Effects of MTCL on EOG fast oscillation

MTCL (10 mg)administered researchControl solutionadministered research

A

B

C

A

B

C

A

B

C

A

B

C

A

B

C

Subject 6(20 years)

Subject 9(24 years)

Subject 10(25 years)

A

B

C

Fig. 3. Some samples of FO patterns of 5 female test subjects. The dotted line in each sample shows FO pattern in theright eye and the solid line shows that in the left eye. Control solution: physiological saline. A, phase A: initial 10 min
before intravenous injection; B, phase B: following 10 min after the injection; C, phase C: additional 10 min after the
injection. A dark arrow in each sample indicates the injection point. , dark period; , light period (horizontal axis).

male and female test subjects, respectively. Afteradministration of MTCL, markedly ﬂuctuated FO
patterns were observed in both eyes of each subject in both groups, especially in the female groupin phases B and C after administration, comparedwith their FO patterns in phase A before administration.

Results
Figures 2 and 3 demonstrate some samples of
FO patterns obtained in the MTCL (10 mg)- andcontrol solution-administered researches in the87

N. Miki et al.

Table 1. The dfFO results obtained in the MTCL (10 mg)- and control solution-administered researches in 10 eyes of 5 male healthy volunteers
Subject
Number Age(year)
1

22

2

21

3

23

4

22

5

21

Measured
eye
Right
Left
Right
Left
Right
Left
Right
Left
Right
Left

Mean
SD

MTCL (10 mg)administered research (μV)
Phase A
Phase B
Phase C

Control solutionadministered research (μV)
Phase A
Phase B
Phase C

126.1
116.5
208.4
238.8
123.4
147.6
173.9
165.2
133.9
159.1

170.4
170.4
224.0
253.5
183.0
197.4
172.1
181.0
193.5
175.7

127.0
104.3
396.0
421.0
175.0
169.0
213.7
228.4
185.5
184.8

46.1
46.9
276.4
320.6
120.2
144.8
178.3
218.3
122.6
160.0

49.2
60.9
197.0
257.4
150.2
145.8
158.2
175.7
157.4
190.4

146.3
178.3
171.2
210.8
130.0
161.4
211.3
193.9
167.8
206.1

159.3
39.4

192.1
27.0

220.5
105.7

163.4
89.4

154.2
61.6

177.7
27.8

P < 0.01

Statistical analysis(Wilcoxon’s rank sum test)NSNS

P < 0.01

NS
NS

NS

NS, not signiﬁcant (P > 0.05)

Control solution: physiological saline.
Phase A: initial 10 min before intravenous injection. Phase B: following 10 min after the injection. Phase C: additional 10 min after the injection.
Table 2. The dfFO results obtained in the MTCL (10 mg)- and control solution-administered researches in 10 eyes of 5 female healthy volunteers
Subject
Number Age(year)
6

20

7

19

8

21

9

24

10

25

Measured
eye
Right
Left
Right
Left
Right
Left
Right
Left
Right
Left

Mean
SD
Statistical analysis(Wilcoxon’s rank sum test)
NS, not signiﬁcant (P > 0.05)

MTCL (10 mg)administered research (μV)
Phase A
Phase B
Phase C

Control solutionadministered research (μV)
Phase A
Phase B
Phase C

391.8
453.0
60.4
64.0
156.4
120.6
219.2
189.6
259.0
271.4

1235.51203.5
79.3
61.0
150.0
152.0
267.6
186.2
293.0
522.3

539.7
499.0
100.3
79.0
250.5
266.0
186.2
146.2
274.3
314.0

308.0
345.6
28.4
36.8
110.4
149.8
198.0
188.2
246.6
289.0

269.2
363.4
79.0
58.2
223.0
178.4
137.6
127.8
162.5
261.0

314.8
352.8
86.2
88.4
69.0
99.0
160.8
156.4
193.2
233.8

210.3
130.2

443.8
415.0

265.5
154.5

190.1
109.9

186.0
94.0

175.4
98.8

P < 0.025

NS

NS

NS
NS

P < 0.05
NS

Control solution: physiological saline.
Phase A: initial 10 min before intravenous injection. Phase B: following 10 min after the injection. Phase C: additional 10 min after the injection.

