CART peptides: Regulators of body weight, reward and other functions

Nature Reviews Neuroscience

Volumn 9, Issue 10, 2008, Pages 747-758

  Rogge, G ^a   Jones, D ^a   Hubert, G W ^a   Lin, Y ^a   Kuhar, M J ^a  

^a EMORY UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COCAINE AND AMPHETAMINE REGULATED TRANSCRIPT PEPTIDE; NEUROTRANSMITTER;

ANXIETY DISORDER; BODY WEIGHT; DEPRESSION; ENDOCRINE FUNCTION; FOOD INTAKE; GENE CONTROL; MESOLIMBIC DOPAMINERGIC SYSTEM; NUCLEUS ACCUMBENS; PRIORITY JOURNAL; REVIEW;

AFFECTIVE SYMPTOMS; ANIMALS; APPETITE REGULATION; BODY WEIGHT; CENTRAL NERVOUS SYSTEM; HUMANS; NERVE TISSUE PROTEINS; RECEPTORS, CELL SURFACE; REWARD; RNA, MESSENGER; SIGNAL TRANSDUCTION;

EID: 52449134616     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/nrn2493     Document Type: Review

References (171)

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. 15, 2471-2481 (1995). This basic paper established the field of CART peptide research. It also demonstrated the psychostimulant effect which, although sometimes controversial, has been confirmed several times, as summarized in reference 100.
2. Spiess, J., Villarreal, J. & Vale, W. Isolation and sequence analysis of a somatostatin-like polypeptide from ovine hypothalamus. Biochemistry 20, 1982-1988 (1981).
3. Thim, L., Kristensen, P., Nielsen, P. F., Wulff, B. S. & Clausen, J. T. Tissue-specific processing of cocaine-and amphetamine-regulated transcript peptides in the rat. Proc. Natl Acad. Sci. USA 96, 2722-2727 (1999). This study elucidated the tissue-specific processing and sequence of specific CART peptides. Reference 8 was a strong follow-up to this work.
4. Dominguez, G. The CART gene: structure and regulation. Peptides 27, 1913-1918 (2006).
5. Thim, L. et al. Purification and characterisation of a new hypothalamic satiety peptide, cocaine and amphetamine regulated transcript (CART), produced in yeast. FEBS Lett. 428, 263-268 (1998).
6. Ludvigsen, S., Thim, L., Blom, A. M. & Wulff, B. S. Solution structure of the satiety factor, CART, reveals new functionality of a well-known fold. Biochemistry 40, 9082-9088 (2001).
7. Dey, A. et al. Biological processing of the cocaine and amphetamine-regulated transcript precursors by prohormone convertases, PC2 and PC1/3. J. Biol. Chem. 278, 15007-15014 (2003).
8. Stein, J., Shah, R., Steiner, D. F. & Dey, A. RNAi-mediated silencing of prohormone convertase (PC) 5/6 expression leads to impairment in processing of cocaine- and amphetamine-regulated transcript (CART) precursor. Biochem. J. 400, 209-215 (2006).
9. Stein, J., Steiner, D. F. & Dey, A. Processing of cocaine-and amphetamine-regulated transcript (CART) precursor proteins by prohormone convertases (PCs) and its implications. Peptides 27, 1919-1925 (2006).
10. Dylag, T., Kotlinksa, J., Rafalski, P., Pachuta, A. & Silberring, J. The activity of CART peptide fragments. Peptides 27, 1926-1933 (2006).
11. Dominguez, G., Lakatos, A. & Kuhar, M. J. Characterization of the cocaine- and amphetamine-regulated transcript (CART) peptide gene promoter and its activation by a cyclic AMP-dependent signaling pathway in GH3 cells. J. Neurochem. 80, 885-893 (2002).
12. Dominguez, G. & Kuhar, M. J. Transcriptional regulation of the CART promoter in CATH.a cells. Brain Res. Mol. Brain Res. 126, 22-29 (2004).
13. Barrett, P., Davidson, J. & Morgan, P. CART gene promoter transcription is regulated by a cyclic adenosine monophosphate response element. Obes. Res. 10, 1291-1298 (2002). This and other work by Barrett was among the first to demonstrate regulation of CART gene expression by transcription factors.
14. 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. 391, 115-132 (1998).
15. Gautvik, K. M. et al. Overview of the most prevalent hypothalamus-specific mRNAs, as identified by directional tag PCR subtraction. Proc. Natl Acad. Sci. USA 93, 8733-8738 (1996).
16. Smith, Y., Koylu, E. O., Couceyro, P. & Kuhar, M. J. Ultrastructural localization of CART (cocaine- and amphetamine- regulated transcript) peptides in the nucleus accumbens of monkeys. Synapse 27, 90-94 (1997).
17. Smith, Y., Kieval, J., Couceyro, P. R. & Kuhar, M. J. CART peptide-immunoreactive neurones in the nucleus accumbens in monkeys: ultrastructural analysis, colocalization studies, and synaptic interactions with dopaminergic afferents. J. Comp. Neurol. 407, 491-511 (1999).
