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(Investigative Ophthalmology and Visual Science. 2002;43:1257-1261.)
© 2002 by The Association for Research in Vision and Ophthalmology, Inc.

Effects of Haloperidol on K+ Currents in Acutely Isolated Rat Retinal Ganglion Cells

Takanobu Akamine1, Yoshihiro Nishimura2, Kunio Ito1, Yukitaka Uji1 and Tetsuro Yamamoto2

1 From the Departments of Ophthalmology and 2 Physiology, Faculty of Medicine, Mie University, Mie, Japan.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. Effects of haloperidol on K+ currents (IKs) of rat retinal ganglion cells (RGCs) were examined, with the hypothesis that its alteration of IKs explains alterations in the pattern electroretinogram (PERG).

METHODS. Fast blue was injected into superior colliculi of rats (3–8 days old) to identify RGCs under epifluorescence illumination after retrograde transport to retinas. Retinas were dissected, treated enzymatically, and dissociated with trituration. Effects of haloperidol on membrane currents at -70 mV, voltage-dependent IK, and Ca2+-dependent K+ currents (KCa) were examined by whole-cell patch voltage clamp. Na+ currents were abolished by tetrodotoxin (1 µM; TTX). Voltage-gated IKs were isolated by Ca2+-free perfusate. Persistent and transient components of the voltage-sensitive IKs were isolated by prepulses, and sensitivity of each component to tetraethylammonium (TEA, 20 mM) and 4-aminopyridine (5 mM) was tested. KCa was identified by its response to TEA, charybdotoxin (CTX), and apamin. Haloperidol (0.01–100 µM) was instilled into the perfusate dissolved in dimethyl sulfoxide (DMSO).

RESULTS. Currents recorded at -70 mV were not affected by haloperidol, whereas the persistent component of the voltage-dependent IK was reversibly reduced by haloperidol, with a dose dependence fitted with the Hill equation (median inhibitory concentration [IC50] = 4.2 µM). The transient component of the voltage-gated IK was less sensitive to haloperidol. Haloperidol (10 nM) blocked the apamin-sensitive KCa but not the CTX-sensitive KCa.

CONCLUSIONS. Haloperidol reduced voltage-dependent IKs in RGCs, but at a higher concentration than that needed to antagonize dopamine receptors. Haloperidol (10 nM) blocked the apamin-sensitive KCa which modulates the firing rate of RGCs and may contribute to the alteration of PERG.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Recently, it has been reported that haloperidol, a neuroleptic compound known as a dopaminergic D1, D2 antagonist,1 increases pattern electroretinogram (PERG) b-wave latency2 and decreases PERG second harmonic amplitude at a low spatial frequency in humans.3 The PERG is assumed to be related to activity in retinal ganglion cells (RGCs),4 5 but the cellular mechanisms underlying the haloperidol-induced alteration of the PERG is unknown. Haloperidol has been reported to reduce voltage-dependent Ca2+ currents6 and Na+ currents,7 but only at concentrations higher than that required to antagonize dopaminergic receptors. It has been reported that haloperidol suppresses voltage-dependent K+ currents in isolated mammalian tumor cells.8 9 and Ca2+-dependent K+ currents (KCa) in neurons of the central nervous system.10 11 We hypothesized that haloperidol may alter the PERG by its action on voltage- or Ca2+-dependent K+ currents, and we examined the effects of haloperidol on these currents in acutely isolated rat RGCs, by the whole-cell patch voltage-clamp recording technique.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell Dissociation
All animals in this study were treated in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Fast blue (Sigma, St. Louis, MO) dissolved in distilled water (1 µL 5% wt/vol) was injected bilaterally into the superior colliculi of cryoanesthetized Sprague-Dawley rats of both sexes (postnatal age, 3–8 days) 2 to 4 days before recording, to allow time for retrograde transport to the retina.7 12 Eyes were enucleated on the recording day with rats under deep cryoanesthesia, and the retina was isolated and cut into small pieces. Retinal cells were dissociated by enzymatic treatment in O2-bubbled Hanks’ solution containing papain (3–5 U/mL; Worthington, Freehold, NJ) and cysteine (0.1 g/mL; Sigma) for 60 minutes at 31°C with gentle trituration with Pasteur pipettes.13

