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. The interaction between the dopaminergic, serotonergic, and endocannabinoid systems in anatomically defined circuits underlies complex aspects of reward-guided behavior.The development of virus-based tracing methods has made it possible to uncover substantial reciprocal connectivity between specific cell types in subcortical brain nuclei, ultimately delineating the circuit and synaptic determinants of the interaction between dopaminergic, serotonergic, and endocannabinoid systems.Temporal differences in the activity and release of dopamine (DA) and serotonin (5-hydroxytryptamine; 5-HT) may explain how seemingly opposite actions can result in adaptive, motivated behavior. By modulating the release of DA and 5-HT through multiple direct and indirect mechanisms, the endocannabinoid (EC) system provides an additional level of complexity.The complexity of coreleasing neurons with anatomical, physiological, and functional heterogeneity is a major challenge in understanding the contribution of these systems to motivation.