18. Vrang, N. Anatomy of hypothalamic CART neurons. Peptides 27, 1970-1980 (2006).
19. Hubert, G. W. & Kuhar, M. J. Colocalization of CART with substance P but not enkephalin in the rat nucleus accumbens. Brain Res. 1050, 8-14 (2005).
20. Murphy, K. G. et al. Quantification and synthesis of cocaine- and amphetamine-regulated transcript peptide (79-102)-like immunoreactivity and mRNA in rat tissues. J. Endocrinol. 166, 659-668 (2000).
21. Kuhar, M. J. & Yoho, L. L. CART peptide analysis by Western blotting. Synapse 33, 163-171 (1999).
22. Ekblad, E. CART in the enteric nervous system. Peptides 27, 2024-2030 (2006).
23. Larsen, P. J. et al. Cocaine- and amphetamine-regulated transcript is present in hypothalamic neuroendocrine neurones and is released to the hypothalamic-pituitary portal circuit. J. Neuroendocrinol. 15, 219-226 (2003). This study demonstrated the presence of CART peptides in the portal blood, which is fundamental to a role for them in endocrine regulation.
24. Koylu, E. O. et al. Immunohistochemical localization of novel CART peptides in rat hypothalamus, pituitary and adrenal gland. J. Neuroendocrinol. 9, 823-833 (1997). This paper and reference 14 presented a detailed description of CART peptide distribution. The distribution suggested many roles for the CART system in endocrine function, stress and feeding.
25. Vicentic, A. CART peptide diurnal variations in blood and brain. Peptides 27, 1942-1948 (2006).
26. Vrang, N., Tang-Christensen, M., Larsen, P. J. & Kristensen, P. Recombinant CART peptide induces c-Fos expression in central areas involved in control of feeding behaviour. Brain Res. 818, 499-509 (1999).
27. 2+ signaling in hippocampal neurons. J. Neurosci. 21, 7474-7480 (2001). This was one of the first papers to demonstrate intracellular signalling by CART peptides, and it also gave evidence of a G-protein coupled CART receptor.
28. Sarkar, S., Wittmann, G., Fekete, C. & Lechan, R. M. Central administration of cocaine- and amphetamine-regulated transcript increases phosphorylation of cAMP response element binding protein in corticotrophin- releasing hormone-producing neurons but not in prothyrotropin-releasing hormone-producing neurons in the hypothalamic paraventricular nucleus. Brain Res. 999, 181-192 (2004).
29. Lakatos, A., Prinster, S., Vicentic, A., Hall, R. A. & Kuhar, M. J. Cocaine- and amphetamine-regulated transcript (CART) peptide activates the extracellular signal-regulated kinase (ERK) pathway in AtT20 cells via putative G-protein coupled receptors. Neurosci. Lett. 384, 198-202 (2005).
30. Sen, A., Bettegowda, A., Jimenez-Krassel, F., Ireland, J. J. & Smith, G. W. Cocaine- and amphetamineregulated transcript regulation of follicle-stimulating hormone signal transduction in bovine granulosa cells. Endocrinology 148, 4400-4410 (2007).
31. Vicentic, A., Lakatos, A. & Kuhar, M. J. CART (cocaine-and amphetamine-regulated transcript) peptide receptors: specific binding in AtT20 cells. Eur. J. Pharmacol. 528, 188-189 (2005).
32. Keller, P. A. et al. Characterization and localization of cocaine- and amphetamine-regulated transcript (CART) binding sites. Peptides 27, 1328-1334 (2006).
33. Maletinska, L. et al. Cocaine- and amphetamine-regulated transcript (CART) peptide specific binding in pheochromocytoma cells PC12. Eur. J. Pharmacol. 559, 109-114 (2007).
34. Jones, D. C. & Kuhar, M. J. CART receptor binding in primary cell cultures of the rat nucleus accumbens. Synapse 62, 122-127 (2008).
35. Hunter, R. G. & Kuhar, M. J. CART peptides as targets for CNS drug development. Curr. Drug Targets CNS Neurol. Disord. 2, 201-205 (2003).
36. Couceyro, P., Paquet, M., Koylu, E., Kuhar, M. J. & Smith, Y. Cocaine- and amphetamine-regulated transcript (CART) peptide immunoreactivity in myenteric plexus neurons of the rat ileum and colocalization with choline acetyltransferase. Synapse 30, 1-8 (1998).
37. Wierup, N., Gunnarsdottir, A., Ekblad, E. & Sundler, F. Characterization of CART-containing neurons and cells in the porcine pancreas, gastro-intestinal tract, adrenal and thyroid glands. BMC Neurosci. 8, 51 (2007).
38. Ekblad, E., Kuhar, M., Wierup, N. & Sundler, F. Cocaine- and amphetamine-regulated transcript: distribution and function in rat gastrointestinal tract. Neurogastroenterol. Motil. 15, 545-557 (2003).