Dissociated cells were plated on ConA (Sigma)-coated dishes filled with an extracellular solution of the following composition (in millimolar): NaCl, 135; KCl, 5; CaCl2, 1; MgCl2, 1; HEPES, 5; and glucose, 10. Retrogradely labeled ganglion cells were observed by using differential interference contrast (DIC) optics and identified morphologically under an epifluorescence microscope (BX50WI; Olympus, Tokyo, Japan) with a V-filter (emission filter, 330–385 nm; cutoff filter, 420 nm) after the electrophysiological data were recorded.

Electrophysiological Recording
Membrane currents were recorded by whole-cell voltage clamp with the use of borosilicate glass pipettes (outer diameter, 1.5 mm; direct current [DC] resistance, 4–10 M{Omega}) made by a two-step puller (PP-83; Narishige, Tokyo, Japan). The pipette solution consisted of (in millimolar): KCl, 140; NaCl, 9; MgCl2, 1; EGTA, 0.2; HEPES, 10; Mg-adenosine triphosphate (ATP), 2; and Na-guanosine triphosphate (GTP), 0.25, adjusted to pH 7.3 with KOH. To investigate voltage-gated K+ currents, the dissociated cells were superfused continuously with Ca2+-free extracellular solution of the following composition (in millimolar): NaCl, 113; KCl, 3; MgCl2, 5; NaH2PO4, 1; NaHCO3, 25; and glucose, 11 with 1 µM tetrodotoxin (TTX). To investigate KCa currents, the following extracellular solution was used (in millimolar): NaCl, 113; KCl, 3; MgCl2, 1; NaH2PO4, 1; NaHCO3, 25; glucose 11; and CaCl2, 2 with 1 µM TTX. The extracellular solutions were bubbled with 95% O2 and 5% CO2 to maintain pH at 7.4.

Haloperidol (Sigma) was dissolved in dimethyl sulfoxide (DMSO) in stock solutions at concentrations of 10 mM. These stock solutions were added to the extracellular perfusate to result in final, diluted concentrations of 0.01 to 100 µM and a final DMSO concentration of less than 1%. All haloperidol solutions were protected from light to prevent drug degeneration. Tetraethylammonium (TEA, 20 mM) replaced equimolar NaCl in the external solution, whereas 4-aminopiridine (4-AP, 5 mM), charybdotoxin (CTX, 100 nM), and apamin (300 nM) were simply added to the external solution.

Whole-cell voltage-clamp recordings were performed, using an amplifier (Axopatch 200A; Axon Instruments, Foster City, CA). Membrane currents were filtered at 5 kHz, digitized, and stored on a computer with software (Axoscope 1.1 and pClamp 6; Axon) that was used for experimental control and data analysis. During recording, the pipette’s series resistance of 13.7 ± 4.1 M{Omega} was compensated by approximately 60%. Data were accepted for analysis only if the series resistance error was less than 10 mV. Liquid junction potentials between the intracellular and extracellular solutions were obtained by measuring a potential shift produced after replacing the extracellular solutions with a solution of the same components as the intracellular solution. Liquid junction potentials of 1.9 ± 0.3 mV (n = 4) were not compensated.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Identification of RGCs
Figure 1A shows the appearance of the dissociated retinal cells when viewed by DIC optics. Because of the dissociation process, most of them did not possess complete axons or dendrites. RGCs were identified as such by the presence of retrogradely transported fast blue dye when viewed under epifluorescence illumination (see the Methods section). One such identified cell is shown in Figure 1B . The soma of identified ganglion cells was smooth and spherical or oval in shape. The data presented in this study were from 76 identified ganglion cells.



