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Dopaminergic deficiency causes delayed visual evoked potentials in rats.

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Dopaminergic Deficiency Causes Delayed
Visual Evoked Potentials in Rats
Marco Onofrj, MD," and Ivan Bodis-Wollner, MD'J-
Flash and pattern visual evoked potentials (VEPs) to two temporal frequencies of stimulation were studied in
nineteen rats. The effect of a tyrosine hydroxylase inhibitor and of a dopamine receptor blocker on the V E P was
explored in ten animals. Significant latency change occurred following injection of either drug, while only the
hydroxylase inhibitor reduced the V E P amplitude. These changes were not caused by the anesthesia used in these
experiments, although the same qnesthetics in higher doses did depress V E P amplitudes. When dopamine blockade
was followed by administration of apomorphine, a dopamine agonist, V E P delays could be partially reversed. Besides conduction defects of myelinated axons, synaptic malfunction may also cause delays in sensory evoked potentials.
Onofrj M, Bodis-Wollner I: Dopaminergic deficiency causes delayed visual evoked potentials in rats.
Ann Neurol 11:484-490, 1982
The demonstration of delayed visual evoked potentials (VEPs) in patients suffering from multiple
sclerosis 1131 was a major impetus for the use
of evoked potential methodology in clinical
neurophysiology and neurology. Their use has not
been weakened by the fact that in the last several
years, delayed VEPs have been found in diseases
other than multiple sclerosis (for a recent review, see
Horsten [ 15]), and it remained tenable to explain
delayed VEPs as a result of abnormal conduction
time in accordance with a concept first proposed in an
experimental model of central demyelination [20].
However, a simple conduction velocity decrement
due to demyelination cannot explain the long delays
found in clinical conditions [ 191. Furthermore, delayed VEPs were also described in Parkinson disease,
a neurological affliction classically defined not as a
demyelinating disease but rather as a condition associated with neurotransmitter deficiency [4]. Moreover, administration of dopamine precursors restored normal VEP latency in parkinsonian patients
[4, lla], and drugs with dopaminergic blocking
properties have delayed VEPs in some schizophrenic
patients [5].
We report studies in a group of rats whose VEPs,
obtained with flash and pattern-reversal stimulation,
were delayed by two different kinds of drugs: (1)
those which act predominantly as inhibitors of
monoamine synthesis, and (2) those which predominantly block dopamine receptors. O u r studies
confirm the data of Dyer et a1 [ 7 ] ,who used flash
stimuli. Furthermore, we extend the relevance of
these rat studies to human visual physiology by using
patterned stimuli, and also by using both agonist and
antagonist manipulations of dopamine receptors. The
VEP effects of neuropharmacological manipulations
establish new concepts in the understanding of latency changes found in human VEPs, affirming conclusions reached in clinical studies.
From the Departments of "Neurology and +Ophthalmology,
Mount Sinai School of Medicine, One Gustave L. Levy PI, New
York, NY 10029.
Recewed July 6, 1981, and in revised form Sept 28. Accepted for
publication Oct 3, 1981.
Nineteen male hooded rats, weighing from 200 to 300 gm,
were maintained in standard laboratory conditions. Preliminary studies were conducted to determine optimal recording sites and to standardize recording techniques. Experiments were conducted in a room specifically designed
for behavioral studies in rats, where temperature remained
at a level of 20" to 22°C. T h e rats' rectal temperature (37"
5 0.2%) was constantly monitored. T h e animals were
placed in a stereotaxic apparatus following pentobarbital
anesthesia ( 3 5 mg/kg) and local anesthesia (1%) xylocaine) of
the cutaneous areas to be subjected to minor experimental
trauma. Silver screw active electrodes (2 mm in diameter)
were placed over area 17 [17], and reference electrodes
were affixed behind the bregma and in some animals were
also inserted into the nasal bone. Experiments were conducted five to seven days after electrode placement. In all
animal studies, electroencephalograms (EEGs) were inspected visually throughout the duration of the experiment, and stimulation was performed only in animals with
open eyes and showing waking EEG patterns [12].
