Dasotraline is a triple reuptake inhibitor that blocks dopamine (DA), norepinephrine (NE), and serotonin [5-hydroxytryptamine (5-HT)] transporters with IC50 values of 4, 6, and 11 nM, respectively, representing a potential new class of antidepressant agents.

This in-vivo electrophysiological study investigates the impact of Dasotraline (SEP-225289), a triple reuptake inhibitor, on the firing activities of locus coeruleus (LC) NE, ventral tegmental area (VTA) DA, and dorsal raphe (DR) 5-HT neurons. Administered acutely, Dasotraline effectively reduces the spontaneous firing rates of these neurons in a dose-dependent manner, primarily through the activation of α2, D2, and 5-HT1A autoreceptors for LC NE, VTA DA, and DR 5-HT neurons, respectively. While Dasotraline notably suppresses LC NE neuronal activity, it only partially reduces VTA DA and DR 5-HT neuron firing rates. The compound shows equal potency in inhibiting 5-HT and NE transporters, extending the recovery time (RT50) for dorsal hippocampus CA3 pyramidal neurons’ firing activity post-inhibition from microiontophoretic applications of 5-HT and NE. Although lower doses of Dasotraline (1 and 2 mg/kg) do not affect CA3 pyramidal neurons' firing activity, a 50% reduction is observed with the highest dose (8 mg/kg). Additionally, when rats are pre-treated with WAY100635, Dasotraline administration (0.5-2 mg/kg i.v.) significantly boosts the firing rate of DR 5-HT neurons, as well as the quantity of single spikes and bursts.