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L-DOPA (Levodopa) remains the gold standard for the treatment of motor symptoms of Parkinson's disease (PD), despite indications that the drug may have detrimental effects in cell culture. Classically, l-DOPA increases the production of dopamine (DA) in nigral dopaminergic neurons, while paradoxically inhibiting the firing of these neurons due to activation of D2 autoreceptors by extracellularly released DA. Using a combination of electrophysiology and calcium microfluorometry in brain slices, we have identified a novel effect of L-DOPA on dopaminergic neurons when D2 receptors were blocked. Under these conditions, L-DOPA (0.03-3 mM) evoked an excitatory effect consisting of two components. The 'early' component observed during and immediately after application of the drug, was associated with increased firing, membrane depolarization and inward current. This excitatory response was strongly attenuated by CNQX (10 μM), pointing to the involvement of TOPA quinone, an auto-oxidation product of L-DOPA and a potent activator of AMPA/kainate receptors. The 'late' phase of excitation persisted >30 min after brief L-DOPA application and was not mediated by ionotropic glutamate receptors, nor by D1, α1-adrenergic, mGluR1 or GABAB receptors. It was eliminated by carbidopa, demonstrating its dependence on conversion of L-DOPA to DA. Exogenous DA (50 μM) also evoked a glutamate-receptor independent increase in firing and an inward current when D2 receptors were blocked. In voltage-clamped neurons, both L-DOPA and DA produced a long-lasting increase in [Ca(2+)]i which was unaffected by block of ionotropic glutamate receptors. These results demonstrate that L-DOPA has dual, inhibitory and excitatory, effects on nigral dopaminergic neurons, and suggest that the excitation and calcium rise may have long-lasting consequences for the activity and survival of these neurons when the expression or function of D2 receptors is impaired., (Copyright © 2013 Elsevier Inc. All rights reserved.)