39. Ellis, L. M. & Mawe, G. M. Distribution and chemical coding of cocaine- and amphetamine-regulated transcript peptide (CART)-immunoreactive neurons in the guinea pig bowel. Cell Tissue Res. 312, 265-274 (2003).
40. Gunnarsdottir, A., Wierup, N., Larsson, L. T., Kuhar, M. J. & Ekblad, E. CART-peptide immunoreactivity in enteric nerves in patients with Hirschsprung's disease. Eur. J. Pediatr. Surg. 17, 184-189 (2007).
41. Lambert, P. D. et al. A role for novel CART peptide fragments in the central control of food intake. Neuropeptides 31, 620-621 (1997).
42. Lambert, P. D. et al. CART peptides in the central control of feeding and interactions with neuropeptide Y. Synapse 29, 293-298 (1998).
43. Kristensen, P. et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393, 72-76 (1998). This landmark paper linked hypothalamic CART peptides to feeding and regulation by leptin.
44. Larsen, P. J. et al. Ups and downs for neuropeptides in body weight homeostasis: pharmacological potential of cocaine amphetamine regulated transcript and pre-proglucagon-derived peptides. Eur. J. Pharmacol. 440, 159-172 (2002).
45. de Lartigue, G., Dimaline, R., Varro, A. & Dockray, G. J. Cocaine- and amphetamine-regulated transcript: stimulation of expression in rat vagal afferent neurons by cholecystokinin and suppression by ghrelin. J. Neurosci. 27, 2876-2882 (2007).
46. 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 96, 13506-13511 (1999).
47. 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 corticotrophin-releasing factor system. Endocrinology 141, 2854-2860 (2000).
48. Asakawa, A. et al. Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice. Horm. Metab. Res. 33, 554-558 (2001).
49. Smedh, U. & Moran, T. H. Peptides that regulate food intake: separable mechanisms for dorsal hindbrain CART peptide to inhibit gastric emptying and food intake. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1418-R1426 (2003).
50. Smedh, U. & Moran, T. H. The dorsal vagal complex as a site for cocaine- and amphetamine-regulated transcript peptide to suppress gastric emptying. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R124-R130 (2006).
51. Yang, S. C., Shieh, K. R. & Li, H. Y. Cocaine- and amphetamine-regulated transcript in the nucleus accumbens participates in the regulation of feeding behavior in rats. Neuroscience 133, 841-851 (2005).
52. 4 receptors is mediated by increases in CART in the nucleus accumbens. Proc. Natl Acad. Sci. USA 104, 16335-16340 (2007).
53. Larsen, P. J., Vrang, N., Petersen, P. C. & Kristensen, P. Chronic intracerebroventricular administration of recombinant CART(42-89) peptide inhibits and causes weight loss in lean and obese Zucker (fa/fa) rats. Obes. Res. 8, 590-596 (2000).
54. Asnicar, M. A. et al. Absence of cocaine- and amphetamine- regulated transcript results in obesity in mice fed a high caloric diet. Endocrinology 142, 4394-4400 (2001).
55. Moffett, M. et al. Studies of cocaine- and amphetamine-regulated transcript (CART) knockout mice. Peptides 27, 2037-2045 (2006).
56. Wierup, N. et al. CART knock out mice have impaired insulin secretion and glucose intolerance, altered beta cell morphology and increased body weight. Regul. Pept. 129, 203-211 (2005).
57. Qing, K. & Chen, Y. Central CART gene delivery by recombinant AAV vector attenuates body weight gain in diet-induced-obese rats. Regul. Pept. 140, 21-26 (2007).
58. Steiner, R. C., Hsiung, H. M. & Picciotto, M. R. Cocaine self-administration and locomotor sensitization are not altered in CART knockout mice. Behav. Brain Res. 171, 56-62 (2006).
59. Tian, D. R. et al. Changes of hypothalamic alpha-MSH and CART peptide expression in diet-induced obese rats. Peptides 25, 2147-2153 (2004).
60. Vrang, N., Kristensen, P., Tang-Christensen, M. & Larsen, P. J. Effects of leptin on arcuate proopiomelanocortin and cocaine-amphetamine- regulated transcript expression are independent of circulating levels of corticosterone. J. Neuroendocrinol. 14, 880-886 (2002).
61. Dhillo, W. S. et al. Hypothalamic interactions between neuropeptide Y, agouti-related protein, cocaine- and amphetamine-regulated transcript and alpha-melanocyte-stimulating hormone in vitro in male rats. J. Neuroendocrinol. 14, 725-730 (2002).
62. Adam, C. L., Archer, Z. A., Findlay, P. A., Thomas, L. & Marie, M. Hypothalamic gene expression in sheep for cocaine- and amphetamine-regulated transcript, proopiomelanocortin, neuropeptide Y, agouti-related peptide and leptin receptor and responses to negative energy balance. Neuroendocrinology 75, 250-256 (2002).