Address reprint requests to Dr Bodis-Wollner, 1200 Fifth Ave,
New York, NY 10029.
484 0364-5134/82/050484-07$01.25@ 1982 by the American Neurological Association
Flash stimuli (350 lux L26al) were delivered at a rate of 2
(transient) and 10 (steady-state) flashes per second by a
Grass photostimulator placed 60 cm from the rat’s eye. The
latter frequency yields an easily definable quasisinusoidal
response without much of the harmonic distortion evident
at lower frequencies of stimulation [22]. Square-wave
gratings of 90% contrast were projected on a screen subtending 120 x 120 degrees at the rat’s eye, and pattern
reversal was effected with a Digitimer stimulator. The selected spatial frequency of the grating was based on the
rat’s maximal contrast sensitivity [2] and on control experiments to be described.
Responses were recorded to 2 reversals per second and,
in most but not all rats, to 10 reversals per second. In addition, several other temporal frequencies were explored in
individual rats. T h e electrophysiological signals were amplified by Grass 5P5 preamplifiers with filter bandpasses
set at 0.13 to 100 Hz. Sixty-four responses to flash stimuli
and 256 responses to pattern-reversal stimuli were summed by a Dagan 5000 averager with 0.2 msec data point
resolution. The averager activated a Plotamatic 7 15M MFE
plotter. Pattern-reversal VEPs had waveforms similar to
those described by Meyer and Salinsky [21]. The components of transient responses that showed maximal stability
of latency in preliminary recordings were: for flashes, an
early positivity (P - mean latency 2 1 standard deviation
of the mean, 45.3 & 2.4 msec) and a negative component
(N - mean latency, 65.1 & 2.8 msec); and for patterns, a
positive component of 85.5 ? 4.7 msec mean latency. For
the steady-state responses, only relative phase shifts caused
by the different experimental conditions were measured.
The phase shift of the quasisinusoidal responses was converted into apparent latency following a method fully described by Regan et al [23]. In essence, apparent latency is
the result of the following calculation: 1/360 multiplied by
the phase of the steady-state VEP and divided by the frequency of stimulation. The product of this operation expresses latencies in seconds, which can then be converted
into milliseconds. Several assumptions are needed in the
application of this method to reveal time delays; for our
study the method has empirical value, and we make no
claim concerning the linearity of the system in question.
There were several control experiments.
First, the reliability of the pattern-reversal VEP was assessed by establishing the effects of refraction, following a
method fully described by Berkley and Watkins [I] who
studied cat VEPs. In our experiments, refraction of the rat’s
e y e was performed with cylindrical lenses of +0.25, +2,
+ 4 , and -2 diopters. Second, we varied the spatial frequency of the pattern in small steps from 0.1 to 0.3 cycle
per degree. To avoid blurring of the pattern, cycloplegic
agents were not used in any of our experiments. Therefore,
to assess the possible influence of changes in pupil diameter, two additional experimehts were performed in each rat
in order to evaluate the effect of retinal luminance on the
VEP latency: the flash intensity was reduced from 350 to
16 lux in several steps, and the background illumination
around the stimulating set was increased by 200 lux behind
the flash stimulator, thus reducing the luminance contrast.
In addition, even though previous studies had shown that
latencies of the early components of flash VEPs in rats are
not affected by moderate anesthesia [8, 22, 241, we directly
assessed the effect of sedation on VEPs by repeated iiljections of pentobarbital at a dosage of 35 mglkg, which was
standard in our experiments. As a control, in four rats only
a saline solution was injected.
Following a preliminary EEG recording, VEPs were measured in ten rats
30 to 40 minutes after anesthesia and drug injection. Alphamethylparatyrosine (AMT, a tyrosine hydroxylase inhibitor), 250 mglkg, was administered intraperitoneally in
five rats, and haloperidol (predominantly a dopamine receptor blocker), 3 mglkg, was injected intraperitoneally in
five other rats. In two of these animals, an apomorphine
solution (0.25 mg/kg) was administered 120 minutes after
completion of the haloperidol experiment. Apomorphine
is predominantly a postsynaptic receptor agonist, though it
is also thought to stimulate the presynaptic dopaminergic
terminal. VEPs were recorded from the time the drug was
injected to twice the time of the maximal acute behavioral
response [3, 10, 271. When needed, a supplementary dose
of 35 mglkg of pentobarbital was administered 60 minutes
after A M T injection.
