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Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois
Submitted 9 March 2006; accepted in final form 27 July 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Nicola et al. 2000; Pennartz et al. 1994). Activity of NAc neurons is regulated by both DA D1- and D2-class receptors (D1Rs and D2Rs, respectively) (Hu and White 1997; Hu et al. 2005; White and Wang 1986). Dysfunction in the mesocorticolimbic DA system has been implicated in certain neuropsychiatric disorders, including drug addiction (Hyman 2005; Hyman and Malenka 2001; Kalivas and Hu 2006; Kalivas et al. 2005; White and Kalivas 1998; Wise 1998). Previous findings indicate that D2R activation modulates the intrinsic excitability of DA-innervated neurons, usually causing a decrease in evoked action potentials (Cepeda et al. 2001; Gulledge and Jaffe 1998; Hu and Wang 1988; Tseng and O'Donnell 2004; West and Grace 2002). This inhibitory effect of D2R modulation on evoked Na+ spike firing has been related to activation of a variety of K+ currents (Congar et al. 2002; Greif et al. 1995; Ljungstrom et al. 2003). However, the mechanisms underlying activation of these K+ currents remain unknown.
However, previous findings also revealed some excitatory effects of D2R stimulation on evoked neuronal activity. For instance, coactivation of D2Rs and D1Rs can depolarize cell membrane in dorsal striatal cells and increase evoked Na+ spike firing in NAc shell cells by inhibition of Na+-K+ ATPase and combination of G
subunits released from D2R/Gi/o coupling and G
s-like subunits from D1R/Gs coupling, respectively (Bertorello et al. 1990; Hopf et al. 2003). Moreover, D2R stimulation also facilitates Ca2+ mobilization (Greengard et al. 1999; Parikh et al. 1996), leading to an enhancement in voltage-sensitive sodium currents by facilitating dephosphorylation of the Na+ channel by calcineurin (Hu et al. 2005). In addition, stimulation of D2Rs also reduces the inward rectification in freshly dissociated mPFC pyramidal neurons by inactivating the cAMP/PKA cascade (Dong et al. 2004), which may induce membrane depolarization from the resting levels if the "leak" K+ currents are suppressed. In spite of the apparent discrepancies in the D2R regulation of ion channel/pump activity that have caused many controversies in the past with respect to the inhibitory or excitatory effects of D2R stimulation, these findings actually indicate that the D2R is functionally involved in modulation of the intrinsic excitability of DA-innervated neurons by dynamically integrating activity of voltage-gated ion channels, including various types of K+ channels at different membrane potentials.
Given the above, we hypothesized that D2R stimulation would significantly change the excitability of medium spiny NAc neurons by modulating the function of a variety of K+ channel subtypes. The present study was performed to determine whether and how D2R stimulation changes the evoked Na+ spike firing, the inward rectification, and the RMP by modulating the activity of voltage-gated potassium channels (VGKCs, mainly IA), IKir, and the "leak" K+ currents (IK-2P) in medium spiny neurons located within the core NAc of rats.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Adolescent male Sprague–Dawley rats (Harlan, Indianapolis, IN), 4–5 wk old (Spear 2000), were group housed in a temperature- and humidity-controlled vivarium under a 12-h light/dark cycle. Food and water were freely available. After 
3 days acclimation to the vivarium, rats were used for acute experiments examining the D2R modulation of the membrane activity of medium spiny neurons (MSNs).
Preparation of brain slices
All procedures were in strict accordance with the Guide for the Care and Use of Laboratory Animals (1996) and were approved by our Institutional Animal Care and Use Committee. Rats were decapitated under halothane anesthesia and the brain was immediately excised and immersed in ice-cold artificial cerebrospinal fluid (aCSF) containing (in mM): NaCl 124, KCl 2.5, NaHCO3 26, MgCl2 2, CaCl2 2, and glucose 10; pH 7.4; 310 mOsm/l. Coronal slices (300 µm) containing the NAc were cut with a vibratome (Leica VT1000S) and incubated in oxygenated (95% O2-5% CO2) aCSF for 1 h at room temperature before recording.
Whole cell current-clamp recordings in brain slices
Brain slices were anchored in a recording chamber and perfused by gravity-fed oxygenated aCSF (34°C) with the -aminobutyric acid type A (GABAA) receptor blocker SR-95531 (4 mM) and the glutamatergic receptor blocker kynurenic acid (2.5 mM) at a flow rate of 2–3 ml/min. Patch recording pipettes (3–5 M
) were pulled from Corning 7056 (Corning, NY) glass capillaries with horizontal pipette puller (Flaming/Brawn P-97, Sutter Instruments, Novato, CA) and filled with internal recording solution (in mM): K+-gluconate 120, HEPES 10, KCl 20, MgCl2 2, Na2ATP 3, Na2GTP 0.3, and biocytin 0.1%. Recordings were initiated in visually identified MSNs within the core of the NAc using differential interference contrast (DIC) microscopy (Stuart et al. 1993) and an Axopatch 200B amplifier (Axon Instruments, Union City, CA). After a whole cell configuration was formed, voltage-clamp mode was converted to current-clamp recording. Voltage signals were amplified in bridge mode and digitized by a DigiData 1200 Series (Axon Instruments) and distributed to a computer running pCLAMP 9 software (Axon Instruments).
Na+-dependent action potentials were generated by injection of step-depolarizing current pulses with 0.05-nA increments, ranging from 0 to 0.5 nA. Characteristics of the action potentials were obtained from the initial spike evoked by the minimal depolarizing current pulse (rheobase) in each MSN recorded. In all cases Na+ spikes were evoked from the resting membrane potential (RMP). The amplitude of action potential (in millivolts) was measured from spike threshold to peak level. The deepness of afterhyperpolarization (AHP amplitude, mV) was measured from the equipotential point of the spike threshold to the maximum deflection of the membrane hyperpolarization after the end of the action potential. The half-action potential duration was measured at half-amplitude level.