63. Elias, C. F. et al. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 21, 1375-1385 (1998).
64. Wang, Z. W. et al. Comparing the hypothalamic and extrahypothalamic actions of endogenous hyperleptinemia. Proc. Natl Acad. Sci. USA 96, 10373-10378 (1999).
65. Elias, C. F. et al. Characterization of CART neurons in rat and human hypothalamus. J. Comp. Neurol. 26, 1-19 (2001).
66. Germano, C. M. et al. Time course effects of adrenalectomy and food intake on CART expression in the hypothalamus. Brain Res. 1166, 55-64 (2007).
67. Osei-Hyiaman, D. et al. Cocaine- and amphetamine-related transcript is involved in the orexigenic effect of endogenous anandamide. Neuroendocrinology 81, 273-282 (2005).
68. Fekete, C. et al. Association of cocaine- and amphetamine- regulated transcript- immunoreactive elements with thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and its role in the regulation of the hypothalamic-pituitary-thyroid axis during fasting. J. Neurosci. 20, 9224-9234 (2000).
69. Fekete, C. & Lechan, R. M. Neuroendocrine implications for the association between cocaine- and amphetamine regulated transcript (CART) and hypophysiotropic thyrotropin-releasing hormone (TRH). Peptides 27, 2012-2018 (2006).
70. Wittmann, G., Liposits, Z., Lechan, R. M. & Fekete, C. Medullary adrenergic neurons contribute to the cocaine- and amphetamine-regulated transcript-immunoreactive innervation of thyrotropin-releasing hormone synthesizing neurons in the hypothalamic paraventricular nucleus. Brain Res. 1006, 1-7 (2004).
71. Wang, C., Billington, C. J., Levine, A. S. & Kotz, C. M. Effect of CART in the hypothalamic paraventricular nucleus on feeding and uncoupling protein gene expression. Neuroreport 11, 3251-3255 (2000).
72. Kong, W. M. et al. A role for arcuate cocaine and amphetamine-regulated transcript in hyperphagia, thermogenesis, and cold adaptation. FASEB J. 17, 1688-1690 (2003).
73. del Giudice, E. M. et al. Mutational screening of the CART gene in obese children: identifying a mutation (Leu34Phe) associated with reduced resting energy expenditure and cosegregating with obesity phenotype in a large family. Diabetes 50, 2157-2160 (2001). This paper demonstrated a relationship between a mutation in the CART gene and obesity among family members. The mutation disrupts CART peptide processing and levels (see reference 74).
74. Yanik, T., Dominguez, G., Kuhar, M. J., Del Giudice, E. M. & Loh, Y. P. The Leu34Phe ProCART mutation leads to cocaine- and amphetamine-regulated transcript (CART) deficiency: a possible cause for obesity in humans. Endocrinology 147, 39-43 (2006).
75. Dominguez, G., del Giudice, E. M. & Kuhar, M. J. CART peptide levels are altered by a mutation associated with obesity at codon 34. Mol. Psychiatry 9, 1065-1066 (2004).
76. Yamada, K. et al. Sequencing of the putative promoter region of the cocaine- and amphetamine-regulated-transcript gene and identification of polymorphic sites associated with obesity. Int. J. Obes. Relat. Metab. Disord. 26, 132-136 (2002).
77. Guerardel, A. et al. Analysis of sequence variability in the CART gene in relation to obesity in a Caucasian population. BMC Genet. 6, 19 (2005).
78. Vasseur, F. et al. Impact of a CART promoter genetic variation on plasma lipid profile in a general population. Mol. Genet. Metab. 90, 199-204 (2007).
79. Challis, B. G. et al. The CART gene and human obesity: mutational analysis and population genetics. Diabetes 49, 872-875 (2000).
80. Fu, M. et al. Association of the cocaine and amphetamine-regulated transcript gene with type 2 diabetes mellitus. Zhonghua Nei Ke Za Zhi 41, 805-808 (2002).
81. Walder, K., Morris, C. & Ravussin, E. A polymorphism in the gene encoding CART is not associated with obesity in Pima Indians. Int. J. Obes. Relat. Metab. Disord. 24, 520-521 (2000).
82. Echwald, S. M. et al. Sequence variants in the human cocaine and amphetamine-regulated transcript (CART) gene in subjects with early onset obesity. Obes Res. 7, 532-536 (1999).
83. Kenealy, S. J., Kim, K. S., Hu, Z. & Rothschild, M. F. Genetic linkage mapping of the porcine cocaine- and amphetamine- regulated transcript (CART) gene. J. Anim. Sci. 77, 791-792 (1999).
84. Aja, S., Robinson, B. M., Mills, K. J., Ladenheim, E. E. & Moran, T. H. Fourth ventricular CART reduces food and water intake and produces a conditioned taste aversion in rats. Behav. Neurosci. 116, 918-921 (2002).
85. Aja, S., Sahandy, S., Ladenheim, E. E., Schwartz, G. J. & Moran, T. H. Intracerebroventricular CART peptide reduces food intake and alters motor behavior at a hindbrain site. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R1862-R1867 (2001).
