The effect of metoclopramide on the ganzfeld electroretinogram

Vwn R,S. Vol. 27, No. 10, pp. 16934700, Rintmi in Great Britain

0042-6989/87 $3.00 + 0.00 Pcrgamoa Journals Ltd

1987

THE EFFECT OF METOCLOP~MIDE ON THE GANZFELD ELECTRORETINOGRAM M. J. J~,‘~s**

P. D. LEVINSON,~*~R. ZIMMLKHMAN,~ J. C. C~I?N,‘~’ C. N. m~s and F. M. DE MONA~T~RIO’ ‘National Eye Institute, Bethesda, Md; 2Hypertension-Endocriine Branch, National Heart, Lung, and Blood Institute, Bethesda, Md; Division of Endocrinology, The Memorial Hospital, Brown University, Pawtucket, R.I.; %hool of Optometry, University of Missouri, Saint Louis, Missouri and 5Neumpsychiatry Branch, National Institute of Mental Health, WAW, St. Elizabeth’s Hospital, Washington, D.C. (Received 14 November 1986; in revisedform 6 April 1987) Abstract-Antece&nt light flashes enhance the amplitude of the electroretinogram (ERG) oseilfatory potentials, but do not modify other ERG responses nor dark-adaptation sensory thresholds. Metoclopramide infusion (i.v.) has a generally attenuating effect on the ERG, which is more evident under conditions of dark- than light-adaptation. Metoclopramide deceases the peak amplitude of the rod b-wave and the dark-adapted cone b-wave in a similar manner, it also significantly increases the implicit time of the rod b-wave, but not of the dark-adapted cone b-wave. In addition rn~~op~ revemes the enhancement of the oscillatory potentials by the antecedent light &x&es. Ganzfcld electroretinogram

Metoclopramide

D2 antagonist

Dopamine

Human

retina. Reserpine, for example, is a retinal monoamine depleter (Haggendal and MahnAlthough the regulatory role for the retinal fors, 1963; Ehinger, 1% Cohen et al., 1983) dopaminergic neurons in visual function is unthat diminishes the oscillatory potentials (OPs) clear (Ehinger, 1966, 1982; Bauer et al., 1980; of the electroretinogram (ERG) in cats; subMariani et al., 1984), their morphological charsequent administration of L-dopa restores these acteristics have been well studied. Following potentials (Gutierrex and Spiguel, 1973).Similar the original description in the rabbit retina by results have been obtained in the rabbit Haggendal and Malmfors (1963), these cells (Hempel, 1973) in which reserpine also causes a have since been characterized histologically in delay in the overall mixed rod-cone ERG rethe cat (Tork and Stone, 1979; Pourcho, 1982), sponses and attenuates both the amplitude of macaque (Holmgren, 1982; Mariani et al., the ERG b-wave and of the OPs. L-Dopa 1984), and human retina (Frederick et al., 1982; infusion restores these components as well Lindberg and Fisher, 1983; Nguyen-Legros et (Hempel, 1973). al., 1984). te~~ydrop~dine N-methyl phenyl Biochemical investigations using radio(NMPTP), a neurotoxin inducing Parkinsonism labelled dopamine in the cat eyecup have shown in man and monkeys (Bums et al., 1983) also that dopamine is released in response to flashes causes damage to rabbit retina and reduces (Bauer ef al., 1980; Reading, 1983; Hamasaki et retinal dopamine (Wang et al., 1985). This is al., 1986) the amount released being dependent associated with a reduction of the amplitude upon the frequency of stimulation, especially and increase of the implicit time of the darkunder conditions of dark-adaptation (Kramer, adapted b-wave elicited by a white flash. These 1971). These observations suggest that dolatter observations suggest that the ERG is a pamine may be related to the process of adaptauseful technique to study the functional role of tion. retinal dopamine. Some evidence suggests that dopamine may be related to other physiological processes in the INTRODUCTION

*Please address correspondence to: Myles Jay Jaffe, NeuropsyctriatryBranch, WAW MMH, St. Elizabeth’s Hospital, Washington, DC 20032. U.S.A.

Two cohorts of normal males were selected from the resident “normal volunteers” of the NIH clinical center. The 8rst group was used to

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M. J. JAFFEet al.