To determine the effects of applied drugs on evoked Na+ spikes as well as on hyperpolarized membrane potentials, the majority of NAc neurons were recorded under a condition in which the RMP was held at –80 mV. This approach gave each individual NAc neuron the same basal (control) potential level and therefore made the results obtained from different cells comparable (Hu et al. 2004). In MSN, it was previously shown that secondary dendrites are a crucial cellular compartment for postsynaptic D2 modulation of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents (Hernandez-Echeagaray et al. 2004). To avoid influences from depolarization/hyperpolarization of dendritic membrane in the soma, AMPA and N-methyl-D-aspartate (NMDA) currents were blocked by kynurenic acid applied in the bath medium (see above). In another group of cells, the drug effects on evoked Na+ spikes were studied by holding the RMP at –50 mV. In these cells, Na+-dependent action potentials were generated by injection of step-depolarizing current pulses with 0.04-nA increments ranging from 0 to 0.2 nA. Injection of higher currents caused artificial distortions in the form of Na+ spikes, which made analysis of evoked action potentials very difficult. Under this depolarized RMP, certain VGKCs were inactivated and their effects on action potentials were eliminated. In addition, to determine the effects of applied drugs on RMP, a group of NAc neurons was recorded at their resting status without any membrane potential holding. To calculate the percentage change in spiking for the time-course experiments, a current pulse was selected to evoke six or seven spikes as basal activity. This current pulse was then used at different time points in all cells. Firing rates of evoked spikes were averaged from a 2-min time period before drug application in each cell. Such values were then normalized to 100% as control and used to compare with that during drug application. To calculate the percentage change in the dose–response curve, the firing rate of evoked spikes was averaged from the last 2 min of quinpirole perfusion (the third to fifth minute) in which quinpirole achieved its maximal effect and then compared with the normalized control (100%).
The current–voltage relationship (I–V curve) was studied with perfusion of the specific Na+ channel blocker tetrodotoxin (TTX, 1 µM) and the calcium channel blocker cadmium (Cd2+, 200 µM). Five minutes after TTX and Cd2+ application, the cell membrane was hyperpolarized by injecting negative current pulses (200-ms duration, –0.8 to 0 nA). Under these conditions, recorded changes in the I–V curve would reflect activation or inactivation of IKir (Nisenbaum and Wilson 1995). Membrane properties were studied in the following manners: RMP was measured in the absence of injected current and the input resistance (Rin, M) was determined from linear regression in the linear range (±0.1-nA range) of the I–V curve established by plotting the steady-state potential change in response to hyperpolarizing current pulses. Time constants were determined by the fit function of pCLAMP software. The whole cell pipette series resistance was <20 M and bridge was compensated. Only NAc cells that had a stable RMP at or more negative than –75 mV with evoked spikes that overshot across 0-mV membrane potentials were used for analysis of membrane properties and further drug treatment.
Drug application
Separate subgroups of NAc neurons were recorded with application of different drugs and ion channel blockers. Selective agonist and antagonist for D2Rs (quinpirole, 10 µM, and eticlopride, 10 µM, respectively) were used to determine whether D2R stimulation affects the evoked action potentials, the inward rectification during membrane hyperpolarization, and RMP. Moreover, the effects of D2R agonists on evoked Na+ spikes were also studied when the membrane potentials were held at a more depolarized membrane potential level (about –50 mV). In addition, the effects of DA on evoked firing were studied with different concentrations (0, 20, 40, and 80 µM). DA at a concentration of 40 µM was used in the time-course experiment. To minimize oxidation, all experiments with DA were conducted in the dark. To confirm the effects of quinpirole on D2R-mediated inhibition of firing, the D1R antagonist SCH-23390 (10 µM) was concurrently applied with DA in the time-course experiments. The selective PKA inhibitor H-89 (10 µM) was applied in bath solution, whereas the Rp isomer of adenosine-3',5'-cyclic monophosphorothioate (Rp-cAMPs, 500 µM), another selective PKA inhibitor, was dialyzed to the cytosol by the recording pipette. Because internally applied Rp-cAMPs might affect RMP during formation and stabilization of whole cell configuration, thereby causing inaccurate measurement of control RMP, data from other experimental groups were pooled to form the control group. Measurements of RMP from this group were then compared with that affected by Rp-cAMPs and quinpirole plus Rp-cAMPs, respectively. The selective phosphatidylinositol-specific PLC (PI-PLC) inhibitor (ET-18-OCH3, 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine, 500 µM) was externally applied in the aCSF medium. These inhibitors were used to determine whether the D2R-mediated changes in NAc neurons were modulated by the cAMP/PKA cascade or through other signaling pathway(s) associated with activation of PLC.
The relatively selective A-type K+ channel blocker 4-aminopyridine (4-AP, at a low concentration of 10 µM) was used to determine whether and how IA was involved in the D2R-mediated changes in evoked action potentials. All drugs were prepared according to manufacturer's specifications (Sigma Chemicals, St. Louis, MO). Bath solutions with such drugs and ion channel blockers were made with aCSF immediately before use.
Statistical analysis
Unpaired Student's t-tests were used to estimate the significance of the difference (*P < 0.05 and **P < 0.01) in the membrane properties between control and drug-treated groups of NAc neurons. Repeated-measures ANOVA was used for comparison of the drug-induced changes in the current–response (evoked spikes) curves as well as in the inward rectification curves between control and drug-treated groups. Comparisons of the drug-induced alterations in evoked action potentials in the time-course experiments were carried out with ANOVA. In addition, post hoc comparisons were carried out using the Newman–Keuls test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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All NAc neurons were MSNs, as evidenced by differential interference contrast (DIC) microscopy, and recorded within the core region (Hu et al. 2004; O'Donnell and Grace 1993). The majority of neurons showed a slow, repetitive spike-firing pattern reported for typical MSNs (Mahon et al. 2000; Nisenbaum et al. 1994). To study the effects of D2R stimulation on the properties of evoked Na+ spikes, a series of current pulses (200 ms) was delivered to NAc neurons, at an interval of 20 s between each pulse. These current pulses ranged from 0 to +0.5 nA, in 0.05-nA steps (Fig. 1 A). Current-evoked spike-response curves showed that bath application of quinpirole (10 µM) significantly and reversibly decreased evoked action potentials in the majority of MSNs (13 of 20 cells recorded, 65%) [control vs. quinpirole, n = 20 cells, repeated-measures ANOVA, F(1,38) = 6.89, P < 0.05; post hoc Newman–Keuls test, *P < 0.05] (Fig. 1B). Quinpirole dose-dependently decreased evoked Na+ spikes at all doses tested (2, 4, 6, and 10 µM) (n = 10 cells for each concentration, unpaired t-test, *P < 0.05) (Fig. 1C). Because greater reduction in firing was observed with 10 µM of the D2R agonist (30.6 ± 3.1%), this concentration was used for later experiments in this study. In time-course experiments, quinpirole-induced reduction in firing occurred quickly and achieved its maximal levels 3–5 min with application of the agonist [n = 13 cells; ANOVA, F(77,803) = 4.75, P < 0.05; post hoc Newman–Keuls test, P < 0.05] (Fig. 1, D–F).