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  		Figure 1. Identification of RGCs. (A) Photomicrograph of an isolated RGC in a 9-day-old rat, obtained using DIC optics. (B) Fluorescence photomicrograph of the same cell retrogradely labeled with fast blue. Bar, 20 µm.

 
Effects of Haloperidol on Currents at Resting Potential
We supposed that the natural resting potential of these cells would be near -70 mV, and voltage- or Ca2+-dependent currents would be absent or minimal at this potential. During voltage-clamp recording, a change in membrane current at a holding potential of -70 mV would correspond to a depolarization or hyperpolarization (depending on the sign of the current change) in current clamp recording. Figure 2 shows membrane currents recorded in a RGC clamped at -70 mV before and after the administration of haloperidol at 100 µM, the highest concentration used in these experiments. No change in membrane current at -70 mV was detected after the application of the haloperidol in the cell in Figure 2 nor in any cell examined (n = 5). Thus, the application of haloperidol caused no change in resting membrane potential. We determined next whether it would affect those outward ionic currents that are evoked only by the depolarization of membrane potential.



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  		Figure 2. Membrane current recorded before, during, and after application of 100 µM haloperidol in an RGC clamped at -70 mV.

 
Transient and Persistent Components of Voltage-Gated K+ Currents
Voltage-gated currents were isolated by recording in TTX (1 µM) containing Ca2+-free solution (see the Methods section). Figure 3A2 shows the voltage-gated outward currents evoked by a series of depolarizing voltage commands (shown in Fig. 3A1 ) that followed a hyperpolarizing prepulse to -150 mV. The appearance of the evoked outward current suggested that it may consist of both a transient and a persistent component, and this proved to be the case. When the series of test depolarizing voltage steps was preceded by a depolarizing prepulse to -50 mV (Fig. 3B1 ), only persistent outward currents were evoked (Fig. 3B2 ). The transient component (Fig. 3C) was then visualized in isolation by the point-by-point subtraction (performed by the use of PClamp 6.0 software; Axon) of the persistent component of Figure 3B2 from the total outward current of Figure 3A2 .



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  		Figure 3. Identification of voltage-dependent K+ currents. (A) Whole-cell outward currents evoked by step commands to between -90 mV and +30 mV after a hyperpolarizing prepulse to -150 mV from a holding potential of -70 mV. (B) Whole-cell outward currents obtained by step commands to between -90 mV and +30 mV after a depolarizing prepulse to -50 mV from a holding potential of -70 mV in the same cell. (C) Transient currents were obtained by subtracting currents in (B2) from those in (A2). Scales in (B2) apply to (A2) and (B2).

 
A separate persistent and transient outward component also was indicated by the different pharmacologic sensitivity of each component. As shown in Figure 4A , the persistent component was reduced reversibly (by 79.6% ± 6.3%, n = 5) after the application of TEA (20 mM). The residual persistent current remaining after the TEA application was not blocked by 4-AP (5 mM, data not shown). In contrast, 4-AP (5 mM) completely and reversibly blocked the transient components in each cell examined (n = 4, Fig. 4B ). On the basis of published data,12 14 15 we assume that the persistent current represents a delayed rectifier K+ current and/or an IB-like current,15 and that the transient current is IA.



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  		Figure 4. Effects of TEA and 4-AP on voltage-dependent K+ currents. (A) Reversible reduction of persistent voltage-gated K+ current by 20 mM TEA. (B) Complete and reversible block of transient voltage-gated K+ currents by 5 mM 4-AP.

