The CART (Cocaine- and Amphetamine-Regulated Transcript) System in Appetite and Drug Addiction

Abstract

CART (cocaine-and amphetamine-regulated transcript) peptides are neuromodulators that are involved in feeding, drug reward, stress, cardiovascular function, and bone remodeling. CART peptides are abundant but discretely distributed in the brain, pituitary and adrenal glands, pancreas, and gut. High expression of CART in discrete hypothalamic nuclei associated with feeding has led to behavioral and pharmacological studies that strongly support an anorectic action of CART in feeding. Subsequent studies on humans and transgenic animals provide additional evidence that CART is important in the regulation of appetite as mutations in the CART gene are linked to eating disorders, including obesity and anorexia. The expression of CART in the mesolimbic dopamine circuit has lead to functional studies demonstrating CART's psychostimulant-like effects on locomotor activity and conditioned place preference in rats. These and other findings demonstrated that CART modulates mesolimbic dopamine systems and affects psychostimulantinduced reward and reinforcing behaviors. The link between CART and psychostimulants was substantiated by demonstrating alterations of the CART system in human cocaine addicts. CART seems to regulate the mesolimbic dopamine system, which serves as a common mechanism of action for both feeding and addiction. Indeed, recent studies that demonstrated CART projections from specific hypothalamic areas associated with feeding to specific mesolimbic areas linked to reward/motivation behaviors provide evidence that CART may be an important connection between food-and drug-related rewards. Given the enormous public health burden of both obesity and drug addiction, future studies exploring the pharmacotherapies targeting CART peptide represent an exciting and challenging research area.CART (cocaine-and amphetamine-regulated transcript) is a peptide that functions as both a central and peripheral neurotransmitter. The CART peptide was first sequenced as a peptide with unknown function (Spiess and Vale, 1980) and then confirmed in a study reporting that a protein product of an mRNA up-regulated in the ventral striatum following acute administration of cocaine and amphetamine (Douglass et al., 1995) was the peptide described by Spiess and Vale (1980). The human propeptide form of CART is processed into two biologically active fragments, 42 to 89 and 49 to 89, which correspond to rat 55 to 102 and 62 to 102 fragments, respectively. Although physical description, synthesis, and processing of the peptides have been well studied , very little is known about their metabolism. CART has been implicated in a variety of physiological processes, including feeding, bone remodeling, sensory processing, endocrine regulation, stress and anxiety, and the rewarding and reinforcing properties of psychostimulants (Hunter and Kuhar, 2003). Moreover, CART was shown to exert effects on neuronal activity, such as N-methyl-D-aspartate receptormediated neurotransmission (Hsun Lin et al., 2005) and ventromedial hypothalamic nucleu...

Time-dependent effects of amphetamine on feeding in rats

“…Whether this hypophagia reflects malaise (Cole et al, 1995;Turchan et al, 1998), a specific deficit in feeding-related motivation (Stanek, 2006;Vicentic and Jones, 2007), or some other condition is uncertain.…”

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

“…Furthermore, CART interacts with other important mediators such as the cannabinoid CB 1 receptor, insulin and leptin, involved in the regulation of feeding [157,158,150]. On the other hand, ICV administration of CART was accompanied by a decrease in plasma insulin and leptin levels and an increase in lipid oxidation, which limits fat storage [159].…”

“…Additionally, POMC expression in the Arc is also regulated by the dopaminergic system via D 2 R [148,149]. CART is a peptide (first isolated from the ovine hypothalamus), and is widely distributed throughout the central and peripheral nervous systems [150,151]. CART protein is encoded by the CARTPT gene, which functions in feeding, reward, stress and pain transmissions [152,153].…”

Cocaine- and amphetamine-regulated transcript: a novel regulator of energy homeostasis expressed in a subpopulation of pancreatic islet cells

“…The amino acid sequences of the bioactive peptides are similar in the long and short forms of pro-CART, but they are numbered differently. Only the short form is found in humans and only amino acid 42 (highlighted in green) is different between the bioactive forms of rats and humans these conclusions; missense mutation and single-nucleotide polymorphisms of Cartpt are associated with obesity [16,19].…”

“…TRH in turn regulates pituitary gland secretion of thyroidstimulating hormone, which alters energy homeostasis by stimulating heat production by muscle and brown adipose tissue [8]. CART also plays a role in motor activity, reward and stress, and has functional properties of an endogenous psychostimulant [8,19]. Further, it is involved in anxietylike behaviour, depression, fear and startle behaviour [8,11].…”