Metabolic hormone action in the VTA: Reward-directed behavior and mechanistic insights

Dysfunctional signaling in midbrain reward circuits perpetuates diseases characterized by compulsive overconsumption of rewarding substances such as substance abuse, binge eating disorder, and obesity. Ventral tegmental area (VTA) dopaminergic activity serves as an index for how rewarding stimuli are perceived and triggers behaviors necessary to obtain future rewards. The evolutionary linking of reward with seeking and consuming palatable foods ensured an organism's survival, and hormone systems that regulate appetite concomitantly developed to regulate motivated behaviors. Today, these same mechanisms serve to regulate reward-directed behavior around food, drugs, alcohol, and social interactions. Understanding how hormonal regulation of VTA dopaminergic output alters motivated behaviors is essential to leveraging therapeutics that target these hormone systems to treat addiction and disordered eating. This review will outline our current understanding of the mechanisms underlying VTA action of the metabolic hormones ghrelin, glucagon-like peptide-1, amylin, leptin, and insulin to regulate behavior around food and drugs of abuse, highlighting commonalities and differences in how these five hormones ultimately modulate VTA dopamine signaling.