Cocaine and amphetamine regulated transcript

Cocaine- and amphetamine-regulated transcript, also known as CART, is a

CART is a neuropeptide that produces similar behavior in animals as cocaine and amphetamine, but conversely blocks the effects of cocaine when they are co-administered. The peptide is found in several areas, among them the ventral tegmental area (VTA) of the brain. When CART was injected into rat VTA, increased locomotor activity was seen, which is one of the signs of "central stimulation" caused by psychostimulants, such as cocaine and amphetamine.^[5] The same rats also tended to return to the place where they were injected. This is called conditioned place preference and is also seen after injection of cocaine.

CART peptides, in particular, CART(55–102), seem to have an important function in the regulation of energy homeostasis and interact with several

CART is released in response to repeated dopamine release in the nucleus accumbens, and may regulate the activity of neurons in this area.[9] CART production is upregulated by CREB,^[10] 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 abuse.^[11][12][13]

Tissue distribution

CART is an

CART is also found in a subset of retinal ganglion cells (RGCs), the primary afferent neurons in the retina. Specifically, it labels ON/OFF Direction Selective Ganglion Cells (ooDSGCs), a subpopulation of RGCs that stratify in both the ON and OFF sublamina of the Inner Plexiform Layer (IPL) of the retina. It is also found in a subset of amacrine cells in the Inner Nuclear Layer.^[16] No role as of yet has been proposed for the peculiar location of this protein in these cell types.

Clinical significance

Studies of CART(54–102) action in rat

CART peptides are inhibitors of food intake (anorectic) and closely associated with leptin and neuropeptide Y, two important food intake regulators. CART hypoactivity in the hypothalamus of depressed animals is associated with hyperphagia and weight gain.^[21][22] CART is thought to play a key role in the opioid mesolimbic dopamine circuit that modulates natural reward processes.^[23] CART also appears to play an important role in higher brain functions like cognition.^[24]

History

CART was found by examining changes in the brain following cocaine or amphetamine administration. CART

The putative receptor target for CART evaded identification through 2011,[26] however in vitro studies strongly suggested that CART binds to a specific G protein-coupled receptor coupled to Gi/Go, resulting in increased ERK release inside the cell.^{[26][27][28][29]} In 2020, CART was identified as the ligand for GPCR160.^[30]

Several fragments of CART have been tested to try and uncover the pharmacophore,^[31][32] but the natural splicing products CART(55–102) and CART(62–102) are still of highest activity, with the reduced activity of smaller fragments thought to indicate that a compact structure retaining all three of CART's disulphide bonds is preferred.^[33]

See also

• Amphetamine
• Cocaine

References