y. Cocaine-amphetamine-regulated transcript (CART) acts in the central nervous system to inhibit gastric acid secretion via brain corticotropin-releasing factor system.  Endocrinology. 2000;  141 2854-2860
• 27 Vrang N, Larsen P J, Kristensen P, Tang-Christensen M. Central administration of cocaine-amphetamine-regulated transcript activates hypothalamic neuroendocrine neurons in the rat.  Endocrinology. 2000;  141 794-801
• 28 Broberger C, Holmberg K, Kuhar M J, Hokfelt T. Cocaine- and amphetamine-regulated transcript in the rat vagus nerve: A putative mediator of cholecystokinin-induced satiety.  Proc Natl Acad Sci USA. 1999;  96 13 506-13 511