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evaluate test-retest reliability and the second to test the effects of metoclopramide: all agreed to abstain from caffeine and tobacco for at least 18 hr prior to the onset of testing. Six normal males with a mean age of 23.7 years (f SD 4.2) gave informed consent to participate in the test-retest study. Eligibility criteria included a best corrected visual acuity of 20/20 or better, normal confrontation visual fields, intraocular pressure, slit lamp and fundus ex~ination. One eye was arbitrarily selected for testing throu~out the study. The subjects were always tested in the late afternoon by the same examiner. Seven normal males with a mean age of 22.4 years (*SD I .4) gave informed consent to participate in the metoclopramide study; all eligibility criteria and procedures were the same as those above. Dark-adaptation and electroretinography (ERG) procedures were exactly the same for both groups. Cycloplegia and mydriasis were obtained with 1% tropicamide and 2.5% neosynephrine in the eye to be tested. Darkwith a adaptation was measured Goldmann-Weekers dark-adaptometer. To standardize prior light-exposure and adaptation for every experiment, all subjects were exposed to 387 ft-L for 4min. Rod adaptation thresholds were then continuously measured over the next 30min with the fellow eye patched. Cone thresholds at 0” eccentricity were measured last. For ERG recordings, the cornea was anesthetized with 0.5% of proparacaine. A bipolar B&an-Allen contact lens electrode was then mounted using buffered methyl~ll~o~ for cushioning. A ground electrode was taped to the forehead. The subject sat facing a ganzfeld stimulation system (Gunkel et al., 1976) that

provided homogeneous test flashes and baekground illumination. Flashes of 1Opsec duration were generated with a modified Grass PS22 photostimulator, and calibrated using a Pritchard 1980B photometer. Five flashintensity levels were used (11, 2, 4, 8 and 16) in an ascending staircase sequence. Under conditions of dark-adaptation, responses from both rods and cones could be recorded. Rod responses were elicited with blue flashes using a Wratten filter 47B, whereas responses from the longer-wavelength (red- and green-sensitive) cones were elicited with red flashes using a Wratten filter 26 (Berson et al., 1968). ERG responses from the blue-sensitive cones were elicited with the same blue flashes (filter 47B) presented on a relatively intense yellow-adapting background using a Wratten titer 21, instead of a dark background (Norren and Padmos, 1973; F. M. de Monasterio and M. J. Jaffe, in preparation). This background provided a retinal ill~inan~ of ca 1Cr.l td (6.1 ft-L) for the average pupil size of the subjects (8.5 mm); the subjects were adapted to this background for at least 2 min before responses were elicited. Finally, light-adapted cone responses were elicited on a white adapting background of cu 103s3td; subjects were exposed to this background for at least 1 min before responses were elicited using flashes of white light. White flashes, also delivered serially beginning with the lowest intensity, were used to elicit the oscillatory potentials (OPs) under conditions of d~k-adaption. To record the OPs, the ERG signals (ordinarily filtered betwe(m 1 and 300 Hz) were filtered between 70 and 250 Hz, and the interstimulus delay (ordinarily 3 s) was 30s (Algevere and Westbeck, 1972). The re-

Table 1. Magnitude of changes induced by antecedent light flashes (%-test”) and by metoclopramide (“MTCL”) Amplitude Test Re-test MTCL Rod R-G cone

b-wave a-wave

Blue cone Light-adapted Cone

b-wave

Implicit time Test Re-test MTCL

b-wave

Oscillatory potentials

a-wave b-wave OPl OP2 OP3

Arrows indicate the direction and significance level for the 2-way ANOVA for repeated mcasum comparing baaeIine values with those obtained following the intervzntion. Single arrow = P ~0.01; double arrow =i P < 0.001; triple arrow = P < 0.0001.

