Modulating the Neuromodulators: Dopamine, Serotonin, and the Endocannabinoid System

Dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT), and endocannabinoids (ECs) are key neuromodulators involved in many aspects of motivated behavior, including reward processing, reinforcement learning, and behavioral flexibility. Among the longstanding views about possible relationships between these neuromodulators is the idea of DA and 5-HT acting as opponents. This view has been challenged by emerging evidence that 5-HT supports reward seeking via activation of DA neurons in the ventral tegmental area. Adding an extra layer of complexity to these interactions, the endocannabinoid system is uniquely placed to influence dopaminergic and serotonergic neurotransmission. In this review we discuss how these three neuromodulatory systems interact at the cellular and circuit levels. Technological advances that facilitate precise identification and control of genetically targeted neuronal populations will help to achieve a better understanding of the complex relationship between these essential systems, and the potential relevance for motivated behavior.