Dissecting the Crosstalk Between Dopaminergic and Serotonergic Systems in the Striatum

Dopamine (DA) and serotonin (5-HT) are neuromodulators implicated in reward processing, decision-making, and motivated behavior. While often viewed as opposing or complementary systems, how DA and 5-HT release are integrated in the striatum remains elusive. Using optogenetics, fiber photometry and slice electrophysiology we found that ventral tegmental area (VTA) DA neuron stimulation increased DA release without affecting 5-HT release. Dorsal raphe nucleus (DRN) 5-HT neuron activation, on the other hand, induced serotonin release and a modest, transient increase in DA in the NAc, likely via glutamate co-release onto VTA DA neurons,. These findings suggest that DA and 5-HT operate largely independently in the striatum, with selective circuit-dependent interactions. This work refines our understanding of DA-5HT interactions and provides a foundation for future research into their roles in motivated behaviors and neuropsychiatric disorders.