CART peptides as modulators of dopamine and psychostimulants and interactions with the mesolimbic dopaminergic system

Abstract

Cocaine- and amphetamine-regulated transcript (CART) peptides (CART 55-102 and CART 62-102) are peptidergic neurotransmitters that are widely but specifically distributed throughout the brain, gut and other parts of the body. They are found in many brain regions associated with drug addiction including the nucleus accumbens, ventral tegmental area and ventral pallidum. Injections of CART 55-102 into the nucleus accumbens have no effect on basal locomotor activity. However, an injection of CART just before an i.p. injection of cocaine reduces the locomotor activating effects of cocaine. These and other data suggest that CART in the accumbens blunts the effects of cocaine. A hypothesis is that CART is homeostatic in the accumbens and tends to oppose large increases in dopamine signaling. These actions would therefore be able to regulate the effects of some abused drugs such as the psychostimulants.

Figure 1

Sequence of the ProCART peptide. In the rat, there are 2 splice variants; amino acids 27–39 (in italics) are spliced out from the long form of 102 amino acids to give the short form of 89 amino acids. The fragments of the long form that have been reliably shown to be active are CART 55-102 and CART 61-102 (in the short form the numbers are CART 42-89 and CART 49-89). In humans, the splicing is complete and only the short 89 amino acid form exists, with some changes in amino acids. Position 42 which is isoleucine in the rat is a valine in the human. Underlined pairs of basic amino acids indicate sites of processing by prohormone convertases.

Figure 2

Identification of specific saturable binding of radiolabeled CARTpeptide to AtT20 cells. The Kd is subnanomolar, and the binding is specific for CART 55-12 and CART 62-102; no other tested peptide or substance inhibited the binding. Reproduced from Vicentic et al., 2005.

Figure 3

A hypothesis in schematic form about a function of CART peptide in the Nucleus accumbens (Acc). Its action is to oppose the changes induced by cocaine. When CART is given alone into the Acc, it has no effect, but when coadministered with DA or cocaine, it tends to block the locomotor effects of those compounds. While the cellular mechanisms of these CART-DA receptor interactions have not yet been clarified, perhaps candidates would be heterologous desensitization and/or interfering downstream signaling pathways from CART and DA receptors.