Depression of Serotonin Synaptic Transmission by the Dopamine Precursor L-DOPA

Imbalance between the dopamine and serotonin (5-HT) neurotransmitter systems has been implicated in the comorbidity of Parkinson’s disease (PD) and psychiatric disorders. L-DOPA, the leading treatment of PD, facilitates the production and release of dopamine. This study assessed the action of L-DOPA on monoamine synaptic transmission in mouse brain slices. Application of L-DOPA augmented the D2-receptor-mediated inhibitory postsynaptic current (IPSC) in dopamine neurons of the substantia nigra. This augmentation was largely due to dopamine release from 5-HT terminals. Selective optogenetic stimulation of 5-HT terminals evoked dopamine release, producing D2-receptor-mediated IPSCs following treatment with L-DOPA. In the dorsal raphe, L-DOPA produced a long-lasting depression of the 5-HT1A-receptor-mediated IPSC in 5-HT neurons. When D2 receptors were expressed in the dorsal raphe, application of L-DOPA resulted in a D2-receptor-mediated IPSC. Thus, treatment with L-DOPA caused ectopic dopamine release from 5-HT terminals and a loss of 5-HT-mediated synaptic transmission. [Display omitted] •L-DOPA augments D2-receptor-mediated synaptic transmission in the midbrain•Serotonin terminals contribute to dopamine synaptic transmission after L-DOPA•L-DOPA depresses 5-HT-mediated synaptic transmission in the dorsal raphe•In the dorsal raphe, serotonin neurons release dopamine from vesicles after L-DOPA Gantz et al. demonstrate that after exposure to L-DOPA, serotonin neurons release dopamine in the midbrain and within the dorsal raphe. The production and vesicular release of dopamine produces a long-lasting depression of 5-HT1A-receptor-mediated synaptic transmission.