Pathway-Specific Depression of Lateral Inhibition by Dopamine Requires Serotonin Receptors in the Nucleus Accumbens

Dopamine modulation of nucleus accumbens (NAc) circuitry is central to theories of reward seeking and reinforcement learning. Despite decades of effort, the acute dopamine actions on the NAc microcircuitry remain puzzling. Here, we dissect out the direct actions of dopamine on lateral inhibition between medium spiny neurons (MSNs) in mouse brain slices and find that dopamine’s acute actions on NAc lateral inhibition are pathway-specific. Dopamine potently and selectively depresses GABAergic transmission from presynaptic dopamine D2 receptor-expressing MSNs (D2-MSNs), while it potentiates transmission from presynaptic dopamine D1 receptor-expressing MSNs. To our surprise, presynaptic D2 receptors mediate only half of the depression induced by either dopamine neuron stimulation or dopamine application. Presynaptic serotonin 5-HT1b receptors are responsible for a significant component of dopamine-induced synaptic depression. Thus, this study clarifies the mechanistic understanding of dopamine actions in the NAc by showing pathway-specific modulation of lateral inhibition and the involvement of both D2 and 5-HT1b receptors in dopamine depression of D2-MSN synapses.