Control Experiments
The refraction of the rat’s eye influenced the
amplitudes but not latencies of the VEP. Both transient and steady-state VEP amplitudes were larger
with refraction. The best result was obtained with + 2
diopter lenses; only smaller increases were achieved
when other lenses were used. With increasing spatial
frequency of the stimulus gratings (from 0.1 to 0.3
cycles per degree), the latency of the positive component increased by 9.13 + 2.37 msec.
A tenfold reduction of flash contrast (achieved by
increasing background illumination) reduced the
amplitude of the flash VEP by a factor of 2 without
changing the latency. A reduction of the flash intensity itself from 350 to 16 lux increased the latedcy of
the P component by 7.71 5 1.9 msec and that of the
N component by 10.5 2 2.3 msec.
A single 35 mg/kg injection of pentobarbital depressed the evoked potential amplitude so that only
the early positive and early negative components of
the flash VEP were recognizable 10 minutes later.
Their amplitude was reduced by a factor of 4 , but
latencies were unchanged compared to those measured in the unanesthetized condition. Fifteen to 20
minutes after injection of the drug the VEP
amplitude began to recover, reaching preanesthetic
levels 30 to 40 minutes later for both pattern and
flash VEPs (Fig 1). At this point, animals were sedated and quiet but responded with blinks and had a
startle reaction to saline eye drops.
Onofrj and Bodis-Wollner: Dopamine and Delayed VEPs in Rats
Fig I . Flash (empty circle) and pattern (striped box) VEPs
recorded in a rat at different times (indicated i n minutes) following injection of 35 mglkg of pentobarbital. Vertical calibration bar corresponds t o 10 pV for traces recorded IS minutes after injection and to 50 pV for the other traces. Two
stimuli per second were delivered. Note that the latency of the
major positive wave (downward defection) is constant.
related to different mechanisms of action of the two
drugs. T,, also depended on the kind of stimulation
used, i.e., flash or pattern, or steady-state and transient stimuli.
Injection of AMT produced a maximum VEP
delay in around 226 40 minutes for the P and N
components of the flash VEP, around 170 ? 40 minutes for the P component of the pattern VEP, and
180 k 40 minutes for steady-state VEPs. The delay
caused by haloperidol was at its maximum in 5 5 k 12
minutes for the P and N components of the flash
VEP, 49 k 11minutes for the pattern VEP, and 46
9.5 minutes for the steady-state VEP, although there
was some variation between curves of different rats.
This may have been caused by differences in drug
Neuropharmacologicul Experiments
Both AMT and haloperidol had marked effects on
the latencies of the reliable VEP components in all
conditions studied; i.e., evoked potentials to both
flash and pattern and to both transient and steadystate stimulation were affected. Figure 2 presents
VEP traces showing the progressive effect of AMT
and of haloperidol. In Figure 3, the VEP latencies in
all rats tested in an untreated condition are compared
to the latencies of treated rats measured at the time
of the maximum effect (T,,,) of the drug. T,,, depended on the kind of drug used and was most likely
F i g 2. (A) VEP traces obtained using either $ash stimuli
(empty circle) or square-wave gratings at 90% contrast
(striped box) i n a rat treated w i t h 250 mglkg of alphamethylparat~rosine(AMT). Numbers beside each VEP
trace represent minutes elapsed from intraperitoneal injection of
drug to the time the trace was recorded. Bottom traces were obtained usidg 10 Hz.fEash stimulation. Note the progressive
delay evident from top to bottom. ( B ) VEPs tofash (empty
circle) and to pattern reversal (striped box) in a rat treated
with 3 mglkg of haloperidol. Traces in the upper right quadrant of the figure represent responses t o 10 H z pattern reversal
and show progressivephase change as a function of time (minutes) following haloperidol injection.