88

Effects of MTCL on EOG fast oscillation

Table 3. Comparison of the dfFO values obtained in the MTCL (10 mg)- and control solution-administered researches in the male and female groups (10 eyes of 5 healthy volunteers each)Research

Statisticalanalysis†

MTCL (10 mg)administered

Mean
SD

Male group (μV)
Phase A
Phase B
Phase C

Female group (μV)
Phase A
Phase B
Phase C

159.3
39.4

210.3
130.2

443.8
415.0

265.5
154.5

NS
190.1
109.9

186.0
94.0

175.4
98.8

192.1
27.0

220.5
105.7
NS
P < 0.05

Control solutionadministered

Mean
SD

163.4
89.4

154.2
61.6

177.7
27.8
NS
NS

NS
† Wilcoxon’s rank sum test: NS, not signiﬁcant (P > 0.05).
Control solution: physiological saline.
Phase A: initial 10 min before intravenous injection. Phase B: following 10 min after the injection. Phase C: additional 10 min after the injection.

higher than that of the 10 eyes of the 5 male test
subjects in phase B (P < 0.05), though no statistically significant differences (P > 0.05) weredetected in the mean level of df FO in phase A orphase C in MTCL (10 mg)-administration (Table
3).

It is of note that a 20-year-old female (Subject6) showed a highly ﬂuctuated FO pattern associated with increased FO potential after administration of MTCL in phase B, though no remarkablechanges were observed in her FO pattern afteradministration of the physiological saline control
solution in phase B (Fig. 3).

Control examination
Main examination

The control examination using physiologicalsaline was performed at least 2 weeks after themain examination. No statistically signiﬁcant differences (P > 0.05) were detected in the mean levels of df FO in either the male or female group in
the comparison of the df FO values in phase A between control solution-administration and MTCL
(10 mg)-administration (Tables 1 and 2), thoughrelatively larger ﬂuctuations in FO potential wereapparently observed in the female sample cases
than in the male ones (Figs. 2 and 3).
After administration of the control solution,
no statistically signiﬁcant differences (P > 0.05)
were detected in the mean level of df FO in either
the male or female group throughout the experiment (Tables 1 and 2), even in the comparison of
the df FO values between the two groups (Table 3).

df FO results obtained in the male and female
groupsAfter administration of MTCL, the meanlevel of df FO significantly increased between
phase A and phase B in the male and female
groups (P < 0.01 and P < 0.025) and between
phase A and phase C in both groups (P < 0.01
and P < 0.05), though no statistically signiﬁcantdifferences (P > 0.05) were detected in the meanlevel of df FO between phase B and phase C in either the male or female group (Tables 1 and 2).
Comparison of dfFO values between the 2 groups
In comparing the df FO values between thetwo groups, the mean level of df FO of the 10 eyesof the 5 female test subjects was significantly
89