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D2R-mediated inhibition in evoked firing was blocked by concurrent application of eticlopride, a selective D2R antagonist. Nevertheless, because some MSNs did not show reduction in evoked spikes in response to D2R stimulation, this antagonist experiment was performed only in spiny cells that showed agonist effect. The D2R-mediated inhibition in spike firing was identified first and washed out. These cells were then recorded with concurrent application of quinpirole and eticlopride with the same concentration (10 µM). Under these conditions, quinpirole-induced reduction in evoked firing was completely blocked by eticlopride [n = 6 cells, ANOVA, F(52,340) = 3.56, P < 0.05, post hoc Newman–Keuls test, P < 0.05] (Fig. 3, A and B).
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It is well established that activation of D2Rs inhibits adenylyl cyclase (AC) activity, thereby reducing cytosolic cAMP levels and PKA activity (Sibley 1995; Stoof and Kebabian 1981, 1982). Therefore if the D2R-mediated decrease in evoked Na+ spikes was regulated by the cAMP/PKA cascade, inhibition of PKA activity should resemble the effects of quinpirole on suppressing evoked action potentials. Indeed, direct inhibition of PKA activity by internally dialyzed Rp-cAMPs (500 µM) mimicked this effect of D2R stimulation on decreasing Na+ spikes with greater potency [(control vs. Rp-cAMPs: n = 13 cells, repeated-measures ANOVA, F(1,22) = 60.41, P < 0.01; post hoc Newman–Keuls test, *P < 0.05] (Fig. 4, A and B). Under this condition, the inhibitory effect of D2R stimulation on firing was occluded and quinpirole was no longer able to produce further reduction in the evoked spikes. Thus there was no significant difference in the current–spike-response curves between NAc neurons recorded with application of Rp-cAMPs alone and those treated with the PKA inhibitor plus quinpirole [Rp-cAMPs vs. Rp-cAMPs + quinpirole: n = 11 cells, repeated-measures ANOVA, F(1,20) = 0.2, P > 0.05] (Fig. 4B). Increasing the depolarizing currents to levels >0.5 nA did not induce further increases in evoked Na+ spikes in either Rp-cAMPs–treated or Rp-cAMPs plus quinpirole–treated cells, indicating that a maximal effect on blocking PKA activity to suppress action potential had been achieved (data not shown). Moreover, bath-applied H-89 (10 µM), a different PKA inhibitor, also decreased evoked Na+ spikes and occluded the inhibitory effects of quinpirole on evoked firing [control vs. H-89: n = 6 cells, repeated-measures ANOVA, F(1,10) = 7.9, P < 0.05, post hoc Newman–Keuls test, *P < 0.05; H-89 vs. H-89 + quinpirole: n = 6 cells, repeated-measures ANOVA, F(1,10) = 0.2, P > 0.05] (Fig. 4, C and D).
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Previous studies indicate that one of the major determinants of neuronal firing are VGKCs (or delayed rectifiers) (Hille 2001). Neostriatal MSNs possess at least three types of VGKCs, including two types of A-currents [e.g., slow-inactivating A-type K+ current (IAs) and fast-inactivating A-type K+ current (IAf)] and a noninactivating K+ current (Surmeier et al. 1991, 1992). Although IAs makes a relatively minor contribution to the total amount of K+ currents generated by VGKCs (Hopf et al. 2003; Surmeier and Kitai 1993), it plays an important role in controlling spike firing because inhibition of IAs increases evoked Na+ spike firing (Mahon et al. 2000; Nisenbaum et al. 1994; Wickens and Wilson 1998). In addition, most striatal MSNs show IAs with the absence of IAf (Surmeier and Kitai 1993), whereas D2R stimulation increases IAs in these cells (Surmeier and Kitai 1993).
To determine whether IAs was functionally involved in the D2R-mediated reduction in evoked Na+ spikes in NAc MSNs, 4-AP (10 µM), a relatively selective inhibitor for IAs at a concentration range of 5–60 µM (Surmeier et al. 1991), was used in our experiments. Bath application of 4-AP appreciably increased evoked action potentials in all MSNs recorded (n = 13 cells). Under this condition, quinpirole failed to inhibit evoked Na+ spikes (Fig. 6 A). Current–spike-response curves indicate that there was a significant increase in the number of evoked action potentials in 4-AP–treated cells compared with that in the control group [control vs. 4-AP: n = 13 cells, repeated-measures ANOVA, F(1,24) = 4.5, P < 0.05; post hoc Newman–Keuls test, *P < 0.05] (Fig. 6B). There also was a significant difference in evoked spikes between NAc neurons treated with 4-AP plus quinpirole and control cells without drug treatment [control vs. 4-AP + quinpirole: n = 13 cells, repeated-measures ANOVA, F(1,24) = 4.42, P < 0.05; post hoc Newman–Keuls test, *P < 0.05]. In contrast, there was no significant difference in the number of evoked spikes between NAc neurons treated with 4-AP alone and 4-AP plus quinpirole [4-AP vs. 4-AP + quinpirole: n = 13 cells, repeated-measures ANOVA, F(1,24) = 0.02, P > 0.05] (Fig. 6B).
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; Surmeier et al. 1991, 1994). To study the properties of evoked Na+ spikes either with or without D2R stimulation, current pulses were applied from 0 to +0.2 nA with 0.04-nA increments. Under this circumstance, D2R stimulation by quinpirole did not cause any significant changes in evoked firing with application of different current intensities [control vs. quinpirole: n = 10 cells, repeated-measures ANOVA, F(1,6) = 5.93, P > 0.05] (Fig. 7, A and B).