50 msec
50 msec
n o
100 ms4c
50 msec
50 msec
486 Annals of Neurology Vol 11 No 5 May 1982
50 msec
0 ..... P PATTERN
P 85.5Z4.75
F i g 3. Comparison of latencies of the PI and N z components
@ash: large empty circle)and P component (pattern reversal:
striped box) in nineteen untreated rats and in ten rats treated
with either A M T (causing dopamine depletion) or haloperidol
(causing dopaminergic blockade). The mean and standard deviation of control VEP latencies are indicated next t o the individual symbols.
In all the treated rats, a graph of delay versus time
showed a well-defined T,, on a semilog plot. Figure
4 shows a semilog plot of the mean VEP delays recorded in four rats (two treated with AMT, two with
haloperidol) whose latency change versus time curves
needed no horizontal alignment (i.e., in these rats absolute T,, was nearly equal). Given Tmax,one can
see that the VEP delay began at a time corresponding approximately to a third to one-half of T,,,. The
Table presents delays of the major VEP components
following drug administration, expressed on a scale
of fractions of the T,,,. The different T,, and latency values reported in the Table show that, with
either drug, transient pattern stimulation was more
sensitive than steady-state o r transient flash stimulation: VEP delays and, correspondingly, the delay versus time curves (Fig 4) take off earliest with transient
pattern stimulation. The negative component of the
transient flash VEP was more delayed than the positive component. The phase shift of the steady-state
VEP (converted into latency [ 2 3 ] ) also appeared
sooner and “saturated” earlier than that of the transient flash VEP, i.e., the delay versus time curve is
steeper and is shifted to the left. The maximum VEP
delay (T,,, latency) was still recordable 10 hours
after injection of AMT in one rat and after injection
of haloperidol in two others. At the dosages used in
these experiments, AMT reduced the VEP amplitude
to one-fourth of its pretreatment value in most animals (see Fig 2). In fact, in two animals AMT de-
40 60
F i g 4. Plot showing the VEP delay induced by haloperidol and
AMT as a function of time elapsed from injection. Latency
changes measuredfor the P and N components of thejash
stimulus, for P of the pattern stimulus, and of the phase (4)of
the steady-state VEP are separately plotted. Phase has been
converted to apparent latency as explained in Methods. Note
that the delay differs for the various components and modalities
of the VEP. Data in this figure represent the mean values obtained in two rats following haloperidol and in two other rats
following A M T treatment. The time of maximum effect (Tmax)
is very different for the two drugs and somewhat different for
the various VEP “components.”
pressed the amplitude of the pattern VEP to such an
extent that the components of the response were unrecognizable. Apomorphine, a drug with predominant dopamine receptor agonist action, at 0.250
mg/kg corrected 70% of the delay caused by
haloperidol in 12 to 30 minutes (Fig 5).
Comparison of Pharmacological a n d Control Experiments
The precise delay of the P component attributed to
administration of these drugs was compared to the
results of control experiments for the following reasons. Although by inspection of the rat eye we could
not detect such changes, assume nevertheless that the
drugs used did reduce pupil size and affect the VEP
because of diminished retinal illumination. A 4-fold
reduction of pupil diameter would be equivalent to a
16-fold decrease in luminance. A two-tailed Student t
test was used for comparison between the “delay” of
P and N obtained when the luminance of the flash
stimulator was reduced by a factor of 2 2 (see results
of the control experiments) and the delay of P and N
due to AMT or haloperidol (see the Table). The latter caused the larger delay, and the difference was
statistically significant (p < 0.01). Assume that the
drugs induced corneal clouding, which may decrease
Onofrj and Bodis-Wollner: Dopamine and Delayed VEPs in Rats 487
50 rnsec
F i g 5. VEP truces shozcr progressiw delay of the trunsient VEP
t o j a s h stimuli follouing haloperidof injection and partial
correction of this delay following apomorphine injection.
Numbers beside the truce3 represent time tin minutes) elupsed
from injection of the drug.
sensitivity to high and also somewhat to low spatial
frequencies [14]. The stimulus we used was a 0.1
cycle per degree square-wave grating which also
contains the third harmonic at 0.3 cycle per degree.
