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Ethanol and spinal presynaptic inhibition in man.

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Ethanol and Spinal
Presynaptic Inhibition in Man
P e t e r Ashby, MD, P e t e r L. Carlen, MD,
Stuart MacLeod, MI), and Prakash Sinha, M E n g
-~
Ethanol, 0.65 g m p e r kilogram of body weight, was administered orally to 6 normal subjects. The mean blood ethanol
levels ranged f r o m 0.74 to 0.99 g m p e r liter ovcr a subsequent 40-minute testing period. T h e proportion of t h e soleus
motoneuron pool activated by the Achilles tendon reflex was reduced. Vibratory inhibition of t h e monosynaptic
r d k x was wed as an estimate of 5pind p~esynapicinhibition. I t w a u m a f f ~ ~ t be dy ethanol.
Ashby P, Carlen PL, MacLeoti S, e t al: Ethanol and spinal presynaptic inhibition in man.
Ann Neurol I:-'r78-480,
E t h a n o l has b e e n r e p o r t e d t o increase presynaptic
inhibition i n s o m e [l-51 b u r n o t all [6]studies of t h e
d r u g in experimental animals. T h i s has led to t h e
suggestion [ 4 ]that e t h a n o l may have a similar effcct in
man in Joses p r o d u c i n g intoxication. The present
study examines this hypothesis.
Methods
Studies werc carried out on 6 normal subjects aged 26 t o 34
pears. The subjects were mostly physicians familiar with
experimental procedures and with the effects of alcohol.
Neurophysiological tests were carried out with the subject
prone, using methods described i n detail elsewhere ['I.
Supramaximal electrical stimuli were delivered to the popliteal nerve ro elicit maximal contractions of the soleus
muscle. The developed tensions were measured with a
strain gauge under the foot and recorded on a Grass polygraph. Vibration was applied to the Achilles tendon with a
Wahl Jumbo vibrator (frequency 60 Hz, undamped amplitude 3 to 4 mm) to evoke a tonic vibration reflex ITVR), and
the stimulus was maintained until the developed tension
reached a plateau. This was repeated three times. Surface
electrodes over the soleus inuscle were used to record the
reflex (H-reflex) and direct muscle (M-wave) responses to
electrical stimulation of the popliteal nerve. Stimulus intensities were increased until a complete H-M recruitment
curve could be plotted. At each stimulus level ten responses
were averaged using a PDP 12 computer. Control runs and
runs with vibration were alrernated. After each run with
vibration, 90 seconds were allowed to elapse to avoid prolonged depression of the H-reflex [XI. Finally, the muscle
compound action potential developed from three to five
Achilles tendon reflexes (AL'Rs) were averaged. This was
also repeated three times.
The M-response was assumed ro represent the electrical
activity of 1OOc; of the soleus motor units. The muscle
compound action potential produced by the ATR coulti he
comparcd with this value and the ATR expresseti as a
percentage of the motoneuron pool activated by the la
monosynaptic pathway (ATRIM ratio). The ratio of the
maximal H-reflex during vibration tH vibration) t o the
maximal H-reflex without vibration ( H control) was used to
inciicare the extent of presynaptic inhibirion of the Ia
monosynaptic pathway induced by vibrarion [ 9I.
Ethanol, 0.65 gm per kilogram of body weight, was
administered in a sugar-free cola drink o v e r 1 0 minutes.
Blood ethanol concentrations were estimated at approximately 5-minute intervals using an Omicron Intoxilyzer
(Omicron Systems Corp, Palo Alto, CAI. When the blood
concentrations reached a peak. t h e ncurophysiolog~cal
studies were repeated. The blood ethanol concentrations
observed over this subsequent rest period declined slowly
(remaining within the range associated with impairment)
and were averaged as the "mean blood ethanol" concentration.
Student's r-test was used to determine whether or not any
significant alterations had occurred i n the neurophysiological measurements.
Results
Blood ethanol concentrations rose o v e r 11 t o 32
minutes t o a p e a k of m o r e than 0 . 7 0 gm per liter in all
subjects. M e a n blood concentrations o v e r t h e subs e q u e n t 40-minute test period ranged from 0.74 to
0.09 gm p e r liter (Table). All subjects r e p o r t e d s e v e r e
intoxication, and all d e v e l o p e d nystagmus.
T h e monosynaptic reflex (A'TW'M) was significantly
r e d u c e d ( p < 0.05). T h e HIM ratio was also r e d u c e d
although this did n o t reach statistical significance.