 
Effects of Haloperidol on Persistent Voltage-Gated K+ Currents
The effects of haloperidol on the persistent voltage-gated K+ current was investigated in 38 cells. During a depolarization to +30 mV, the average amplitude of the persistent component just before the end of the voltage command was 1.2 ± 0.5 nA. Haloperidol (10 µM) dissolved in DMSO (<1%) reduced the amplitude of persistent K+ currents evoked at +30 mV by 62.8% (Fig. 5B) . In contrast, the application of 1% DMSO alone had no effect (Fig. 5A) . After washout of the haloperidol, the amplitude of the persistent component recovered to the control level (Fig. 5B , Washout). The persistent K+ current activated at +30 mV was completely suppressed (reversibly) by 100 µM haloperidol (Fig. 5C) .



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  		Figure 5. Effects of haloperidol on persistent voltage-gated K+ current. Persistent voltage-gated K+ current by voltage step to +30 mV from a holding potential of -70 (A) before and after application of DMSO; (B) before and after application of 10 µM haloperidol, which reversibly blocked the current by 62.8%; and (C) before and after application of 100 µM haloperidol in another cell. The current was completely suppressed reversibly. Scales in (A) apply to (B) and (C).

 
We investigated the effect of different concentrations of haloperidol on the persistent K+ current components. Figure 6 shows a plot of persistent K+ current amplitude at +30 mV (values in haloperidol are normalized to predrug control levels) against the concentration of haloperidol. The data points were fitted by the Hill equation, I/Imax = 1 - xn /(xn + {chi}n50), where x represents the concentration of haloperidol, n the Hill constant, and {chi}50 the median inhibitory concentration (IC50). The best fit to the data points occurred when n = 0.89 and {chi}50 = 4.2 µM.



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  		Figure 6. The reduction by various concentrations of haloperidol of the persistent component of the voltage-gated K+ current evoked by a voltage step to +30 mV. The persistent K+ component was normalized to its control value and was plotted against the logarithm of the haloperidol concentration. Numbers in parentheses above each data point indicate the number of cells tested at that concentration. Bars, SD. Solid curve: fit of the data points by the Hill equation.

 
Effects of Haloperidol on IA
In contrast to its effect on the persistent component of the voltage-gated K+ current, haloperidol at a concentration of 100 µM reduced the peak amplitude of IA (activated at +30 mV) by only 41.8% ± 9.4% (n = 4; see Fig. 7 ). As with the persistent component, 1% DMSO alone had no significant effects on IA.



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  		Figure 7. Effects of haloperidol on the transient component of the voltage-gated K+ current. The transient component was evoked by a voltage step to +30 mV from a holding potential of -70 mV, before and after application of 100 µM haloperidol. Haloperidol reversibly reduced the transient component by 45.6%.

 
Effects of Haloperidol on Ca2+-Dependent K+ Currents
We investigated the effects of haloperidol on Ca2+-dependent K+ currents (KCa) using a concentration of 10 nM, because this concentration had very little effect on the voltage-gated K+ currents (see Fig. 6 ) and is reported to have no effect on the Ca2+ current itself.6

In these experiments, the extracellular solution contained Ca2+ (2 mM). TTX (1 µM) was present to block voltage-gated Na+ currents, and 4-AP (5 mM) was present to block IA in all experiments. In different sets of experiments, the extracellular solution also contained a blocker of one known type of KCa, so that the effect of haloperidol on the other type of KCa could be tested specifically. For example, the experimental solution in Figure 8A contained apamin (300 nM) in addition to TTX and 4-AP to block SK-type KCa channels.16 Figure 8A shows outward currents evoked by a voltage command to +30 mV from a holding potential of -70 mV. Under the experimental conditions, the evoked current is expected to consist of the persistent component of the voltage-gated K+ current and KCa flowing through BK-type channels. Haloperidol had little effect on the amplitude of the outward current. This small effect might be expected if the evoked outward current consisted entirely of the persistent component of the voltage-gated K+ current. However, the subsequent application of CTX (100 nM, a blocker of BK-type KCa channels16 ) in the continuous presence of 10 nM haloperidol reduced the outward currents by 25.1% (Fig. 8A , 10 nM Haloperidol + Charybdotoxin). This result demonstrates that BK-type channels, in fact, contributed to the outward current in Figure 8A , but that these channels were little affected by 10 nM haloperidol. The average reduction of the outward current by 10 nM haloperidol under the experimental conditions in Figure 8A was 4.1% ± 1.6% (n = 4), whereas 100 nM CTX (plus haloperidol) reduced the outward current by 20.1% ± 8.6% (n = 4). The high affinity of CTX for its respective channels made it difficult to wash out.17 18