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One of the defining electrophysiological properties of striatal MSNs is a pronounced inward rectification, which mainly represents activation of inwardly rectifying K+ currents (IKir) evoked by membrane hyperpolarization (Nisenbaum and Wilson 1995). To determine whether D2R stimulation affected the activity of IKir, the inward rectification was studied by comparing the I–V curves across cells during membrane hyperpolarization between NAc neurons with or without D2R stimulation. Furthermore, because D2R stimulation not only can decrease activity of the cAMP/PKA cascade (Sibley 1995; Stoof and Kebabian 1981, 1982), but also can activate the PLC1-IP3-calcineurin-signaling cascade in striatal MSNs (Hernandez-Lopez et al. 2000), we also investigated whether the potential changes in IKir mediated by D2Rs were related to the two distinct signaling pathways.
With injection of negative current pulses (0 to –0.8 nA), membrane potentials of control neurons were hyperpolarized from the initial level of –80 mV to about –125 mV. An apparent inward rectification was induced, indicating activation of IKir (and other hyperpolarization-activated currents). Quinpirole significantly attenuated the inward rectification, leading the membrane potential to a more hyperpolarized level (shifting the I–V plot downward and inducing greater linearity) [control vs. quinpirole: n = 13 cells, repeated-measures ANOVA, F(1,21) = 7.4, P < 0.02; post hoc Newman–Keuls test, *P < 0.05] (Fig. 8, A and B). However, this D2R action on reducing the inward rectification was completely blocked by concurrent bath application of the PI-PLC inhibitor ET-18-OCH3 (500 µM) (Fig. 8A). There was a significant difference in the I–V curves between NAc neurons recorded with quinpirole alone and cells recorded with ET-18-OCH3 plus quinpirole [quinpirole vs. ET-18-OCH3 + quinpirole: n = 10 cells, repeated-measures ANOVA, F(1,18) = 10.07, P < 0.01; post hoc Newman–Keuls test, *P < 0.05] (Fig. 8B). There was no significant difference between control NAc cells and neurons treated with ET-18-OCH3 plus quinpirole [control vs. ET-18-OCH3 + quinpirole: n = 10 cells, repeated-measures ANOVA, F(1,18) = 0.15, P > 0.05] (Fig. 8B). In addition, inhibition of PI-PLC by ET-18-OCH3 alone caused no significant change in the inward rectification [control vs. ET-18-OCH3: n = 10 cells, repeated-measures ANOVA, F(1,17) = 0.13, P > 0.05] (Fig. 8, A and B).
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D2R stimulation depolarized RMP
It is well known that, despite their name, certain inward rectifiers carry outward K+ currents to maintain the RMP of neurons (Hille 2001). Blockade of these outflowing K+ currents leads to depolarization from RMP (Nasif et al. 2005). Because these K+ channels belong to the superfamily of the inward rectifier and activity of inwardly rectifying K+ channels is reduced with D2R stimulation (see above), we also studied whether the RMP of NAc neurons was modulated by D2Rs. In this experiment, RMP was not clamped during recording. Quinpirole induced a small but significant membrane depolarization in all NAc neurons recorded (control vs. quinpirole: –82.92 ± 0.63 vs. –80.73 ± 0.85 mV, n = 14 cells, paired t-test, *P < 0.05). This effect of quinpirole on RMP was washed out and returned to more hyperpolarized levels (Fig. 9 A). There was no significant difference in RMP recorded from cells in control group versus washout group (–82.92 ± 0.63 vs. –82.47 ± 1.27 mV, n = 14 cells, paired t-test, P > 0.05) (Fig. 9B). However, concurrent bath application of the selective PI-PLC inhibitor ET-18-OCH3 blocked this effect of D2R stimulation on RMP (control vs. quinpirole + ET-18-OCH3: –80.73 ± 0.87 vs. –80.15 ± 0.77 mV, n = 12 cells; paired t-test; P > 0.05), without inducing any significant changes in RMP (control vs. ET-18-OCH3: –80.73 ± 0.87 vs. –80.66 ± 1.08 mV, n = 12 cells, paired t-test, P > 0.05) (Fig. 9C). In contrast, coapplication of Rp-cAMPs failed to block quinpirole-induced depolarization in RMP (Rp-cAMPs vs. Rp-cAMPs + quinpirole: –80.01 ± 0.7 vs. –78.01 ± 0.74 mV; n = 11 cells, paired t-test, *P < 0.05; and control vs. Rp-cAMPs + quinpirole: –80.6 ± 0.6 vs. –78.01 ± 0.74 mV, n = 11 cells, unpaired t-test; **P < 0.01) (Fig. 9D). Rp-cAMPs alone did not produce a significant change in RMP compared with control (control vs. Rp-AMPs: –80.6 ± 0.6 vs. –80.01 ± 0.7 mV, n = 11 cells, unpaired t-test, P > 0.05).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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D2R-mediated IAs activation decreases evoked Na+ spikes
The major finding of this study is that D2R stimulation, either by DA or the selective D2R agonist quinpirole, suppressed evoked Na+ spikes. The predominant mechanism underlying the D2R-modulated suppression of evoked Na+ spikes should be attributed to activation of IAs in the core NAc cells. K+ channels are one of the key regulators of the intrinsic excitability in both dorsal and ventral striatal MSNs (Hu et al. 2004; Surmeier and Kitai 1993, 1997; Wickens and Wilson 1998). There are at least three major K+ currents activated by membrane depolarization in striatal MSNs (Nisenbaum and Wilson 1995; Surmeier et al. 1991). Among them, IAs plays an important role in regulating firing (Mahon et al. 2000; Nisenbaum et al. 1994; Wickens and Wilson 1998). D2R stimulation usually enhances IAs, although D1R stimulation decreases the current in striatal MSNs (Surmeier and Kitai 1993). Associated with D2R stimulation, evoked action potentials are decreased in dorsal striatal cells, not only with increased IAs but also with decreased Ca2+ influx through L-type Ca2+ channels, which is mediated by a novel G/PLC1/IP3/Ca2+/calcineurin pathway (Hernandez-Lopez et al. 2000).