T h e r e was n o consistent alteration i n vibratory inhibition of the monosynaptic reflex (H vibrationIH
c o n t r o l ratio) a n d t h e r e f o r e n o indication that ethanol
From the Division of h-eurology and Clinical Pharmacolog)-,PacAccepted for publication h'ov 1, 1976.
ulry of Medicine, University of Toronto, and Toronto Western
Hospital and *ddiction Research ~ ~ ~ ,T ~ ~~ Ont,
j ~~ ~ Address
i~ ~ reprint
~~ , requests
~ to Dr
~ Carlen,, 33 Russell St, Toronto, Om.
Canada M5S 2S1.
Canada.
478
Changrs ProJziird by Ethanol 10.65 g v d k g )
Age
ATWM (?f 1
Mean Blood
Ethanol
(gm/L)
Before
After
Difference
23.4
52.9
12.5
44.2
6.4
-36.4
14.4
10.9
8.'
3.6
-0.5
4.0
14.7
Subject
(yr)
1
2
26
33
32
0.758
0.7 38
0.8 15
10
28
0.840
0.835
0.990
35.9
18.4
39.7
3
4
5
6
34
36
31.5
Mean
SD
25.0
6.9
0.829
0.089
H Vibration/H
Before
(ci,)
After
Difference
0
9.5
4.8
12.5
8.0
-
11.1
8.1
78.6
42.9
64.0
50.0
17.5
12.5
1.5
- 12.7
3.0
-
14.6
7 .I
-4.7a
5.6
p < 0.05
Significance
9.6
NS
aNegativity indicates a decrease in presynaptic inhibition.
b
o
b
7
\----.-.
0
in these concentrations increases presynaptic inhibition in man (Figure).
Ethanol has no effect on the amplitude of the muscle compound action potential or on the twitch tension produced by supramaximal stimulation of the
motor nerve. A TVR (which probably results from
polysynaptic activation ofmotoneurons) was obtained
in only 2 subjects. It was not reduced following
ethanol.
Discussion
There is no evidence from the present findings to
suggest that ethanol in doses producing intoxication in
man enhances presynapcic inhibition. This differs
from the conclusions based o n animal investigations.
Possible explanations for this difference include the
following.
1. The methods used to measure presynaptic inhibition are different. This type of inhibition has been
attributed to depolarization of afferent therminals by
axoaxonic synapses [lo]. In the studies of ethanol in
animal preparations, the degree of spinal presynaptic
inhibition has usually been estimated either by testing
for primary afferent depolarization or by recording
dorsal root potentials or dorsal root reflexes. These
methods cannot be applied to man. However, inhibition of the monosynaptic reflex by vibration in the cat
is considered to be due to presynaptic inhibition [ I 1,
121, and the inhibition of this reflex by vibration in
man appears to have similar characteristics [9, 131.
Other drugs considered to increase presynaptic inhibition enhance vibratory inhibition of the monosynaptic reflex in man [14, 151.
2. The concentrations of ethanol used in the animal preparations have generally been higher (1 to 4
gm per liter) than those used in the present study
[2-41. Although Laskey and Capek [ 5 ] demonstrated
changes in the dorsal root reflex and in the inhibition
of the monosynaptic reflex by conditioning stimuli
with concentrations (0.5 gm per liter) comparable to
those used in the present study, the effects were
greater with higher concentrations.
3. Ethanol was administered intravenously in
most of the animal studies. Since the alterations in
spinal reflcxes that are observed following ethanol
ingestion probably represent the net effects of the
conflicting or biphasic actions of the drug at several
sites [lbl, the rate of administration may be important. The development of acute tolerance following
oral administration in the present study might account
for the failure to detect changes in presynaptic inhibition.
Ethanol produced a significant reduction in the amplitude of the ankle jerk. As the €3-reflex was also
reduced, this cannot be attributed to depression of
Brief Communication: Ashby et al: Ethanol and Spinal Presynaptic Inhibition in Man
479
spindle excitability. Both facilitation and depression
of tendon reflexes have been noted in previous studies
in man, some of this variability being related to the
subjects’ previous exposure to ethanol [ 171. Depression of the monosynaptic reflex by ethanol has been
observed in the spinalized animal [ 5 , 6 , 18, 171, so this
may be a segmental effect resulting from alterations in
transmitter release [ 2 0 ] or from a direct inhibitory
effect of ethanol o n excitable membranes [6,161. This
reduction in motoneuron excitability could contribute to the clinical features of acute ethanol intoxication.
T h e authors are grateful to Dr E. M. Sellers, Dr D. Zilm, and the
nursing staff of the Clinical Pharmacology Unit of the Addiction
Research Foundarion for their assistance with the studies, and t u
Mrs E. Bailey tor preparing the manuscript. T h e illustration =-as
photographed by the Audiovisual Dcpartmenr of the Toronto
Western Hospital.
References
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