86. Aja, S., Schwartz, G. J., Kuhar, M. J. & Moran, T. H. Intracerebroventricular CART peptide reduces rat ingestive behavior and alters licking microstructure. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R1613-R1619 (2001).
87. Keating, G. L., Kuhar, M. J. & Rye, D. B. High dose CART induces abnormal EEG activity and behavioral seizures. Neuropeptides 42, 199-204 (2008).
88. Abbott, C. R. et al. Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei. Endocrinology 142, 3457-3463 (2001).
89. Albertson, D. N. et al. Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J. Neurochem. 88, 1211-1219 (2004).
90. Tang, W. X., Fasulo, W. H., Mash, D. C. & Hemby, S. E. Molecular profiling of midbrain dopamine regions in cocaine overdose victims. J. Neurochem. 85, 911-924 (2003).
91. Jung, S. K. et al. Association between polymorphism in intron 1 of cocaine- and amphetamine-regulated transcript gene with alcoholism, but not with bipolar disorder and schizophrenia in Korean population. Neurosci. Lett. 365, 54-57 (2004).
92. Salinas, A., Wilde, J. D. & Maldve, R. E. Ethanol enhancement of cocaine- and amphetamine-regulated transcript mRNA and peptide expression in the nucleus accumbens. J. Neurochem. 97, 408-415 (2006).
93. Ogden, C. A. et al. Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach. Mol. Psychiatry 9, 1007-1029 (2004).
94. Vrang, N., Larsen, P. J. & Kristensen, P. Cocaine-amphetamine regulated transcript (CART) expression is not regulated by amphetamine. Neuroreport 13, 1215-1218 (2002).
95. Marie-Claire, C. et al. Fos but not Cart (cocaine and amphetamine regulated transcript) is overexpressed by several drugs of abuse: a comparative study using real-time quantitative polymerase chain reaction in rat brain. Neurosci. Lett. 345, 77-80 (2003).
96. Jones, D. C. & Kuhar, M. J. Cocaine-amphetamine-regulated transcript expression in the rat nucleus accumbens is regulated by adenylyl cyclase and the cyclic adenosine 5′-monophosphate/protein kinase A second messenger system. J. Pharmacol. Exp. Ther. 317, 454-461 (2006).
97. Fagergren, P. & Hurd, Y. L. Mesolimbic gender differences in peptide CART mRNA expression: effects of cocaine. Neuroreport 10, 3449-3452 (1999).
98. Brenz Verca, M. S., Widmer, D. A., Wagner, G. C. & Dreyer, J. Cocaine-induced expression of the tetraspanin CD81 and its relation to hypothalamic function. Mol. Cell. Neurosci. 17, 303-316 (2001).
99. Hunter, R. G., Vicentic, A., Rogge, G. & Kuhar, M. J. The effects of cocaine on CART expression in the rat nucleus accumbens: a possible role for corticosterone. Eur. J. Pharmacol. 517, 45-50 (2005).
100. Hubert, G. W. & Kuhar, M. J. Cocaine administration increases the fraction of CART cells in the rat nucleus accumbens that co-immunostain for c-Fos. Neuropeptides 42, 339-343 (2008).
101. Beaudry, G., Zekki, H., Rouillard, C. & Levesque, D. Clozapine and dopamine D3 receptor antisense reduce cocaine- and amphetamine-regulated transcript expression in the rat nucleus accumbens shell. Synapse 51, 233-240 (2004).
102. Hunter, R. G. et al. Regulation of CART mRNA in the rat nucleus accumbens via D3 dopamine receptors. Neuropharmacology 50, 858-864 (2006).
103. Hubert, G. W. & Kuhar, M. J. Colocalization of CART peptide with prodynorphin and dopamine D1 receptors in the rat nucleus accumbens. Neuropeptides 40, 409-415 (2006).
104. Kimmel, H. L., Gong, W., Vechia, S. D., Hunter, R. G. & Kuhar, M. J. Intra-ventral tegmental area injection of rat cocaine and amphetamine- regulated transcript peptide 55-102 induces locomotor activity and promotes conditioned place preference. J. Pharmacol. Exp. Ther. 294, 784-792 (2000).
105. Shieh, K. R. Effects of the cocaine- and amphetamine-regulated transcript peptide on the turnover of central dopaminergic neurons. Neuropharmacology 44, 940-948 (2003).
106. Dallvechia-Adams, S., Kuhar, M. J. & Smith, Y. Cocaine- and amphetamine-regulated transcript peptide projections in the ventral midbrain: colocalization with γ-aminobutyric acid, melanin-concentrating hormone, dynorphin, and synaptic interactions with dopamine neurons. J. Comp. Neurol. 448, 360-372 (2002).
107. Freeman, W. M. et al. Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration. Neuropsychopharmacology 33, 1807-1817 (2008).
108. Jaworski, J. N., Kozel, M. A., Philpot, K. B. & Kuhar, M. J. Intra-accumbal injection of CART (cocaine-amphetamine regulated transcript) peptide reduces cocaine-induced locomotor activity. J. Pharmacol. Exp. Ther. 307, 1038-1044 (2003).
