D-1 RECEPTOR ACTIVATION ENHANCES EVOKED DISCHARGE IN NEOSTRIATAL MEDIUM SPINY NEURONS BY MODULATING AN L-TYPE CA2+ CONDUCTANCE

Most in vitro studies of D-1 dopaminergic modulation of excitability i n neostriatal medium spiny neurons have revealed inhibitory effects. Y et studies made in more intact preparations have shown that D-1 recept ors can enhance or inhibit the responses to excitatory stimuli. One ex planation for these differences is that the effects of D-1 receptors o n excitability are dependent on changes in the membrane potential occu rring in response to cortical inputs that are seen only in intact prep arations. To test this hypothesis, we obtained voltage recordings from medium spiny neurons in slices and examined the impact of D-1 recepto r stimulation at depolarized and hyperpolarized membrane potentials. A s previously reported, evoked discharge was inhibited by D-1 agonists when holding at negative membrane potentials (approximately -80 mV). H owever, at more depolarized potentials (approximately -55 mV), D-1 ago nists enhanced evoked activity. At these potentials, D-1 agonists or c AMP analogs prolonged or induced slow subthreshold depolarizations and increased the duration of barium- or TEA-induced Ca2+-dependent actio n potentials. Both effects were blocked by L-type Ca2+ channel antagon ists (nicardipine, calciseptine) and were occluded by the L-type chann el agonist BayK 8644-arguing that the D-1 receptor-mediated effects on evoked activity at depolarized membrane potential were mediated by en hancement of L-type Ca2+ currents. These results reconcile previous in vitro and in vivo studies by showing that D-1 dopamine receptor activ ation can either inhibit or enhance evoked activity, depending on the level of membrane depolarization.