Reciprocal regulation of striatal dopamine and serotonin release in healthy and parkinsonian mice

The striatum is densely innervated by midbrain dopamine (DA) neurons but also receives a further sparse monoaminergic innervation by raphe serotonin (5-HT) neurons. Striatal 5-HT has been suggested to have some opposing functions to DA but also to regulate DA release which might support (or counteract) this functional antagonism. We explored the reciprocal modulation of electrically evoked striatal DA and 5-HT release and the underlying cell circuits by using fast-scan cyclic voltammetry to detect DA, a new G-protein-coupled receptor sensor for 5-HT (GRAB5-HT3.0) and whole-cell recordings in acute ex vivo brain slices from healthy and parkinsonian mice. We found that evoked striatal 5-HT release was inhibited by D1 and D2 receptors agonists CY208243 and quinpirole. Reciprocally, evoked DA release was reduced by 5-HT4R agonist RS67333 and this reduction was abolished in the presence of an antagonist for nicotinic acetylcholine receptors (nAChRs), DHβE, suggesting that 5-HT4Rs regulate DA release indirectly via actions on cholinergic interneurons. Finally, in an 18-month-old human alpha-synuclein-overexpressing mouse model of Parkinson’s disease (PD), we found a reduction in the 5-HT4R-mediated inhibition of DA, restricted to the dorsal striatum, the region more vulnerable in PD. In summary, these data indicate that striatal DA and 5-HT reciprocally inhibit each other’s release, partly involving ACh. This interaction might support inverse availabilities of DA/5-HT through which they co-operate to minimise their downstream functional antagonism. Some loss to this interaction in a mouse model of PD suggests that dysregulation of DA-5-HT-ACh dynamics might contribute to dysfunction in disease.