109. Kim, J. H., Creekmore, E. & Vezina, P. Microinjection of CART peptide 55-102 into the nucleus accumbens blocks amphetamine-induced locomotion. Neuropeptides 37, 369-373 (2003).
110. Kim, S., Yoon, H. S. & Kim, J. H. CART peptide 55-102 microinjected into the nucleus accumbens inhibits the expression of behavioral sensitization by amphetamine. Regul. Pept. 144, 6-9 (2007).
111. Jaworski, J. N., Hansen, S. T., Kuhar, M. J. & Mark, G. P. Injection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens reduces cocaine-self-administration in rats. Behav. Brain Res. 191, 266-271 (2008). This drug self-administration paper demonstrated that CART peptides might suppress cocaine-induced reward.
112. Couceyro, P. R., Koylu, E. O. & Kuhar, M. J. Further studies on the anatomical distribution of CART by in situ hybridization. J. Chem. Neuroanat. 12, 229-241 (1997).
113. Stanley, S. A. et al. Actions of cocaine- and amphetamine- regulated transcript (CART) peptide on regulation of appetite and hypothalamo-pituitary axes in vitro and in vivo in male rats. Brain Res. 893, 186-194 (2001). This was one of the first papers to demonstrate a relationship between CART peptides and the stress-response system.
114. Kuriyama, G. et al. Cocaine- and amphetamine-regulated transcript peptide in the rat anterior pituitary gland is localized in gonadotrophs and suppresses prolactin secretion. Endocrinology 145, 2542-2550 (2004).
115. Raptis, S. et al. Cocaine- and amphetamine-regulated transcript co-contained in thyrotropin-releasing hormone (TRH) neurons of the hypothalamic paraventricular nucleus modulates TRH-induced prolactin secretion. Endocrinology 145, 1695-1699 (2004).
116. Baranowska, B., Wolinska-Witort, E., Martynska, L., Chmielowska, M. & Baranowska-Bik, A. Effects of cocaine-amphetamine regulated transcript (CART) on hormone release. Regul. Pept. 122, 55-59 (2004).
117. Smith, S. M. et al. Cocaine- and amphetamine-regulated transcript is localized in pituitary lactotropes and is regulated during lactation. Endocrinology 147, 1213-1223 (2006).
118. Baranowska, B. et al. Controversial opinions on the role of CART in prolactin release. Neuro Endocrinol. Lett. 27, 60-62 (2007).
119. Dun, N. J., Dun, S. L., Kwok, E. H., Yang, J. & Chang, J. Cocaine- and amphetamine-regulated transcript-immunoreactivity in the rat sympatho-adrenal axis. Neurosci. Lett. 283, 97-100 (2000).
120. Dun, S. L., Chianca, D. A. Jr, Dun, N. J., Yang, J. & Chang, J. K. Differential expression of cocaine- and amphetamine-regulated transcript-immunoreactivity in the rat spinal preganglionic nuclei. Neurosci. Lett. 294, 143-146 (2000).
121. Dun, S. L., Ng, Y. K., Brailoiu, G. C., Ling, E. A. & Dun, N. J. Cocaine- and amphetamine-regulated transcript peptide-immunoreactivity in adrenergic C1 neurons projecting to the intermediolateral cell column of the rat. J. Chem. Neuroanat. 23, 123-132 (2002).
122. Dall Vechia, S., Lambert, P. D., Couceyro, P. C., Kuhar, M. J. & Smith, Y. CART peptide immunoreactivity in the hypothalamus and pituitary in monkeys: analysis of ultrastructural features and synaptic connections in the paraventricular nucleus. J. Comp. Neurol. 416, 291-308 (2000).
123. Broberger, C. Hypothalamic cocaine- and amphetamine-regulated transcript (CART) neurons: histochemical relationship to thyrotropin-releasing hormone, melanin-concentrating hormone, orexin/hypocretin and neuropeptide Y. Brain Res. 848, 101-113 (1999).
124. Dun, S. L., Brailoiu, G. C., Yang, J., Chang, J. K. & Dun, N. J. Cocaine- and amphetamine-regulated transcript peptide and sympatho-adrenal axis. Peptides 27, 1949-1955 (2006).
125. Vrang, N., Larsen, P. J., Tang-Christensen, M., Larsen, L. K. & Kristensen, P. Hypothalamic cocaine-amphetamine regulated transcript (CART) is regulated by glucocorticoids. Brain Res. 965, 45-50 (2003).
126. Smith, S. M. et al. Cocaine- and amphetamine-regulated transcript activates the hypothalamic-pituitary-adrenal axis through a corticotropin- releasing factor receptor-dependent mechanism. Endocrinology 145, 5202-5209 (2004).
127. Balkan, B., Koylu, E. O., Kuhar, M. J. & Pogun, S. The effect of adrenalectomy on cocaine and amphetamine-regulated transcript (CART) expression in the hypothalamic nuclei of the rat. Brain Res. 917, 15-20 (2001).
