Reversal of dopamine-mediated firing inhibition through activation of the dopamine transporter in substantia nigra pars compacta neurons

BACKGROUND AND PURPOSEOne of the hallmarks of ventral midbrain dopamine-releasing neurons is membrane hyperpolarization in response to stimulation of somato-dendritic D-2 receptors. At early postnatal age, under sustained dopamine, this inhibitory response is followed by a slow recovery, resulting in dopamine inhibition reversal (DIR). In the present investigation, we aimed to get a better insight into the cellular mechanisms underlying DIR.EXPERIMENTAL APPROACHWe performed single-unit extracellular recordings with a multi-electrode array device and conventional patch-clamp recordings on midbrain mouse slices.KEY RESULTSWhile continuous dopamine (100 mu M) perfusion gave rise to firing inhibition that recovered in 10 to 15 min, the same effect was not obtained with the D-2 receptor agonist quinpirole (100 nM). Moreover, firing inhibition caused by the GABA(B) receptor agonist baclofen (300 nM) was reversed by dopamine (100 mu M), albeit D-2 receptors had been blocked by sulpiride (10 mu M). Conversely, the block of the dopamine transporter (DAT) with cocaine (30 mu M) prevented firing recovery by dopamine under GABA(B) receptor stimulation. Accordingly, in whole-cell recordings from single cells, the baclofen-induced outward current was counteracted by dopamine (100 mu M) in the presence of sulpiride (10 mu M ), and this effect was prevented by the DAT antagonists cocaine (30 mu M) and GBR12909 (2 mu M).CONCLUSIONS AND IMPLICATIONSOur results indicate that the DAT plays a major role in DIR, mediating it under conditions of sustained dopamine exposure, and point to DAT as an important target for pharmacological therapies leading to prolonged enhancement of the dopaminergic signal.