Accordingly, findings from the present study further indicate that D2R-modulated reduction in evoked firing recorded in MSNs of the core NAc should be attributed primarily to activation of A-type K+ channels because either blockade or inactivation of A-type K+ channels abolishes the D2R-mediated inhibition in evoked Na+ spikes. These results are consistent with and supportive of previous findings regarding the inhibitory effects of A-type K+ channels on evoked action potentials in striatal MSNs. Interestingly, IAs is also found to be inhibited by coactivation of D1Rs and D2Rs in NAc cells located within the shell region, leading to an increase in evoked firing (Hopf et al. 2003). However, unlike activation of A-type K+ channels in the core NAc cells, which is regulated most likely by the D2R and neuronal Ca2+ sensor proteins (see following text), increased firing in the shell NAc cells is mediated by combined G subunits released from D2R/Gi/o coupling and Gs-like subunits from D1R/Gs coupling (Hopf et al. 2003). In addition, increased firing in striatal cells can also be induced by coactivation of the D1R and D2R by a synergistic inhibition of Na+-K+ ATPase (Bertorello et al. 1990). Given the above, we propose that 1) activation of the D2R in different NAc circuitries modulates activity of various types of ion channels by regulating multiple signaling pathways, which leads to an integrated change in neuronal intrinsic excitability; and 2) MSNs located in the core and shell region of the NAc have distinct characteristics that may be related to their unique functions in the reward pathway.
Interestingly, some differences were observed between DA-induced inhibition in evoked firing (roughly 80% of baseline) and that induced by coapplication of DA and SCH-23390 (roughly 60% of baseline). The mechanism of this phenomenon should be attributed to involvement of D1R modulation of ion channel activity. It is established that stimulation of D1Rs leads to activation of L-type Ca2+ channels in medium spiny striatal cells (Hernandez-Lopez et al. 1997). This specific effect of D1R modulation on the L-channel activity ought actually to increase the intrinsic excitability of these neurons in response to membrane depolarization. Thus blockade of D1Rs with enhanced stimulation of D2Rs could induce an integrated regulation that leads to a greater suppression in evoked action potentials than DA does. It should be particularly true when the effects of D2R-coupled A-type K+ channels are predominant.
The mechanism underlying activation of IAs
Despite numerous previous findings demonstrating a D2R-modulated reduction in Na+ spikes in striatal MSNs, the exact mechanism underlying this D2R action is unknown. The present study reveals that the D2R-modulated increase in IAs is regulated by inhibition of PKA activity, suggesting that at least two PKA-related mechanisms may be involved. The first one seems to be associated with decreased phosphorylation of IA channels by PKA because this kinase is inhibited by quinpirole, Rp-cAMPs, or H-89. However, because PKA-induced phosphorylation usually increases activity of the delayed rectifier (IK), including IA channels (Hille 2001; Koh et al. 1996), this scenario is unlikely. The other one could be related to a D2R-facilitated increase in Ca2+ mobilization, which elevates cytosolic free Ca2+ levels ([Ca2+]in) in striatal MSNs (Nishi et al. 1997, 1999). We previously determined that the D2R-mediated increase in intracellular Ca2+ release is regulated by disinhibition of IP3 receptors after inhibition of PKA activity in NAc neurons (Hu et al. 2005). Based on these findings, we propose that D2R-mediated activation of IAs in core NAc neurons is regulated by a signaling pathway involving inhibition of PKA activity and facilitation of Ca2+ mobilization.
Recent findings reveal that the neuronal Ca2+-sensor (NCS) proteins [e.g., NCS-1 and K+ channel-interacting proteins (KChIPs)] modulate IA, leading to an increase in IA density and prolonged IA deactivation (An et al. 2000). More important, because some of these NCS proteins are functionally and conformationally coupled to D2Rs (for review see Bergson et al. 2003; Burgoyne et al. 2004), whereas a D2R-mediated increase in free [Ca2+]in effectively activates them (Kabbani et al. 2002), these NCS proteins may play a critical role in D2R modulation of IA and inhibition of firing. Thus it is most likely that the D2R-mediated reduction of evoked Na+ spikes in the core NAc cells results from a consequence of inhibition of PKA activity, disinhibition of IP3 receptors, facilitation of Ca2+ release, and activation of the NCS proteins, which eventually increases IAs.
D2R-mediated attenuation of inward rectification is modulated by activated PLC
Another important finding in this study is that D2R stimulation decreases the inward rectification in the core NAc cells. Previous investigations found that several subtypes of Kir channels, including the classic inwardly rectifying K+ channels (IRK1–3 or Kir 2.1–3) and G-protein–activated inward rectifiers (GIRK1 and 3, or Kir 3.1 and Kir 3.3) are located in NAc neurons (Karschin et al. 1996). It is also well established that Kir channels, which are activated in response to membrane hyperpolarization and inactivated during depolarization, exert their role in diverse cellular functions, especially in regulating K+ homeostasis, synaptic inhibition, neuronal firing, and resting conductance (D'Ambrosio et al. 2002; Hille 2001; Wang 1995).
Findings from the present study indicate that the D2R-modulated decrease in the inward rectification was regulated by a D2R-coupled PI-PLC pathway because D2R-mediated reduction in the inward rectification was abolished by inhibition of PI-PLC activity, but not of PKA. Although this finding is supported by considerable evidence that indicates that activation of PLC is associated with reduced activity of Kir channels (e.g., both IRKs and GIRKs) (Leaney et al. 2001; Sharon et al. 1997; Takano et al. 1995), the mechanism underlying D2R-modulated decrease in the inward rectification during membrane hyperpolarization in NAc cells remains unknown. However, it is possible that the reduced inward rectification is related to a decrease in the cytosolic levels of phosphatidylinositol-4,5-bisphosphate (PIP2). On D2R-coupled activation, PLC hydrolyzes PIP2 and decreases local levels of PIP2 in cells (Stauffer et al. 1998; van der Wal et al. 2001). This decrease in cellular PIP2 levels could reduce Kir activity by two pathways. First, because binding of PIP2 to certain sites of Kir channels increases activity of the channel (Du et al. 2004; Huang et al. 1998; Kobrinsky et al. 2000), reduced PIP2 availability would diminish activity of IRKs and GIRKs (Meyer et al. 2001), thereby decreasing the inward rectification. Second, PIP2 is hydrolyzed by PLC to form IP3 and diacylglycerol (DAG). DAG activates protein kinase C (PKC), which can also inhibit Kir channel activity (Mao et al. 2004; Stevens et al. 1999) that should also decrease the inward rectification. Given the above, we propose that the D2R-mediated reduction in the inward rectification (representing decreased IKir) should be attributed to activation of PI-PLC and a consequent reduction of intracellular PIP2 levels.
