D1Receptor Activation Enhances Evoked Discharge in Neostriatal Medium Spiny Neurons by Modulating an L-Type Ca2+Conductance

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Abstract
Mostin vitrostudies of D1dopaminergic modulation of excitability in neostriatal medium spiny neurons have revealed inhibitory effects. Yet studies made in more intact preparations have shown that D1receptors can enhance or inhibit the responses to excitatory stimuli. One explanation for these differences is that the effects of D1receptors on excitability are dependent on changes in the membrane potential occurring in response to cortical inputs that are seen only in intact preparations. To test this hypothesis, we obtained voltage recordings from medium spiny neurons in slices and examined the impact of D1receptor stimulation at depolarized and hyperpolarized membrane potentials. As previously reported, evoked discharge was inhibited by D1agonists when holding at negative membrane potentials (approximately −80 mV). However, at more depolarized potentials (approximately −55 mV), D1agonists enhanced evoked activity. At these potentials, D1agonists or cAMP analogs prolonged or induced slow subthreshold depolarizations and increased the duration of barium- or TEA-induced Ca2+-dependent action potentials. Both effects were blocked by L-type Ca2+channel antagonists (nicardipine, calciseptine) and were occluded by the L-type channel agonist BayK 8644—arguing that the D1receptor-mediated effects on evoked activity at depolarized membrane potential were mediated by enhancement of L-type Ca2+currents. These results reconcile previousin vitroandin vivostudies by showing that D1dopamine receptor activation can either inhibit or enhance evoked activity, depending on the level of membrane depolarization.