128. Balkan, B., Koylu, E., Pogun, S. & Kuhar, M. J. Effects of adrenalectomy on CART expression in the rat arcuate nucleus. Synapse 50, 14-19 (2003).
129. Savontaus, E., Conwell, I. M. & Wardlaw, S. L. Effects of adrenalectomy on AGRP, POMC, NPY and CART gene expression in the basal hypothalamus of fed and fasted rats. Brain Res. 958, 130-138 (2002).
130. Stanley, S. A. et al. Regulation of rat pituitary cocaineand amphetamine-regulated transcript (CART) by CRH and glucocorticoids. Am. J. Physiol. Endocrinol. Metab. 287, E583-E590 (2004).
131. Koylu, E. O. et al. Co-localization of cart peptide immunoreactivity and nitric oxide synthase activity in rat hypothalamus. Brain Res. 868, 352-357 (2000).
132. Vicentic, A., Hunter, R. G. & Kuhar, M. J. Effect of corticosterone on CART peptide levels in rat blood. Peptides 26, 531-533 (2005).
133. Sergeyev, V., Broberger, C. & Hokfelt, T. Effect of LPS administration on the expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat hypothalamus. Brain Res. Mol. Brain Res. 90, 93-100 (2001).
134. Kong, W. M. et al. A role for arcuate cocaine and amphetamine-regulated transcript in hyperphagia, thermogenesis, and cold adaptation. FASEB J. 17, 1688-1690 (2003).
135. Gozen, O. et al. Sex differences in the regulation of cocaine and amphetamine-regulated transcript expression in hypothalamic nuclei of rats by forced swim stress. Synapse 61, 561-568 (2007).
136. Hunter, R. G. et al. Regulation of CART mRNA by stress and corticosteroids in the hippocampus and amygdala. Brain Res. 1152, 234-240 (2007).
137. Kask, A., Schioth, H. B., Mutulis, F., Wikberg, J. E. & Rago, L. Anorexigenic cocaine- and amphetamine-regulated transcript peptide intensifies fear reactions in rats. Brain Res. 857, 283-285 (2000).
138. Chaki, S., Kawashima, N., Suzuki, Y., Shimazaki, T. & Okuyama, S. Cocaine- and amphetamine-regulated transcript peptide produces anxiety-like behavior in rodents. Eur. J. Pharmacol. 464, 49-54 (2003).
139. Stanek, L. M. Cocaine- and amphetamine related transcript (CART) and anxiety. Peptides 27, 2005-2011 (2006).
140. Bjorkqvist, M. et al. Cocaine- and amphetamine-regulated transcript is increased in Huntington disease. Mov. Disord. 22, 1952-1954 (2007).
141. Orsetti, M., Di Briscoe, F., Canonico, P. L., Genazzani, A. A. & Ghi, P. Gene regulation in the frontal cortex of rats exposed to the chronic mild stress paradigm, an animal model of human depression. Eur. J. Neurosci. 27, 2156-2164 (2008).
142. del Giudice, E. M. et al. Adolescents carrying a missense mutation in the CART gene exhibit increased anxiety and depression. Depress. Anxiety 23, 90-92 (2006).
143. Fenwick, N. M., Martin, C. L. & Llewellyn-Smith, I. J. Immunoreactivity for cocaine- and amphetamine-regulated transcript in rat sympathetic preganglionic neurons projecting to sympathetic ganglia and the adrenal medulla. J. Comp. Neurol. 495, 422-433 (2006).
144. Burman, K. J., Sartor, D. M., Verberne, A. J. & Llewellyn-Smith, I. J. Cocaine- and amphetamine-regulated transcript in catecholamine and noncatecholamine presympathetic vasomotor neurons of rat rostral ventrolateral medulla. J. Comp. Neurol. 476, 19-31 (2004).
145. Richardson, R. J., Grkovic, I. & Anderson, C. R. Cocaine- and amphetamine-related transcript peptide and somatostatin in rat intracardiac ganglia. Cell Tissue Res. 324, 17-24 (2006).
146. Matsumura, K., Tsuchihashi, T. & Abe, I. Central human cocaine- and amphetamine-regulated transcript peptide 55-102 increases arterial pressure in conscious rabbits. Hypertension 38, 1096-1100 (2001).
147. Hwang, L. L., Chen, C. T., Li, T. L., Chiu, C. Z. & Chi, S. F. Central pressor effects of CART peptides in anesthetized rats. Neuropeptides 38, 69-76 (2004).
148. Iliff, J. J., Alkayed, N. J., Gloshani, K. J., Traystman, R. J. & West, G. A. Cocaine- and amphetamine-regulated transcript (CART) peptide: a vasoactive role in the cerebral circulation. J. Cereb. Blood Flow Metab. 25, 1376-1385 (2005).
149. Kozsurek, M. et al. Cocaine- and amphetamine-regulated transcript peptide (CART) is present in peptidergic C primary afferents and axons of excitatory interneurons with a possible role in nociception in the superficial laminae of the rat spinal cord. Eur. J. Neurosci. 26, 1624-1631 (2007).