D2R-mediated depolarization of RMP is also modulated by activation of PLC
Despite their name, certain inward rectifiers carry outward ("background" or "leak") K+ currents that are activated at the RMP (Hille 2001). This type of K+ channel consists of the two-pore domain (K2P) and serves as a molecular determinant of several "leak" K+ currents (Goldstein et al. 2001; Kang and Kim 2006; Lesage and Lazdunski 2000). These K2P channels allow K+ currents (IK-2P) outflow, helping to set and stabilize RMP at levels slightly above the K+ equilibrium potential. These K+ channels are highly expressed in the NAc (Karschin et al. 1996; Talley et al. 2001). Blockade of this K+ efflux depolarizes RMP in neurons (Nasif et al. 2005). Our findings not only show a D2R-modulated membrane depolarization from RMP, but also unmask its mechanism in which activation of PI-PLC was responsible for this D2R action on decreasing "leak" K+ currents. This result from our study is in agreement with a recent finding that demonstrates that activity of K2P channels is decreased by agonist-activated PLC and hydrolysis of PIP2 (Lopes et al. 2005). Taken together, these findings suggest that the D2R-mediated RMP depolarization is regulated by activation of PLC and depletion of PIP2, which lead to a decreased K2P channel activity.
In conclusion, in this study we determined that D2R modulation inhibits evoked Na+ spike firing by activating IA, reduces the inward rectification by diminishing IKir, and depolarizes RMP likely by decreasing the "leak" currents (IK-2P) in MSNs located in the core NAc. We also reveal that the integrated D2R actions are regulated by multiple signaling pathways, including but not limited to the cAMP/PKA cascade, D2R-coupled intracellular Ca2+ release, and D2R-associated Gq/PI-PLC/PIP2 pathway. By modulating IAs, IKir, and IK-2P along with voltage-sensitive INa and ICa (see above) at different membrane potential levels, the D2R dynamically and integratively regulates the intrinsic excitability of NAc spiny neurons. Given that D2Rs play an important role in the pathophysiology and treatment of neurodegenerative diseases, attention-deficit–hyperactivity disorder, schizophrenia, and drug addiction, novel findings from the present study should assist future investigations focusing on elucidation of the mechanisms underlying these diseases.
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Address for reprint requests and other correspondence: X.-T. Hu, Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064-3095 (E-mail: xiu-ti.hu{at}rosalindfranklin.edu)
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Bergson C, Levenson R, Goldman-Rakic PS, and Lidow MS. Dopamine receptor-interacting proteins: the Ca(2+) connection in dopamine signaling. Trends Pharmacol Sci 24: 486–492, 2003.[CrossRef][Medline]
Bertorello AM, Hopfield JF, Aperia A, and Greengard P. Inhibition by dopamine of (Na(+)+K+)ATPase activity in neostriatal neurons through D1 and D2 dopamine receptor synergism. Nature 347: 386–388, 1990.[CrossRef][Medline]
Burgoyne RD, O'Callaghan DW, Hasdemir B, Haynes LP, and Tepikin AV. Neuronal Ca2+-sensor proteins: multitalented regulators of neuronal function. Trends Neurosci 27: 203–209, 2004.[CrossRef][Web of Science][Medline]
Cepeda C, Hurst RS, Altemus KL, Flores-Hernandez J, Calvert CR, Jokel ES, Grandy DK, Low MJ, Rubinstein M, Ariano MA, and Levine MS. Facilitated glutamatergic transmission in the striatum of D2 dopamine receptor-deficient mice. J Neurophysiol 85: 659–670, 2001.
Congar P, Bergevin A, and Trudeau LE. D2 receptors inhibit the secretory process downstream from calcium influx in dopaminergic neurons: implication of K+ channels. J Neurophysiol 87: 1046–1056, 2002.
D'Ambrosio R, Gordon DS, and Winn HR. Differential role of KIR channel and Na(+)/K(+)-pump in the regulation of extracellular K(+) in rat hippocampus. J Neurophysiol 87: 87–102, 2002.
Dong Y, Cooper D, Nasif F, Hu X-T, and White FJ. Dopamine modulates inwardly rectifying potassium currents in medial prefrontal cortex pyramidal neurons. J Neurosci 24: 3077–3085, 2004.
Du X, Zhang H, Lopes C, Mirshahi T, Rohacs T, and Logothetis DE. Characteristic interactions with phosphatidylinositol-4,5-bisphosphate determine regulation of Kir channels by diverse modulators. J Biol Chem 279: 37271–37281, 2004.
Gabel LA and Nisenbaum ES. Biophysical characterization and functional consequences of a slowly inactivating potassium current in neostriatal neurons. J Neurophysiol 79: 1989–2002, 1998.
Goldstein SA, Bockenhauer D, O'Kelly I, and Zilberberg N. Potassium leak channels and the KCNK family of two-P-domain subunits. Nat Rev Neurosci 2: 175–184, 2001.[Web of Science][Medline]
Greengard P, Allen PB, and Nairn AC. Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 23: 435–447, 1999.[CrossRef][Web of Science][Medline]
Greif GJ, Lin YJ, and Freedman JE. Role of cyclic AMP in dopamine modulation of potassium channels on rat striatal neurons: regulation of a subconductance state. Synapse 21: 275–277, 1995.[CrossRef][Web of Science][Medline]
Gulledge AT and Jaffe DB. Dopamine decreases the excitability of layer V pyramidal cells in the rat prefrontal cortex. J Neurosci 18: 9139–9151, 1998.