ERG and metoclopramide

sponse to the first flash of each intensity was discarded. The first testing session was conducted for all subjects as described above. At its conclusion, every subject rested in ambient light for about ten minutes after which period the entire procedure, starting with the Goldmann-Weekers adaptometer, was begun again. The entire ERG process was then repeated for the test-retest group (about 45 min elapsed between the end of the first ERG series and the beginning of the re-test series.) Prior to this second ERG, those in the drug group received a 2ml i.v. bolus injection of 10 mg of metoclopramide in less than 30 s. A l@min equilibration period was provided before the second ERG series was begun; most subjects experienced transient anxiety during this interval. In practice, the total period of dark-adaptation prior to the second ERG was about 40min for both groups, although the dark-adaptation period for those given metoclopramide was slightly longer. Since the elimination half-life of this drug is between 2.6 and 4.5 hr (Harrington et al., 1983), and since a typical ERG recording required approximately 30 mitt, the entire ERG could be conducted while the drug level remained high.

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The amplitudes of the first three of five OPs recorded in this study showed differences significant at P = 0.0001 or less. The other OPs did not show a significant change. This difference reflected the consistent increase of peak amplitude during the second ERG, strongly suggesting an enhancing effect produced by the first ERG series (rather than simple dispersion of the data). The mean increase in the peak amplitude across all 5 intensity levels used was by a mean factor of 1.16 (&SD 0.03) for OPl, 1.18 (&SD 0.07) for OP2

Data analysis The effects of metoclopramide were evaluated with an analysis of variance for repeated measures and two “within” factors. These factors were the presence of drug and the intensity level of the stimulus. Since the data sets were unbalanced, we used the general linear model procedure for the analysis of variance based on the SAS software package (SAS Institute; Cary, N.C.), with an algorithm using simultaneous comparisons for matched-pairs of data.

RESULTS

Peak amplitude data Test-retest peak amplitudes were not significantly different from one another insofar as a-wave and b-wave responses were concerned, indicating acceptable reliability (Table 1). For the rod b-waves in our sample, amplitude did not increase with the most intense flashes. At the higher intensities, an a-wave developed which decreased the peak amplitude of the b-wave since the b-wave was measured from the baseline (cf. Armington, 1974, pp. 253-255).

Fig. 1. (Top) Oscillatory potentials of the ERG elicited under conditions of dark-adaptation with white &ashes. Waveforms are from a single subject; the ERG was recorded 4 times in two sessions, separated by a period of 4 weeks. Dotted lines tepresent the baseline waveform; solid lines represent the waveform after intervention. (A) Effect of the initial flash series, showing that previous light Bashes increase the amplitude of the oscillatory potentials. Although the amplitude of all 5 OPs appear to be increased in this subject, analysis of variance for all of the subjects reveal that only the enhancement of OPI. OP2 and 0P3 is statistically significant. B: Effect of mctodopramide on the OPS: The drug nqatcs the enhancement of amplitude by the light fiashcs and incraases the &lay of the.responses. Calibration: 35 PV vertically and 8 msec horizontally. (Bottom) ERG response under conditions of dark-adaptation elicited using Wrattan Mar 26 (red) before (dotted line) and after (solid line) i.v. infusion of metoclopmmidc. The drug reduces the ~tin~itudc of the cone u-wave (a) and b-wave (bJ and creasas the implicit time of these nsponscs. The rod component of this rqnxtsc is also attenuated. Calibration: 5OpV v&ically and 2Omsec horizontally

M. J. Jm

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and 1.15 (f SD 0.03) for 0P3. These increases are virtually identical to one another. OP recordings for one subject are shown in Fig. 1 (top). The enhancement was not due to a protracted light-adaptation effect on either rod or cone mediated activity. Sensory rod and cone dark-adapted thresholds measured in 13 subjects before and after the first ERG series showed no obvious differences, indicating a negligible effect of the ERG flashes on sensory thresholds. A similar absence of effect was obtained following metoclopramide infusion in 2 subjects although the cone-rod break became less distinct and appeared to occur slightly earlier than in the control condition. Amplitude vs intensity plots, demonstrating the effects of metoclopramide, are shown in Figs 2 and 3(D). Metoclopramide has a generally attenuating effect on ERG amplitude. Under conditions of dark-adaptation, the rod b-wave

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and the longer-wavelength cone u-wave and b-wave were depressed uniformly across all intensity levels by mean factors of 0.86 ( f SD 0.02), 0.81 (&SD 0.06) and 0.76 (*SD 0.10) respectively [Fig 2(A, B, D)]. Figure 1 (bottom) illustrates the effect of metoclopramide on the longer-wavelength cone responses. The “bluecone” response was attenuated only at the highest intensity tested [Fig. 2(C)], in agreement with a previous report (Jaffe et al., 1985). Under the influence of metoclopramide, the peak amplitudes of the OPs, measured from the previous trough to the peak, were mostly unchanged from the control values, except for a reduction of 0P2 [Fig. 3(D)]. Given our finding of OP enhancement by the antecedent (control) ERG series [Fig. 3(A-C)], however, the overall lack of a significant change of OP amplitude during the second ERG series indicates that metoclopramide reverses this enhancing effect.