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  		Figure 8. Effects of haloperidol on Ca2+-dependent K+ currents. Outward currents were evoked by a voltage step to +30 mV from a holding potential of -70 mV in Ca2+-containing solution. (A) In the presence of TTX, 4-AP, and apamin the addition of 10 nM haloperidol blocked 5.6% of the outward current. When 100 nM CTX was added to the perfusate, the outward current was reduced by 25.1%. (B) In the presence of TTX, 4-AP, and TEA 10 nM haloperidol blocked 37.5% of the outward current. The addition of 300 nM apamin to the perfusate reduced the current by 40.2%. (C) In the presence of TTX, 4-AP, and TEA control (1). (2) Haloperidol (10 nM ) blocked 42.4% of the outward current. (3) Washout of 10 nM haloperidol. (4) Addition of 300 nM apamin to the perfusate reduced the current by 48.6%. (5) When 10 nM haloperidol was added to the perfusate containing 300 nM apamin, the outward current was not further reduced.

 
The experiment shown in Figure 8B is similar to that in Figure 8A , except that the perfusate contained 20 mM TEA to block BK-type KCa channels16 in addition to 4-AP and TTX. We would expect the surviving outward current to consist of the apamin-sensitive SK-type of KCa channel, together with a small residual persistent, voltage-sensitive K+ current (which is relatively insensitive to 10 nM haloperidol; Fig. 6 ). Haloperidol (10 nM) dissolved in DMSO (<1%) reduced the amplitude of the outward currents by 37.5% (Fig. 8A , 10 nM Haloperidol). After this reduction, the addition of apamin (300 nM) did not affect the remaining current (Fig. 8B ; 10 nM Haloperidol + Apamin) The high affinity of apamin for its channels made it difficult to wash out.17 18 The mean reduction of the outward current by 10 nM haloperidol alone was 25.1% ± 14.2% (n = 4). The mean reduction by 10 nM haloperidol plus 300 nM apamin was 30.2% ± 14.7% (n = 4). From these results, it appears that 10 nM haloperidol reduced the KCa flowing through SK-type channels.

The experiment shown in Figure 8C is similar to that in Figure 8B . After washout of 10 nM haloperidol and recovery of the control outward currents (Fig. 8C 3) , 300 nM apamin reduced the outward currents by the same percentage (4) as did the application of haloperidol alone (2) and further application of 10 nM haloperidol did not cause the outward current reduction (5).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Haloperidol is an antagonist of dopaminergic D1 and D2 receptors1 that is widely used as a neuroleptic agent. Recently, haloperidol has been reported to affect the PERG,2 3 which is assumed to reflect the activities of RGCs.4 5 In our study, membrane current at -70 mV, the presumed resting potential of RGCs, was not affected even by 100 µM haloperidol, indicating that even this high dose of the drug does not alter the resting potential of ganglion cells. In the present study, we found that haloperidol reduced depolarization-activated, voltage-dependent K+ currents and apamin-sensitive KCa. Suppressive effects of haloperidol on Ca2+ and Na+ currents in RGCs have been reported.6 7

We had hypothesized that the reduction of K+ currents might explain the alteration of PERG by haloperidol. Stanzione et al.2 3 reported that PERG is affected by haloperidol at a therapeutic dose. Although the IC50 of the haloperidol-induced reduction of the persistent, voltage-gated K+ current component (4.2 µM) was lower than that reported for Ca2+ and Na+ currents (27.1 µM),6 7 these values are significantly higher than both the therapeutic serum concentrations of haloperidol (estimated at 0.8–2.7 nM)19 and the effective concentration for antagonism of dopamine receptors (1–1.2 nM).1 20 We estimate the IC50 for the IA current to be more than 100 µM. In addition, we found that 10 nM haloperidol did not affect the BK-type KCa current (Fig. 8A) . Therefore the haloperidol effects reported by Stanzione et al.2 3 could not be due to changes in these RGC currents.

