D 1 Receptor Activation Enhances Evoked Discharge in Neostriatal Medium Spiny Neurons by Modulating an L-Type Ca 2 1 Conductance

Most in vitro studies of D1 dopaminergic modulation of excitability in neostriatal medium spiny neurons have revealed inhibitory effects. Yet studies made in more intact preparations have shown that D1 receptors can enhance or inhibit the responses to excitatory stimuli. One explanation for these differences is that the effects of D1 receptors 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 D1 receptor stimulation at depolarized and hyperpolarized membrane potentials. As previously reported, evoked discharge was inhibited by D1 agonists when holding at negative membrane potentials (approximately 280 mV). However, at more depolarized potentials (approximately 255 mV), D1 agonists enhanced evoked activity. At these potentials, D1 agonists or cAMP analogs prolonged or induced slow subthreshold depolarizations and increased the duration of bariumor TEAinduced Ca-dependent action potentials. Both effects were blocked by L-type Ca channel antagonists (nicardipine, calciseptine) and were occluded by the L-type channel agonist BayK 8644—arguing that the D1 receptor-mediated effects on evoked activity at depolarized membrane potential were mediated by enhancement of L-type Ca currents. These results reconcile previous in vitro and in vivo studies by showing that D1 dopamine receptor activation can either inhibit or enhance evoked activity, depending on the level of membrane depolarization.