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

Abstract

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.

Modeling functions of striatal dopamine modulation in learning and planning

“…To simulate the findings of Hernandez-Lopez et al (1997), we propose a phenomenological model for membrane effects mediated by dopamine D1 class receptors (Fig. 4A).…”

“…A constant δ denotes the decay rate of the D1 effects. Since the D1 agonist effects decay to a value of 40% over 10 minutes (see figure 4B in Hernandez-Lopez et al, 1997), we estimate the value of the decay rate δ of the dopamine membrane effects to be 0.99985, which corresponds to 0.015 % decrease for each 100 msec. Note that this value depends on the mode of the D1 agonist application, since the D1 agonist effects decay faster if the agonists are applied directly on isolated cells (Surmeier et al, 1995) and much faster if dopamine neurons are activated in vivo (Gonon, 1997).…”

“…Note that this value depends on the mode of the D1 agonist application, since the D1 agonist effects decay faster if the agonists are applied directly on isolated cells (Surmeier et al, 1995) and much faster if dopamine neurons are activated in vivo (Gonon, 1997). Therefore, we use the value δ =0.99985 to reproduce the experiment of Hernandez-Lopez et al (1997) but will adjust this value for the in vivo model (see next section). The signal DA(t) corresponds to the dopamine D1 agonist concentration and the parameter η is a scaling factor.…”

“…To test the proposed model, we simulate the experimental conditions of Hernandez-Lopez et al (1997) (Fig. 3).…”

Regulation of neuromodulator receptor efficacy—implications for whole-neuron and synaptic plasticity

“…However, it has been difficult to assess these effects precisely with the help of in vitro slices, and there is some disagreement concerning the effects of the dopamine D1 receptor. The D1 receptor enhances or reduces the contribution of a number of ion channels, such as high-voltage activated calcium channels (L-type calcium channels are enhanced in neostriatal spiny neurons (22), N-and P-type calcium channels are blocked (23)). It also affects sodium (25) and potassium channels (21).…”