N. Miki et al.

It is widely accepted that the retinal neurotransmitter dopamine interacts with two major
types of dopamine receptors: the D1 and D2 dopamine receptors (Kebabian and Calne, 1979). Each
receptor has its own agonists and antagonists (Kebabian and Calne, 1979; Dubocovich and Weiner,
1985; Tran and Dickman, 1992).
In the mammalian retina, the D1 dopamine
receptors are mostly concentrated in the inner
plexiform, the inner nuclear and ganglion cell layers; they are scarcely present in the outer nuclear
layer or the photoreceptor inner and outer segments, while the D2 dopamine receptors are present in the outer retinal layers—the rods, cones
and the retinal pigment epithelium (Dearry andBrunside, 1988; Gallmore and Steinberg, 1990;
Tran and Dickman, 1992).
The D1 dopamine receptors are linked tothe stimulation of adenylate cyclase and increasecAMP, whereas the D2 dopamine receptors arecoupled negatively to adenylate cyclase and decrease cAMP. That is, the D1 and D2 dopamine
receptors are localized differentially in the retina
to mediate different physiologic effects of dopamine (Tran and Dickman, 1992).
Thus it is supposed that a blockade of dopaminergic D2 autoreceptor by MTCL may accelerate the release of endogenous dopamine from theinner retinal layers through negative feedback(Dubocovich and Weiner, 1985; Maruiwa et al.,
1992; Tran and Dickman, 1992). Some endogenous dopamine would reach to the outer retinal
layers by diffusion or through inter-plexiform
cells in the retina (Nguyen-Legros et al., 1989;
Tran and Dickman, 1992), and bring about a hyperpolarized change in the basal membrane of
the retinal pigment epithelium associated withincreased electric resistance of the basal membrane. At the same time, hyperpolaric responseof visual cells to light stimuli suppressed by
MTCL (Maruiwa et al., 1992) would bring about
the decrease of sensitivity of visual cells to lightstimulation, resulting in irregularly ﬂuctuated FO
patterns associated with increased FO potential
and increase of the df FO values in MTCL (10Discussion
In the present study, the measuring time of 30 min
was tentatively divided into 3 phases (A, B and
C) of 10 min each, and the results obtained fromeach phase were compared with one another, tominimize the inﬂuence of SO on FO (Kolder andBrecher, 1965; Kolder, 1974; Nikara et al., 1974;
De Rouck and Kayembe, 1981; Thaler et al., 1982;
Welber, 1989) and to reﬂect on reaction time after
MTCL administration (Schulze-Delrieu, 1979;
Maruiwa et al., 1992).
The ratio of the osmotic pressure from
Primperan injection which was adopted in thepresent survey is approximately 1.0 to physiological saline used as a control solution. Thus it is
difﬁcult to imagine that the osmotic pressure in
the blood might inﬂuence the FO potential (Kawasaki et al., 1977; Dawis et al., 1985; Shirao
et al., 1987). Though the pH of this injection isrelatively low (2.5 to 4.5), it may be presumed
that the pH in the blood would scarcely change
after administration of this agent due to the small
amount in the injection (2 mL) and buffer reaction in the blood, evoking no inﬂuences on the FO
potential as well as in the SO potential (Maruiwa
et al., 1992).
The agent’s permeation into the intraocularportion is unclear, but MTCL passes throughthe blood-brain barrier (Schulze-Delrieu, 1979;
Maruiwa et al., 1992). Thus it is thought that its
permeation into the retinal side may be brought
about through the blood-retinal barrier.
In the present study, the mean value of df FO
signiﬁcantly increased between phase A (the initial 10 min before intravenous injection of 10 mg
of MTCL) and phase B (the 10 min after injection) in the male and female groups (P < 0.01 and
P < 0.025) and between phase A and phase C (theadditional 10 min after injection) in both groups(P < 0.01 and P < 0.05) (Tables 1 and 2). This
indicates that the effects of the dopamine receptor blocker on the FO potential were longer than
expected.
90

Effects of MTCL on EOG fast oscillationmg)-administration in the present survey. However, it is thought that direct erethism by released
endogeneous dopamine is a rare possibility in theretinal pigment epithelium.
Accordingly, it may be presumed that sucha dopaminergic reaction in the outer retinal layers, especially in the retinal pigment epithelium
which was observed in the present FO study, may
be brought about by a direct effect of MTCL on
the D2 dopamine receptors in the retinal pigment
epithelium even in man.
In the main examination, the mean level of
df FO of the female group was signiﬁcantly higher
than that of the male group in phase B (P < 0.05)(Table 3). As a control, the experimental procedure was performed with physiological saline
administration, and no changes were observed.
The data suggest that there exists some difference
between young males and females concerning
sensitivity to dopamine, as previously postulated
by Nakao and others (1994) and that young females may show a higher-than-male sensitivity to
dopamine in the occurrence of the FO potential,
as partly demonstrated in the present study (Figs.
2 and 3).
The reason why a stronger reaction to dopamine is revealed in young females could be
because: i) the physiologic effects of dopamine
which are mediated by speciﬁc receptors on target
neurons are stronger in females; ii) the sensitivity
to dopamine itself is higher in females; and iii)
speciﬁc dopamine receptors in the retina are more
numerous in females than in males.
Further investigation on more test subjects
is needed to clarify the exact reason and mechanisms causing this difference based on sex in theyoung generation concerning sensitivity to dopamine, with special emphasis on the difference insex in much younger or older people, in addition
to in vivo and in vitro animal experiments.

and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, for his generous help.
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Received November 2, 2005; accepted November 17, 2005
Corresponding author: Akihiko Tamai, MD

92