150. Damaj, M. I., Martin, B. R. & Kuhar, M. J. Antinociceptive effects of supraspinal rat cart (55-102) peptide in mice. Brain Res. 983, 233-236 (2003).
151. Bannon, A. W. et al. Multiple behavioral effects of cocaine- and amphetamine-regulated transcript (CART) peptides in mice: CART 42-89 and CART 49-89 differ in potency and activity. J. Pharmacol. Exp. Ther. 299, 1021-1026 (2001).
152. Damaj, M. I., Hunter, R. G., Martin, B. R. & Kuhar, M. J. Intrathecal CART (55-102) enhances the spinal analgesic actions of morphine in mice. Brain Res. 1024, 146-149 (2004).
153. Damaj, M. I., Zheng, J., Martin, B. R. & Kuhar, M. J. Intrathecal CART (55-102) attenuates hyperalgesia and allodynia in a mouse model of neuropathic but not inflammatory pain. Peptides 27, 2019-2023 (2006).
154. Elefteriou, F. et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434, 514-520 (2005).
155. Ahn, J. D., Dubern, B., Lubrano-Berthelier, C., Clement, K. & Karsenty, G. Cart overexpression is the only identifiable cause of high bone mass in melanocortin 4 receptor deficiency. Endocrinology 147, 3196-3202 (2006).
156. Patel, M. S. & Elefteriou, F. The new field of neuroskeletal biology. Calcif. Tissue Int. 80, 337-347 (2007).
157. Louis, J. C. M. Methods of preventing neuron degeneration and promoting neuron regeneration. Amgen, Int. Patent Appl. Publication #WO96/34619 (1996).
158. Xu, Y. et al. Role of cocaine- and amphetamine-regulated transcript in estradiol-mediated neuroprotection. Proc. Natl Acad. Sci. USA 103, 14489-14494 (2006).
159. Wu, B., Hu, S., Yang, M., Pan, H. & Zhu, S. CART peptide promotes the survival of hippocampal neurons by upregulating brain-derived neurotrophic factor. Biochem. Biophys. Res. Commun. 347, 656-661 (2006).
160. Brischoux, F., Fellmann, D. & Risold, P. Y. Ontogenetic development of the diencephalic MCH neurons: a hypothalamic 'MCH area' hypothesis. Eur. J. Neurosci. 13, 1733-1744 (2001).
161. Brischoux, F., Griffond, B., Fellmann, D. & Risold, P. Y. Early and transient ontogenetic expression of the cocaine- and amphetamine-regulated transcript peptide in the rat mesencephalon: correlation with tyrosine hydroxylase expression. J. Neurobiol. 52, 221-229 (2002).
162. Dun, S. L., Castellino, S. J., Yang, J., Chang, J. K. & Dun, N. J. Cocaine- and amphetamine-regulated transcript peptide-immunoreactivity in dorsal motor nucleus of the vagus neurons of immature rats. Brain Res. Dev. Brain Res. 131, 93-102 (2001).
163. Adan, R. A., Vanderschuren, L. J. & la Fleur, E. S. Anti-obesity drugs and neural circuits of feeding. Trends Pharmacol. Sci. 29, 208-217 (2008).
164. Meister, B. Neurotransmitters in key neurons of the hypothalamus that regulate feeding behavior and body weight. Physiol. Behav. 92, 263-271 (2007).
165. Chaudhri, O. B., Salem, V., Murphy, K. G. & Bloom, S. R. Gastrointestinal satiety signals. Annu. Rev. Physiol. 70, 239-255 (2008).
166. Saper, C. B., Chou, T. C. & Elmquist, J. K. The need to feed: homeostatic and hedonic control of eating. Neuron 36, 199-211 (2002).
167. Jensen, P. B. et al. The hypothalamic satiety peptide CART is expressed in anorectic and nonanorectic pancreatic islet tumors and in the normal islet of Langerhans. FEBS Lett. 447, 139-143 (1999).
168. Wierup, N. et al. Cocaine- and amphetamine-regulated transcript (CART) is expressed in several islet cell types during rat development. J. Histochem. Cytochem. 52, 169-177 (2004).
169. Wierup, N., Bjorkqvist, M., Kuhar, M. J., Mulder, H. & Sundler, F. CART regulates islet hormone secretion and is expressed in the beta-cells of type 2 diabetic rats. Diabetes 55, 305-311 (2006).
170. Hubert, G. W., Jones, D. C., Moffett, M. C., Rogge, G. & Kuhar, M. J. CART peptides as modulators of dopamine and psychostimulants and interactions with the mesolimbic dopaminergic system. Biochem. Pharmacol. 75, 57-62 (2008).
171. Barrett, P. et al. The differential regulation of CART gene expression in a pituitary cell line and primary cell cultures of ovine pars tuberalis cells. J. Neuroendocrinol. 13, 347-352 (2001).