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PHARMACOLOGY

COMPARATIVE

EFFECT

OF AMPHETAMINE

CAFFEINE

ON S P O N T A N E O U S

ACTIVITY

CORTICAL

UNITS

RESPONSES

OF

THE

CAUDATE

AND THEIR

AND
OF

SENSOMOTOR

TO STIMULATION

NUCLEUS

~,. B. A r u s h a n y a n ,
a n d K. G. A i v a z o v

Yu.

A.

Belozertsev,

UDC 612.825.1.014.46':615.214.31

In acute e x p e r i m e n t s on anesthetized cats activity of s e n s o m o t o r c o r t i c a l units was r e c o r d e d


during low-frequency stimulation of the head of the caudate nucleus. Amphetamine (1 mg/kg),
although not significantly affecting the spontaneous firing r a t e , i n c r e a s e d the n u m b e r of spontaneously active c o r t i c a l units. Meanwhile inhibition of these units during stimulation of the
caudate nucleus was weakened. A m p h e t a m i n e had a s t r o n g e r s u p p r e s s i v e action on the inhibition a r i s i n g f r o m the v e n t r o - l a t e r a l portion than f r o m the d o r s o - m e d i a l portion of the head.
In the case of caffeine the location of the stimulating e l e c t r o d e s was unimportant.
KEY WORDS: c e r e b r a l cortex; b a s a l ganglia; drug action.

Arushanyan [1] has postulated that the p s y c h o s t i m u l a n t effect m a y be a c c o m p a n i e d by weakening of


inhibitory control of the caudate nucleus o v e r c o r t i c a l activity. It t h e r e f o r e s e e m e d interesting to c o m p a r e
the effect of d o s e s of a m p h e t a m i n e and caffeine, adequate to produce psychostimulation, on spontaneous
activity of s e n s o m o t o r c o r t i c a l neurons and also on their r e s p o n s e s evoked by stimulation of the caudate
nucleus~
The p r e s e n t investigation is a continuation of o t h e r s s t a r t e d p r e v i o u s l y for the purpose of studying the
c e n t r a l p r o p e r t i e s of p s y c h o s t i m u l a n t s [4, 6].
EXPERIMENTAL

METHOD

E x p e r i m e n t s w e r e c a r r i e d out on 52 unanesthetized c a t s immobilized with muscle relaxants. The


technique of recording unit activity f r o m the s e n s o m o t o r a r e a of the neocortex, of stimulating the b a s a l
ganglia, and of analyzing the r e s u l t s was d e s c r i b e d e a r l i e r [2, 4]. The drugs for testing w e r e injected i n t r a venously at a r e s t r i c t e d speed in o r d e r to avoid fluctuations of a r t e r i a l p r e s s u r e . A wide range of d o s e s
was used (1-5 m g / k g for a m p h e t a m i n e and 10-40 m g / k g for caffeine). According to data in the l i t e r a t u r e
and the r e s u l t s of the w r i t e r s ' e x p e r i m e n t s on cats, the optimal dose of a m p h e t a m i n e giving a definite i n c r e a s e in the various b e h a v i o r a l t e s t s is 1 m g / k g and the analogous dose of caffeine is 15-20 m g / k g . A t tention in this investigation was t h e r e f o r e concentrated on the effect of the above doses.
EXPERIMENTAL

RESULTS

Spontaneous Activity. O v e r 300 neurons in the s e n s o m o t o r c o r e t x mainly in the region of the p o s t e r i o r


