Role of Appetite-Regulating Peptides in the Pathophysiology of Addiction: Implications for Pharmacotherapy

Food intake and appetite are regulated by various circulating hormones including ghrelin and glucagon-like-peptide 1 (GLP-1). Ghrelin, mainly released from the stomach, increases food intake, induces appetite, enhances adiposity as well as releases growth hormone. Hypothalamic "ghrelin receptors" (GHS-R1A) have a critical role in food intake regulation, but GHS-R1A are also expressed in reward related areas. GLP-1 is produced in the intestinal mucosa as well as in the hindbrain in response to nutrient ingestion. This gut-brain hormone reduces food intake as well as regulates glucose homeostasis, foremost via GLP-1 receptors in hypothalamus and brain stem. However, GLP-1 receptors are expressed in areas intimately associated with reward regulation. Given that regulation of food and drug intake share common neurobiological substrates, the possibility that ghrelin and GLP-1 play an important role in reward regulation should be considered. Indeed, this leading article describes that the orexigenic peptide ghrelin activates the cholinergic-dopaminergic reward link, an important part of the reward systems in the brain associated with reinforcement and thereby increases the incentive salience for motivated behaviors via this system. We also review the role of ghrelin signaling for reward induced by alcohol and addictive drugs from a preclinical, clinical and human genetic perspective. In addition, the recent findings showing that GLP-1 controls reward induced by alcohol, amphetamine, cocaine and nicotine in rodents are overviewed herein. Finally, the role of several other appetite regulatory hormones for reward and addiction is briefly discussed. Collectively, these data suggest that ghrelin and GLP-1 receptors may be novel targets for development of pharmacological treatments of alcohol and drug dependence.