The latency of the P component of the pattern
evoked potential to 0.3 cycle per degree stimulation
was significantly (p < 0.01) different from the P latency at Tm,, of both AMT- and haloperidol-treated
rats. Thus, none of the VEP delays obtained with
manipulation of luminance or increase of spatial frequency of the stimulus were comparable t o the delays
observed following dopamine depletion or blockade.
Our major aim in these studies was to assess
monoaminergic effects on VEPs in the rat. We concentrated on patterns as stimuli, since patterns are
predominantly used for measuring human VEPs and
have been applied with success in electrophysiological studies to reveal functional properties of single
neurons at different levels of the mammalian visual
pathway. We found that: (1) catecholaminergic depletion significantly delays the pattern VEP, and the
delay can be measured for each of the major, statistically reliable components for both flash and pattern
VEPs of the rat; (2) blockade of dopamine receptors
affects VEP latency more than VEP amplitude (see
Figs 2, 5 ) ; (3) the precise magnitude of the change in
VEP latency depends on stimulus conditions such as
flash versus pattern stimulation and transient versus
steady-state response; and finally ( 4 ) VEP delays can
be corrected by apomorphine, a drug with predominant dopamine agonist action. Each of the drugs
used in these experiments has actions on other
monoamines besides dopamine; however, the common link among the three drugs is their predominant
action on dopaminergic neural transmission. Thus
one can be reasonably sure (although not absolutely
certain) that the VEP changes under the influence of
each of these drugs were caused by dopaminergic
We did not use cycloplegics since we wished to
study pattern VEPs. One may argue that all the observed effects could be caused by the following
mechanism, unrelated to the afferent visual pathways. VEP latency correlates inversely with retinal
luminance. If the pupil constricts, it allows less light
to reach the retina. Thus, if the drugs used in these
experiments induced pupillary constriction through
some as yet unidentified mechanism, the VEP delays
could be explained as a result of reduced luminance.
We did not notice any pupillary constriction, and the
observed VEP delays cannot be accounted for by
simple reduction of the luminance on the retina for
other reasons either. For one, as already noted, an
increase in total luminance with concomitant reduction of the flash contrast did not affect the VEP latency. Second, as we have shown, the magnitude of
the VEP latency changes caused by dopamine deple-
Atlevage Latency Change ufter Administration of Haloperidol or Alphamethylparatyrosine in Five Rats
Each for Various Stimulus Conditions and Componentsa
N Component
(Flash VEP)
P Component
(Flash VEP)
. ..
12.8 I
15.5 2 4.7
11.6 & 2.3
14.6 2 4.7
12.5 I
18.6 t- 6.3
P Component
(Pattern VEP)
0.6 i 0.9
Apparent Latency
1.4 t 1.7
5.6 2 0.9
13.6 t 3.7
20.2 t 4.8
18.4 t 4.2
20.6 2 4.4
20.6 i 4.1
25.0 t- 4.5
10.0 2 1.6
13.9 I
10.8 2 1.6
16.0 t 4.5
aDelays, which are expressed in milliseconds, are related to the time of maximum effect (Tmx) and to fractions of it. T,,, ranged from 35 to 70 minutes for
haloperidol and from 150 to 240 minutes for AMT. I t is apparent that there was progressive rather than sudden VEP change following administration of either
drug. Haloperidol dosage, 3 mg/kg; A M T , 250 mglkg.
488 Annals of Neurology
Vol 11 No 5
May 1982
tion or blockade was such that an overall luminance
reduction greater than 22-fold would have been
needed to match these. Thus our studies make it very
unlikely that pupillary change rather than interference with neural transmission along the visual pathway could explain the observed VEP delays.