sigmoid gyrus were tested: 30 of them w e r e studied in detail before and a f t e r injection of a m p h e t a m i n e and
22 in the e x p e r i m e n t s with caffeine. The r e s u l t s showed that neither drug, in a p s y c h o s t i m u l a n t dose had
a significant effect on the mean spontaneous firing rate r e g a r d l e s s of the location and functional p r o p e r t i e s
D e p a r t m e n t of P h a r m a c o l o g y , Medical Institute, Chita. (Presented by A c a d e m i c i a n of the A c a d e m y of
Medical Sciences of the USSR V. V . Zakusov.) T r a n s l a t e d f r o m Byulleten' ~ k s p e r i m e n t a l ' n o i Biologii i
Meditsiny, Vol. 78, No. 7, pp. 59-62, July, 1974. Original a r t i c l e submitted S e p t e m b e r 28, 1973.
9 1974 Consultants Bureau, a division of Plenum Publishing Corporation, 227 West 17th Street, New York, N. Y. 10011.
No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means,
electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission of the publisher. A
copy of this article is available from the publisher for $15.00.

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Fig. 1. Changes in h i s t o g r a m of consecutive interspike


intervals of spontaneous activity of a s e n s o m o t o r neuron
under the influence of amphetamine. Ordinate, mean numb e r of interspike intervals from five epochs (epoch of analy s i s 2 sec); a b s c i s s a , duration of interspike intervals (in
msec). A) Initial spontaneous activity; B and C) after injection of amphetamine in doses of 1 and 2 mg/kg, r e s p e c tively.
of the neurons. In both c a s e s the rate increased v e r y little (from 14 to 16 s p i k e s / s e c ) , but the difference
was not significant. A statistically significant i n c r e a s e in frequency was observed only when the doses
were doubled.
Analysis of h i s t o g r a m s of the consecutive f i r s t - o r d e r interspike intervals showed no difference b e tween the action of the drugs. With the cumulation of the amphetamine o r caffeine, the evolution of the hist o g r a m s was typical and uniform. With an i n c r e a s e in dose and in the frequency of the spontaneous activity
they all acquired a m o r e a s y m m e t r i c a l f o r m , r e s e m b l i n g the P o i s s o n distribution of intervals (Fig. 1). The
d e c r e a s e in variability of the firing rate of the cells was accompanied by a d e c r e a s e in the number of long
interspike intervals and an i n c r e a s e in the n u m b e r of short.

ao I

20 . . . . . . . . . . . . . .

0
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20 .

/0
0

80

1601 ~0

120 200 280 360 4dO 520

Fig. 2. Effect of amphetamine and caffeine


on poststimulus h i s t o g r a m of s e n s o m o t o r
neurons in response to single stimulation of
the head of the caudate nucleus. Ordinate,
firing rate (spikes/sec); a b s c i s s a , time of
r e c o r d i n g unit activity (in msec). Columns
show mean value of spike activity (for 10
cells in each group) before and after application of a s i n g l e pulse to the caudate nucleus (moment of stimulation m a r k e d by a r row). Obliquely shaded part of column r e p r e s e n t s effect of drug in the case of an inc r e a s e , and c r o s s - h a t c h e d part r e p r e s e n t s
effect in the case of a lowering of the initial firing rate. Broken line shows mean
spontaneous firing rate. A) Effect of a m phetamine, 1 mg/kg; B) after injection of
caffeine, 20 mg/kg.

Meanwhile the psychostimulan~s c l e a r l y i n c r e a s e d


the percentage of spontaneously firing units. Along the
length of one t r a c k through all l a y e r s of the c o r t e x their
n u m b e r increased on the average (data for three tracks) by
40% for amphetamine and by 64 % for caffeine. No p r e dominant effect of the drugs on the cells in any p a r t i c u l a r
c o r t i c a l l a y e r could be detected.
Responses to Stimulation of the Caudate Nucleus. In
most c a s e s the s e n s o m o t o r neurons responded to lowfrequency (2-10/sec) stimulation of the head of the caudate
nucleus by inhibition of spike activity [3, 8, 9]. Single
stimulation (1-2/sec) frequently led Lo a w e l l - m a r k e d
pause, usually a r i s i n g i m m e d i a t e l y after the stimulus and
las~ing 150-200 msec. As analysis of the poststimulus
h i s t o g r a m s shows, amphetamine and caffeine c l e a r l y dep r e s s e d this type of inhibitory response. Suppression not
only of the late but also of the initial phase of the response
was observed. Comparison of the drugs shows that a m phetamine, in full a g r e e m e n t with e a r l i e r observations [4l,
is inferior to caffeine in its ability to disturb the inhibitory
pause in response to stimulation of the caudate nucleus
(Fig. 2). Caffeine also m o r e frequently r e v e r s e s the inhibition into facilitation.
Inhibition of unit activity during repetitive (10/sec)
stimulation of the caudate nucleus also was weakened by
the psychostimulants, and often inhibitory r e s p o n s e s gave
way to facilitatory. When inhibition remained, its intensity,
777

