Antidepressants Alter Mesostriatal Dopamine Interactions with Serotonin Signaling

The striatum and its dense dopaminergic innervation originating in the substantia nigra pars compacta and the ventral tegmental area compose the mesostriatal dopamine system. The nigrostriatal system is particularly involved in habit learning and in motor coordination; the dopaminergic projections from the ventral tegmental area to the ventral striatum are most well known for their role in shaping behaviors leading to reward. In close proximity to the very dense dopaminergic innervation, the stratum also receives more moderate serotonergic innervation. After vesicular release from their terminals, dopamine and serotonin (5-hydroxytryptamine, 5-HT) signals are controlled by transporter reuptake. Dopamine transporters (DATs) reuptake dopamine, and they are expressed at a very high density in the striatum. Serotonin transporters (SERTs) normally efficiently reuptake 5-HT, but DATs also display a low affinity for 5-HT. When selective serotonin reuptake inhibitors (SSRIs, e.g., antidepressants such as fluoxetine) elevate extracellular 5-HT, the dense striatal DATs uptake 5-HT into dopamine terminals. Subsequently, 5-HT enters dopaminergic synaptic vesicles, where it is coreleased with dopamine. Evidence indicates that the small 5-HT release accompanying the dopamine signal takes roughly a couple weeks to develop. Antidepressants that block serotonin transporters or other factors that elevate extracellular serotonin alter the temporal and spatial relationship between dopamine and serotonin signaling in the striatum.