Hernandez-Echeagaray E, Starling AJ, Cepeda C, and Levine MS. Modulation of AMPA currents by D2 dopamine receptors in striatal medium-sized spiny neurons: are dendrites necessary? Eur J Neurosci 19: 2455–2463, 2004.[CrossRef][Web of Science][Medline]
Hernandez-Lopez S, Bargas J, Surmeier DJ, Reyes A, and Galarraga E. D1 receptor activation enhances evoked discharge in neostriatal medium spiny neurons by modulating an L-type Ca2+ conductance. J Neurosci 17: 3334–3342, 1997.
Hernandez-Lopez S, Tkatch T, Perez-Garci E, Galarraga E, Bargas J, Hamm H, and Surmeier DJ. D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1-IP3-calcineurin-signaling cascade. J Neurosci 20: 8987–8995, 2000.
Hille B. Ion Channels of Excitable Membranes (3rd ed.). Sunderland, MA: Sinauer, 2001.
Hopf FW, Cascini MG, Gordon AS, Diamond I, and Bonci A. Cooperative activation of dopamine D1 and D2 receptors increases spike firing of nucleus accumbens neurons via G-protein betagamma subunits. J Neurosci 23: 5079–5087, 2003.
Hu X-T, Basu S, and White FJ. Repeated cocaine administration suppresses HVA-Ca2+ potentials and enhances activity of K+ channels in rat nucleus accumbens neurons. J Neurophysiol 92: 1597–1607, 2004.
Hu X-T, Dong Y, Zhang XF, and White FJ. Dopamine D2 receptor-activated Ca2+ signaling modulates voltage-sensitive sodium currents in rat nucleus accumbens neurons. J Neurophysiol 93: 1406–1417, 2005.
Hu X-T and Wang RY. Comparison of effects of D-1 and D-2 dopamine receptor agonists on neurons in the rat caudate putamen: an electrophysiological study. J Neurosci 8: 4340–4348, 1988.[Abstract]
Hu X-T and White FJ. Dopamine enhances glutamate-induced excitation of rat striatal neurons by cooperative activation of D1 and D2 class receptors. Neurosci Lett 224: 61–65, 1997.[CrossRef][Web of Science][Medline]
Huang CL, Feng S, and Hilgemann DW. Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma. Nature 391: 803–806, 1998.[CrossRef][Medline]
Hyman SE. Addiction: a disease of learning and memory. Am J Psychiatry 162: 1414–1422, 2005.
Hyman SE and Malenka RC. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2: 695–703, 2001.[CrossRef][Web of Science][Medline]
Kabbani N, Negyessy L, Lin R, Goldman-Rakic P, and Levenson R. Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor. J Neurosci 22: 8476–8486, 2002.
Kalivas PW and Hu X-T. Exciting inhibition in psychostimulant addiction. Trends Neurosci In press.
Kalivas PW, Volkow N, and Seamans J. Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45: 647–650, 2005.[CrossRef][Web of Science][Medline]
Kang D and Kim D. TREK-2 (K2P10.1) and TRESK (K2P18) are major background K+ channels in dorsal root ganglion neurons. Am J Physiol Cell Physiology 291: C138–C146, 2006.
Karschin C, Dissmann E, Stuhmer W, and Karschin A. IRK(1–3) and GIRK(1–4) inwardly rectifying K+ channel mRNAs are differentially expressed in the adult rat brain. J Neurosci 16: 3559–3570, 1996.
Kobrinsky E, Mirshahi T, Zhang H, Jin T, and Logothetis DE. Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization. Nat Cell Biol 2: 507–514, 2000.[CrossRef][Web of Science][Medline]
Koh SD, Sanders KM, and Carl A. Regulation of smooth muscle delayed rectifier K+ channels by protein kinase A. Pfluegers Arch 432: 401–412, 1996.[CrossRef][Web of Science][Medline]
Leaney JL, Dekker LV, and Tinker A. Regulation of a G protein-gated inwardly rectifying K+ channel by a Ca(2+)-independent protein kinase C. J Physiol 534: 367–379, 2001.
Lesage F and Lazdunski M. Molecular and functional properties of two-pore-domain potassium channels. Am J Physiol Renal Fluid Electrolyte Physiol 279: F793–F801, 2000.
Ljungstrom T, Grunnet M, Jensen BS, and Olesen SP. Functional coupling between heterologously expressed dopamine D(2) receptors and KCNQ channels. Pfluegers Arch 446: 684–694, 2003.[CrossRef][Web of Science][Medline]
Lopes CM, Rohacs T, Czirjak G, Balla T, Enyedi P, and Logothetis DE. PIP2 hydrolysis underlies agonist-induced inhibition and regulates voltage gating of two-pore domain K+ channels. J Physiol 564: 117–129, 2005.
Mahon S, Delord B, Deniau JM, and Charpier S. Intrinsic properties of rat striatal output neurones and time-dependent facilitation of cortical inputs in vivo. J Physiol 527: 345–354, 2000.
Mao J, Wang X, Chen F, Wang R, Rojas A, Shi Y, Piao H, and Jiang C. Molecular basis for the inhibition of G protein-coupled inward rectifier K(+) channels by protein kinase C. Proc Natl Acad Sci USA 101: 1087–1092, 2004.
Meyer T, Wellner-Kienitz MC, Biewald A, Bender K, Eickel A, and Pott L. Depletion of phosphatidylinositol-4,5-bisphosphate by activation of phospholipase C-coupled receptors causes slow inhibition but not desensitization of G protein-gated inward rectifier K+ current in atrial myocytes. J Biol Chem 276: 5650–5658, 2001.
Nasif FJ, Sidiropoulou K, Hu X-T, and White FJ. Repeated cocaine administration increases membrane excitability of pyramidal neurons in the rat medial prefrontal cortex. J Pharmacol Exp Ther 312: 1305–1313, 2005.
Nicola SM, Surmeier J, and Malenka RC. Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens. Annu Rev Neurosci 23: 185–215, 2000.[CrossRef][Web of Science][Medline]
Nisenbaum ES and Wilson CJ. Potassium currents responsible for inward and outward rectification in rat neostriatal spiny projection neurons. J Neurosci 15: 4449–4463, 1995.[Abstract]
Nisenbaum ES, Xu ZC, and Wilson CJ. Contribution of a slowly inactivating potassium current to the transition to firing of neostriatal spiny projection neurons. J Neurophysiol 71: 1174–1189, 1994.