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Fig. 2. Peak amplitude vs intensity plots for ERG responses. Graphs in both columns plot peak amplitude bV) against flash intensity (nit-seconds). Symbols represent mean + 1 SD. The baseline response (open square) and the response following the administration of i.v. mctoclopramidc (filled square) arc shown. (A) Metoclopramide (MTCL) effect on rod amplitude. (B) MTCL effect on longer-wavelength RG cone u-wave peak amplitude. (C) MTCL effect on blue cone b-wave pcnk amplitude. (D) MTCL effect on RG cone b-wave peak amplitude. Q MTCL c&t on light-adapted a-wave pa& amplitude of cones. (F) MTCL effect on light-adapted b-wave peak amplitude of cones.

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Fig. 3. Peak amplitude vs intensity plots of the oscillatory potentials. Open symbols represent baseline values (mean + 1 SD) and solid symbols represent values fobwing an intervention. (A), (B), and (C)show the enhancing dTcct of tight b&es alone on the amplitude of OPI, OP2 and 0P3 reap&ively; the amplitude of ali three OPs is enhanced across all intensities. (D) Metoclopramide mverses the enhancing e&t of light Bashes, oP2 is shown.

The amplitude of OP2 decreased by a mean factor of 0.89 ( f SD 0.09), a value which actually represents a decrease by a factor of 0.75 when the enhancement effect of flashes alone is taken into account. Under conditions of light-adaptation, both the u-wave and b-wave peak amplitudes were uniformly attenuated by metoclopramide [Fig. 2(E-F)]. This reduction was by a mean factor of 0.90 (&SD 0.04) for the u-wave, and of 0.96 (f SD 0.02) for the b-wave. In contrast, the typical d-wave of the same cone responses was not significantly altered by metoclopramide. Implicit time data The initial ERG series seemed to have a small effect on the implicit time of the subsequent ERG. The light-adapted b-wave increased by a mean factor of 1.02 ( f SD 0.01) upon retest whereas OPl increased by 1.01 (&SD 0.01). Administration of metoclopramide delayed rod implicit time by a mean factor of 1.02 ( f SD 0.01) [Fig. 4(A)], but did not alter the implicit time of dark-adapted cone responses. Each of the first 3 OPs were delayed by an overall mean factor of 1.02 ( f SD 0.01) [Fig 4(D, E, F)]. The light-adapted u-wave was una&cted whereas

the b-wave was prolonged by a mean factor of 1.03 ( f SD 0.01) [Fig 4(C)]. DISCUSSION

Metoclopramide is a relatively specific antagonist to the dopamine D2 receptor sites, which are not linked to dopamine-sensitive adenylate cyclase (Kebabian and Calne, 1979;Kebabian et al., 1982). D2 binding sites have been found on amacrine cells of rabbit retina (Dubocovich and Weiner, 1981) and on the rod outer segments of bovine retina (Brann and Jelsema, 1985; M. L. Dubocovich, personal communication), where they seem to regulate cyclic-GMP levels within the outer segments in a manner analogous to light (Jelsema et al., 1985). Our results show that antecedent test flashes can modify retinal activity mediating the OPs for periods lasting at least 1 hr. This effect occurs without concomitant changes of dark-adapted sensory thresholds, and is countered by metoclopramide. The enhancement effect we have observed is likely to depend on the use of brief light flashes and may be related to the known release of multiple putative neuro-transmitters in response to such flashes, including dopamine

1698

M. J. JA~FEet al.

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Fig. 4. Implicit time vs intensity plots. Opeu symbols represent baseline values (mean + 1SD), and solid symbols represent values obtained followingMTCL. (A) MTCL delays the rod implicit time. (B) MTCL quickens the blue-cone implicit time. (Statisticaliy significant only at P < 0.05.) (C)MTCL delays the light-adapted cone b-wave. (D), (E) and (F) respectively show MTCL delays the implicit time of OPI, 0P2 and OP3.