By a statistical comparison of pooled group data,
Dyer et a1 [7] first demonstrated delays in the flash
VEP of rats treated with AMT and haloperidol, and
suggested that dopamine rather than norepinephrine
is responsible for these changes. However, adrenergic mechanisms of evoked potential generation must
also be considered. Delayed brainstem acoustic
evoked responses were recorded in rats following
phentolamine or propranolol blockade of neuronal
utilization of glucose, suggesting in fact that adrenergic blockade may play a role in delaying those evoked
potentials [ 113. Our data on VEP changes caused by
hdoperidol and VEP latency restored by apomorphine correction strongly suggest that one may attribute VEP delays to dopamine deficiency and not to
adrenolytic effects. Nonetheless, the reducrion of
VEP amplitude observed after AMT but not after
haloperidol administration may be dependent on additional adrenergic effects. This could be due to reduction of the number of discharging neurons as a
result of the blockade of glucose utilization [ l l l .
The most conservative explanation for VEP delays
caused by dopaminergic blockade or deficiency
points to the retina for two reasons. Dyer et a1 171
found no delays in the cortical VEPs obtained
through direct optic nerve stimulation in dopaminedepleted rats. Furthermore, the point of maximal
dopamine activity in the visual system is the inner
nuclear layer of the retina, where dopaminergic
neurons would be well placed to participate in lateral
interactions and feedback loops [ 181. Retinal
dopamine-containing neurons are considered a type
of amacrine cell [9]. Werblin [28] has suggested that
amacrine cells of the Necturzls, in general, have the
function of converting graded potentials of ganglion
cells. Whether or not amacrine cells have similar
functions irrespective of the specific transmitter involved is not known, but partial degradation of amacrine cell activity due to dopamine depletion could
modify the timing of ganglion cell responsiveness.
Dyer et a1 [7] hypothesized that “if dopamine depletion alters the timing of ganglion cell responses it
would alter the ability to resolve rapidly flickering
light.” Our finding that steady-state VEPs are especially sensitive to dopamine depletion or blockade is
consistent with this suggestion.
Of particular importance is our finding that a delay
produced by dopamine depletion or blockade is
more evident for contrast-dependent stimuli (pattern
VEP) than for flashes, and for high-frequency repeti-
tive stimuli (steady-state VEPs) than for low temporal
frequencies. This is noteworthy for the following reason. Current data demonstrate the presence of both
X and Y ganglion cell classes in the retina not only of
monkeys and cats, but also of rats [16]. Electrophysiological studies of cat retinal ganglion cells
[25] reveal that the response of Y cells speeds up
more than that of X cells when contrast is increased.
It was inferred that a “contrast gain control born in
the inner plexiform layer” affected changes in latency
and in dynamics of the responses of X and Y cells to
square-wave contrast reversal of sine gratings. For
this contrast gain control, which affected temporal
properties and latencies of ganglion cell responses to
grating stimuli, “a common retinal locus among the
amacrine cells” [26] was postulated. An impaired
contrast gain control exercised by amacrine cells may
be one reason why the VEP in dopamine-deficient
rats and humans [4-61 is especially sensitive when
contrast stimuli are used. However, despite the
similarity of the human and rat data, the relationship
of VEP delays and retinal functions and of rat and
human data in general need further studies.
Nevertheless, these data in rats, combined with
studies in humans [5], imply a not negligible role for
dopamine in maintaining normal VEP latency, and
suggest that sensory evoked potential methods may
be useful if applied to neuropharmacological assessment of neurotransmitter deficiency syndromes.
These findings also imply that VEP latency changes
may not necessarily be due to impaired conduction
velocity, but could be dependent on synaptic malfunction. McDonald [ 191 noted that delays similar to
those commonly seen in multiple sclerosis and optic
neuritis “have not been observed across focal experimental demyelinating lesions,” and hypothesized
that factors other than conduction time contribute to
the delay. Our studies emphasize the importance of
considering synaptic mechanisms as vital links in the
generation of VEPs.
Supported in part by Grant EY01708 from the National Eye Institute, Core Center Grant EY01867 from the National Institutes
of Health, Grant NS11631 from the Clinical Center for Research
in Parkinson’s and Allied Diseases, and Grant RR-0007 1 from the
Division of Research Resources, General Clinical Research Center
Branch, National Institutes of Health.
We thank Drs Bernard Cohen, Gerald Cohen, William Merrigan,
and Pedro Pasik for their constructive comments on the manuscript, and Miss Caroline h a k e , who typed, helped edit, and prepared the illustrations for this article.
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