Abstract BACKGROUND AND PURPOSE: One of the hallmarks of ventral midbrain dopamine (DA)-releasing neurons is membrane hyperpolarization in response to somato-dendritic D2 receptors (D2 Rs) stimulation. At early postnatal age, under sustained DA, 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 onto the cellular mechanisms underlying DIR. EXPERIMENTAL APPROACH: We performed single unit extracellular recordings with a multi-electrode array (MEA) device and conventional patch-clamp recordings on midbrain mouse slices. KEY RESULTS: While continuous DA (100 μM) perfusion gave rise to firing inhibition that recovered in 10 to 15 min, the same effect was not obtained with the D2 R agonist quinpirole (100 nM). Moreover, firing inhibition caused by the GABAB receptor agonist baclofen (300 nM), was reverted by DA (100 μM), albeit D2 Rs had been blocked by sulpiride (10 μM). Conversely, the block of the DA transporter (DAT) with cocaine (30 μM) prevented firing recovery by DA under GABAB receptor stimulation. Accordingly, in whole cell recordings from single cells the baclofen-induced outward current was counteracted by DA (100 μM) in the presence of sulpiride (10 μM), and this effect was prevented by the DAT antagonists cocaine (30 μM) and GBR12909 (2 μM). CONCLUSIONS AND IMPLICATIONS: Our results indicate a major role played by DAT in causing DIR under conditions of sustained DA exposure and point to DAT as an important target for pharmacological therapies leading to prolonged enhancement of the DAergic signal.
|Titolo:||Reversal of dopamine-mediated firing inhibition through activation of the dopamine transporter in substantia nigra pars compacta neurons.|
GUATTEO, EZIA [Conceptualization]
|Data di pubblicazione:||2018|
|Appare nelle tipologie:||1.1 Articolo in rivista|