(Kramer, 1971; Reading, 1983;Hamasaki er al., 1986). In addition, exposure to light flashes has also been shown to stimulate tyrosine hydroxylase activity and increase the rate of dopamine formation in uivo (Iuvone ef al., 1978). The association between the location of dopamineconning cells and the electrical locus of the OPs coupled with our finding that metoclopramide increases the implicit time of the first 3 OPs, but blocks the flash-mediated increase of their amplitude, suggests that dopamine modulates OP biogenesis in human retina. We have also shown that metoclopramide depresses the peak amplitude of both rod and cone mediated ERG responses. The reduction of the rod b-wave was of almost the same magnitude as that of the cone b-wave, demonstrating a similar influence upon both photoreceptor mechanisms. In addition, this influence was, at least for cone ERG activity, more profound under conditions of dark- than lightadaptation. There is evidence that endogenously released dopamine stimulates the inhibitory (D2) auto-

receptors and that the release of dopa~ne is regulated by a negative feedback mechanism mediated by these receptors @anger et al., 1980). Thus, by blocking the D2 sites, a bolus infusion of metoclopramide can be expected to increase dopamine levels by interrupting this negative feedback loop (cf. Arbilla et al., 1985). Since dopamine could act by binding to other classes of dopamine receptors, such as Dl sites, the ERG changes we have observed might reflect the consequences not only of D2 receptor blockade, but also of elevated dopamine levels. From this perspective, two mechanisms may be possible. If physiological levels of endogenous dopamine were to enhance ERG biogenesis, the binding of metoclopramide to D2 sites would then block this dopamine contribution at both the outer (photor~tor) and inner (amacrine ceii).layers. Such a mechanism is consistent with the effects of r.-dopa on the ERG of the reserpinized cat and rabbit retina (Gutierrez and Spiguel, 1973;Hempell973) and the general enhancement effect of L-dopa infusion on the ERG of patients with Parkinson’s disease (I&e et af., 1987). Conversely, high

ERG and met~lopm~de

levels of dopamine may have the opposite effect, in a manner similar to the dose-dependent, biphasic behavior shown for the effects of muscimol on light-stimulated tyrosint hydroxylase activity in intact rat retina (Marshburn and Iuvone, 1981). This mechanism (which might be mediated by Dl sites) is consistent with the attenuating effects of millimolar dopamine concentrations applied directly to rabbit retina (Starr, 1975). Finally, our results also show that metoclopramide affects both the implicit time and peak amplitude of the oscillatory potentials and the rod ERG (consistent with the dopamine/ ERG studies of Wachtmeister and Dowling, 1978), but only the peak amplitude of the dark-adapted cone ERG. This differential result is somewhat unexpected and implies that metoclopramide causes a localized change in dopamine pharmacokinetics for cones, but a diffuse changes for rods and amacrine cells. There is, however, no neurochemical evidence to support such an effect in response to a systemically administered D2 antagonist. Another explanation may involve the different topographical distribution of rods and cones, since D2 sites have been demonstrated in mammalian ,ptina for amacrine cells and rods, but not yet for cones. The distribution of dopaminergic amacrine cells, presumably the primary source of endogenous retinal dopamine, is similar to that of rods (Mariani et al., 1984). Because both cell types show a peak density at an eccentricity of cu 15”, any increase in the availabi~ty of dopamine from these amacrine cells is well matched by the density distribution of the rod D2 sites. This is not the case for the cones, however, whose peak density is at the fovea1 center. Hence, it is not unreasonable to envision the effect of dopamine on cone pathways as being more localized to the annular region corresponding to the peak density of the dopaminergic amacrine cells, We conclude that both light flashes and metoclopramide affect the human ERG. The observed changes are probably modulated, at least in part, by dopamine, and are more profound under conditions of dark-adaptation. AcknowLxfgeme~r-This manuscript was prepared in partial

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