In spite of the recognition that striatal D(2) receptors are critical determinants in a variety of psychomotor disorders, the cellular mechanisms by which these receptors shape neuronal activity have remained a mystery. The studies presented here reveal that D(2) receptor stimulation in enkephalin-expressing medium spiny neurons suppresses transmembrane Ca(2+) currents through L-type Ca(2+) channels, resulting in diminished excitability. This modulation is mediated by G(beta)(gamma) activation of phospholipase C, mobilization of intracellular Ca(2+) stores, and activation of the calcium-dependent phosphatase calcineurin. In addition to providing a unifying mechanism to explain the apparently divergent effects of D(2) receptors in striatal medium spiny neurons, this novel signaling linkage provides a foundation for understanding how this pivotal receptor shapes striatal excitability and gene expression.

Most in vitro studies of D 1 dopaminergic modulation of excitability in neostriatal medium spiny neurons have revealed inhibitory effects. Yet studies made in more intact preparations have shown that D 1 receptors can enhance or inhibit the responses to excitatory stimuli. One explanation for these differences is that the effects of D 1 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 D 1 receptor stimulation at depolarized and hyperpolarized membrane potentials. As previously reported, evoked discharge was inhibited by D 1 agonists when holding at negative membrane potentials (approximately Ϫ80 mV ). However, at more depolarized potentials (approximately Ϫ55 mV ), D 1 agonists enhanced evoked activity. At these potentials, D 1 agonists or cAMP analogs prolonged or induced slow subthreshold depolarizations and increased the duration of barium-or TEAinduced Ca 2ϩ -dependent action potentials. Both effects were blocked by L-type Ca 2ϩ channel antagonists (nicardipine, calciseptine) and were occluded by the L-type channel agonist BayK 8644 -arguing that the D 1 receptor-mediated effects on evoked activity at depolarized membrane potential were mediated by enhancement of L-type Ca 2ϩ currents. These results reconcile previous in vitro and in vivo studies by showing that D 1 dopamine receptor activation can either inhibit or enhance evoked activity, depending on the level of membrane depolarization.

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Striatal cholinergic interneurons are critical elements of the striatal circuitry controlling motor planning, movement, and associative learning. Intrastriatal release of dopamine and inhibition of interneuron activity is thought to be a critical link between behaviorally relevant events, such as reward, and alterations in striatal function. However, the mechanisms mediating this modulation are unclear. Using a combination of electrophysiological, molecular, and computational approaches, the studies reported here show that D 2 dopamine receptor modulation of Na ϩ currents underlying autonomous spiking contributes to a slowing of discharge rate, such as that seen in vivo. Four lines of evidence support this conclusion. First, D 2 receptor stimulation in tissue slices reduced the autonomous spiking in the presence of synaptic blockers. Second, in acutely isolated neurons, D 2 receptor activation led to a reduction in Na ϩ currents underlying pacemaking. The modulation was mediated by a protein kinase C-dependent enhancement of channel entry into a slow-inactivated state at depolarized potentials. Third, the sodium channel blocker TTX mimicked the effects of D 2 receptor agonists on pacemaking. Fourth, simulation of cholinergic interneuron pacemaking revealed that a modest increase in the entry of Na ϩ channels into the slowinactivated state was sufficient to account for the slowing of pacemaker discharge. These studies establish a cellular mechanism linking dopamine and the reduction in striatal cholinergic interneuron activity seen in the initial stages of associative learning.

In a rat corticostriatal slice, brief, suprathreshold, repetitive cortical stimulation evoked long‐lasting plateau potentials in neostriatal neurons. Plateau potentials were often followed by spontaneous voltage transitions between two preferred membrane potentials. While the induction of plateau potentials was disrupted by non‐NMDA and NMDA glutamate receptor antagonists, the maintenance of spontaneous voltage transitions was only blocked by NMDA receptor and L‐type Ca2+ channel antagonists. The frequency and duration of depolarized events, resembling up‐states described in vivo, were increased by NMDA and L‐type Ca2+ channel agonists as well as by GABAA receptor and K+ channel antagonists. NMDA created a region of negative slope conductance and a positive slope crossing indicative of membrane bistability in the current‐voltage relationship. NMDA‐induced bistability was partially blocked by L‐type Ca2+ channel antagonists. Although evoked by synaptic stimulation, plateau potentials and voltage oscillations could not be evoked by somatic current injection – suggesting a dendritic origin. These data show that NMDA and L‐type Ca2+ conductances of spiny neurons are capable of rendering them bistable. This may help to support prolonged depolarizations and voltage oscillations under certain conditions.