Previous studies have been reported to show that dopamine receptors are localized in the RGC layer of adult rats.21 However, it is reported that endogenous dopamine cells are first found in 10-day-old rats.22 Therefore, dopamine receptors may not be completely established on the RGCs of 5- to 10-day-old rats7 in our studies. For this reason, the suppressive effects of haloperidol on K+ currents revealed in this study may not be mediated through dopamine receptors. Previous studies6 7 11 have also shown the possibility that haloperidol blocks Ca2+, Na+, and BK-type KCa channels independent of dopamine receptor activation.

The sensitivity of the persistent and transient voltage-gated K+ currents to haloperidol, TEA, and 4-AP differed, suggesting that these two current components reflect at least two K+ channel subtypes. The following subtypes of the voltage-gated K+ currents (Kv) have been identified in mouse RGCs immunohistochemically: Kv 1.2, Kv 1.3, Kv 1.4, Kv 2.1, and Kv 4.2.23 The persistent, TEA-sensitive voltage-gated K+ currents we studied are similar to the currents produced by Kv 1.1 and Kv 1.4.14 15 However, Suessbrich et al.24 reported that haloperidol (3 µM) had very little effect on Kv 1.1, Kv 1.2, Kv 1.4, Kv 1.5, inward rectifier channel (Kir 2.1), and Isk expressed in Xenopus oocytes, whereas we found that 3 µM haloperidol reduced the persistent voltage-gated K+ current by approximately 50%. Our results suggest that haloperidol may suppress both the Kv 1.1 and Kv 1.4 K+ channel subtypes in the ganglion cells or that the haloperidol-sensitive current we found is caused by erg channels the mRNA of which is reported to be abundant in a rat retina25 and which is blocked by haloperidol when expressed in oocytes.24

On the other hand, we found evidence that 10 nM haloperidol reduced current flowing through the SK-type KCa channel (Figs. 8B 8C) . Although 10 nM haloperidol is slightly higher than the therapeutic concentration,19 alteration of the PERG by haloperidol2 3 may be due in part to the effect of haloperidol on SK-type KCa channels. In RGCs, apamin application increased both the spontaneous firing rate18 and the firing rate evoked by current injection.17 It is therefore possible that haloperidol modulates the RGC firing rate and that this is responsible in part for the changes in PERG reported by Stanzione et al.2 3 Firing rates of ganglion cells are reduced during light adaptation (the decline in light sensitivity as the background brightness increases).26 27 If a low dose of haloperidol (10 nM) increases the ganglion cell firing rate, it may also affect retinal function by reducing the light adaptation. Further investigation is needed to test these hypotheses and to determine the functional role of the suppression of voltage-dependent K+ currents by the high doses of haloperidol that we observed.


   Acknowledgements
 
The authors thank Peter Schwindt, University of Washington, Seattle, Washington, for reading the manuscript and making useful comments and Junko Kobayashi and Kaori Kawamura for excellent assistance.


   Footnotes
 
Supported by Grants-in-Aid 1377102, 06680808, and 11680806 from the Ministry of Education, Science and Culture of Japan.

Submitted for publication June 19, 2001; revised November 20, 2001; accepted November 30, 2001.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Takanobu Akamine, Department of Ophthalmology, Mie University, Faculty of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; akamine{at}momo.so-net.ne.jp


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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