Nishi A, Snyder GL, and Greengard P. Bidirectional regulation of DARPP-32 phosphorylation by dopamine. J Neurosci 17: 8147–8155, 1997.
O'Donnell P and Grace AA. Physiological and morphological properties of accumbens core and shell neurons recorded in vitro. Synapse 13: 135–160, 1993.[CrossRef][Web of Science][Medline]
Parikh H, Liu L, Sibley DR, and Chiodo LA. D2S and D2L dopamine receptors stably transfected in NG108-15 cells increase intracellular calcium via different signal transduction mechanisms. Neuroscience-Net 1: 10007, 1996.
Pennartz CM, Groenewegen HJ, and Lopes da Silva FH. The nucleus accumbens as a complex of functionally distinct neuronal ensembles: an integration of behavioural, electrophysiological and anatomical data. Prog Neurobiol 42: 719–761, 1994.[CrossRef][Web of Science][Medline]
Sharon D, Vorobiov D, and Dascal N. Positive and negative coupling of the metabotropic glutamate receptors to a G protein-activated K+ channel, GIRK, in Xenopus oocytes. J Gen Physiol 109: 477–490, 1997.
Sibley DR. Molecular biology of dopamine receptors. In: Molecular and Cellular Mechanisms of Neostriatal Function, edited by Ariano MA and Surmeier DJ. Austin, TX: Landes, 1995, p. 255–272.
Spear LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24: 417–463, 2000.[CrossRef][Web of Science][Medline]
Stauffer TP, Ahn S, and Meyer T. Receptor-induced transient reduction in plasma membrane PtdIns(4,5)P2 concentration monitored in living cells. Curr Biol 8: 343–346, 1998.[CrossRef][Web of Science][Medline]
Stevens EB, Shah BS, Pinnock RD, and Lee K. Bombesin receptors inhibit G protein-coupled inwardly rectifying K+ channels expressed in Xenopus oocytes through a protein kinase C-dependent pathway. Mol Pharmacol 55: 1020–1027, 1999.
Stoof JC and Kebabian JW. Opposing roles for D-1 and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatum. Nature 294: 366–368, 1981.[CrossRef][Medline]
Stoof JC and Kebabian JW. Independent in vitro regulation by the D-2 dopamine receptor of dopamine-stimulated efflux of cyclic AMP and K+-stimulated release of acetylcholine from rat neostriatum. Brain Res 250: 263–270, 1982.[CrossRef][Web of Science][Medline]
Stuart GJ, Dodt HU, and Sakmann B. Patch-clamp recordings from the soma and dendrites of neurons in brain slices using infrared video microscopy. Pfluegers Arch 423: 511–518, 1993.[CrossRef][Web of Science][Medline]
Surmeier DJ and Kitai ST. D1 and D2 dopamine receptor modulation of sodium and potassium currents in rat neostriatal neurons. Prog Brain Res 99: 309–324, 1993.[Web of Science][Medline]
Surmeier DJ and Kitai ST. State-dependent regulation of neuronal excitability by dopamine. Nihon Shinkei Seishin Yakurigaku Zasshi 17: 105–110, 1997.[Medline]
Surmeier DJ, Stefani A, Foehring RC, and Kitai ST. Developmental regulation of a slowly-inactivating potassium conductance in rat neostriatal neurons. Neurosci Lett 122: 41–46, 1991.[CrossRef][Web of Science][Medline]
Surmeier DJ, Wilson CJ, and Eberwine J. Patch-clamp techniques for studying potassium currents in mammalian brain neurons. In: Ion Channels of Excitable Cells: Methods in Neurosciences, edited by Narahaski T. Orlando, FL: Academic Press, 1994, vol. 19, p. 39–67.
Surmeier DJ, Xu ZC, Wilson CJ, Stefani A, and Kitai ST. Grafted neostriatal neurons express a late-developing transient potassium current. Neuroscience 48: 849–856, 1992.[CrossRef][Web of Science][Medline]
Takano K, Stanfield PR, Nakajima S, and Nakajima Y. Protein kinase C-mediated inhibition of an inward rectifier potassium channel by substance P in nucleus basalis neurons. Neuron 14: 999–1008, 1995.[CrossRef][Web of Science][Medline]
Talley EM, Solorzano G, Lei Q, Kim D, and Bayliss DA. CNS distribution of members of the two-pore-domain (KCNK) potassium channel family. J Neurosci 21: 7491–7505, 2001.
Tseng KY and O'Donnell P. Dopamine–glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J Neurosci 24: 5131–5139, 2004.
van der Wal J, Habets R, Varnai P, Balla T, and Jalink K. Monitoring agonist-induced phospholipase C activation in live cells by fluorescence resonance energy transfer. J Biol Chem 276: 15337–15344, 2001.
Wang WH. Regulation of the hyperpolarization-activated K+ channel in the lateral membrane of the cortical collecting duct. J Gen Physiol 106: 25–43, 1995.
West AR and Grace AA. Opposite influences of endogenous dopamine D1 and D2 receptor activation on activity states and electrophysiological properties of striatal neurons: studies combining in vivo intracellular recordings and reverse microdialysis. J Neurosci 22: 294–304, 2002.
White FJ and Kalivas PW. Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend 51: 141–153, 1998.[CrossRef][Web of Science][Medline]
White FJ and Wang RY. Electrophysiological evidence for the existence of both D-1 and D-2 dopamine receptors in the rat nucleus accumbens. J Neurosci 6: 274–280, 1986.[Abstract]
Wickens JR and Wilson CJ. Regulation of action-potential firing in spiny neurons of the rat neostriatum in vivo. J Neurophysiol 79: 2358–2364, 1998.
Wise RA. Drug-activation of brain reward pathways. Drug Alcohol Depend 51: 13–22, 1998.[CrossRef][Web of Science][Medline]
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30%) was achieved with 10 µM. Bars represent means ± SE. D: quinpirole-induced decrease in firing was reversible and washed out by fresh bath solution. E and F: time–response curves indicate that the D2R-mediated inhibition in evoked Na+ spikes achieved its maximal levels about 5 min after bath application of quinpirole (10 µM). It returned to control levels after 3–5 min of washout (E: single cell; F: n = 12 cells, with post hoc test, P < 0.05).
