Cocaine- and Amphetamine-Regulated Transcript (CART) Fragments

Definition
Cocaine and amphetamine regulated transcript (CART) is a neuropeptide which in humans is encoded by the CARTPT gene and has roles in reward, feeding, and stress, and it has the functional properties of an endogenous psychostimulant1.

Discovery
CART was found by examining changes in the brain following cocaine or amphetamine administration. CART mRNA increased with cocaine administration2. One of the goals was to find an endogenous anorexigenic substance. CART inhibited rat food intake, as seen when naturally-occurring CART peptides were blocked by injecting antibodies to CART, feeding increased2.

Classification
CART is a neurotransmitter1.

Structural Characteristics
In rat the CART gene encodes a peptide of either 129 or 116 amino acid residues whereas only the short form exists in humans3. The predicted signal sequence is 27 amino acid residues resulting in a propeptide of 102 or 89 residues3. The C-terminal end of CART, consisting of 48 amino acid residues and 3 disulphide bonds, is thought to constitute a biologically active part of the molecule3.

Mode of action
The putative receptor target for CART has not yet been identified, however in vitro studies strongly suggest that CART binds to a specific G protein-coupled receptor resulting in increased ERK release inside the cell4.

Functions
CART, a neurotrasnmittor produces similar behaviour in animals to cocaine and amphetamine, but conversely blocks the effects of cocaine when they are co-administered. The peptide is found in several areas of the brain. When CART is injected into rat brain, increased locomotor activity is seen, which is one of the signs of "central stimulation" caused by substances such as cocaine and amphetamine5. CART peptides, particularly CART (55–102), seem to have an important function in the regulation of energy homeostasis, and interact with several central appetite circuits6. CART is released in response to repeated dopamine release in the nucleus accumbens, and may regulate the activity of neurons in this area. CART production is upregulated by CREB, a protein thought to be involved with the development of drug addiction, and CART may be an important therapeutic target in the treatment of stimulant abuse7.

References
1. Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N, Larsen PJ, Hastrup S (1998). Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature, 393 (6680): 72–6.
2. Spiess, J., Villarreal, J., Vale, W (1981). Isolation and sequence analysis of a somatostatin-like polypeptide from ovine hypothalamus. Biochemistry, 20 (7), 1982–1988.
3. Thim L, Kristensen P, Larsen P.J and Wulff BS (1998). CART, a new anorectic peptide. The International Journal of Biochemistry & Cell Biology, 30 (12), 1281-128.
4. Lakatos A, Prinster S, Vicentic A, Hall RA, Kuhar MJ (2005). Cocaine- and amphetamine-regulated transcript (CART) peptide activates the extracellular signal-regulated kinase (ERK) pathway in AtT20 cells via putative G-protein coupled receptors. Neuroscience Lett., 384 (1-2): 198–202.
6. Kuhar MJ, Adams S, Dominguez G, Jaworski J, Balkan B (2002). CART peptides. Neuropeptides, 36 (1): 1–8.
7. Murphy KG (2005). Dissecting the role of cocaine- and amphetamine-regulated transcript (CART) in the control of appetite. Brief Funct Genomic Proteomic, 4 (2): 95–111.
8. Fagergren P, Hurd Y (2007). CART mRNA expression in rat monkey and human brain: relevance to cocaine abuse. Physiology & Behavior, 92 (1-2): 218–25.