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Fig. 3. Action of caffeine and


a m p h e t a m i n e on inhibition of
s e n s o m o t o r neurons depending
on location of stimulating e l e c trodes in head of caudate nucleus. Ordinate, intensity (in %)
of inhibition (upward columns)
and facilitation (downward c o l umn). Columns on s c h e m e of
frontal section through head of
caudate nucleus indicate change
in intensity of inhibition evoked
by stimulation of different points
of the nucleus (in % of initial level)
under the influence of caffeine, 20
m g / k g (I), and a m p h e t a m i n e , 1 mg/kg
(II). Caffeine c o m p l e t e l y abolished
inhibition f r o m the d o r s o - m e d i a l
portion w h e r e a s a m p h e t a m i n e , a c companied by stimulation of the
v e n t r o - l a t e r a l p a r t s of the nucleus,
led to r e v e r s a l of inhibition into
facilitation. Position of columns
c o r r e s p o n d s to location of e l e c t r o d e s .

as shown by the aggregated data, fell in a s i m i l a r m a n n e r


for both drugs (the index of inhibition fell f r o m 0.47 to 0.11).
A definite relationship was found: the higher the initial value
of the inhibition, the w e a k e r the action of the drugs. By inc r e a s i n g the strength of stimulation it was possible to r e s t o r e
a r e s p o n s e s u p p r e s s e d by the drug. On the whole, caffeine and
a m p h e t a m i n e gave s i m i l a r changes in the ratio between the
n u m b e r s of inhibitory and facilitatory r e s p o n s e s . Whereas
n o r m a l l y the mean n u m b e r of inhibitory r e s p o n s e s was 65 %,
under the influence of the drugs it fell to 40 %. F o r this r e a s o n
stimulation of the caudate nucleus was m o r e often ineffective
(the n u m b e r of c a s e s in which the c e l l s did not respond was
virtually doubled), and m o r e r e s p o n s e s of activation o c c u r r e d
(20% instead of 10%). With an i n c r e a s e in the dose of the drugs
(amphetamine up to 2-3 m g / k g and caffeine to 30-40 mg/kg)
these changes b e c a m e m o r e m a r k e d still.

By the above c r i t e r i a no s h a r p d i f f e r e n c e s could be d e tected in the action o f a m p h e t a m i n e and caffeine, but n e v e r t h e l e s s it was not c o m p l e t e l y identical. The location of the s t i m u lating e l e c t r o d e s in the caudate nucleus is not always u n i m p o r tant for the effect of psychostimulants. Different p a r t s of its
head a r e known to affect m o t o r r e s p o n s e s and activity of s e n s o m o t o r c o r t i c a l neurons differently [5, 7, 10]: inhibition is
evoked m o r e often f r o m the v e n t r o - l a t e r a l region than f r o m
the d o r s o - m e d i a l and it is s t r o n g e r . C o m p a r i s o n of the action
of the d r u g s with r e s p e c t to r e s p o n s e s to stimulation of the
caudate nucleus and the location of the stimulating e l e c t r o d e s
showed that caffeine abolishes r e s p o n s e s to stimulation of all
p a r t s of the nucleus with equal s u c c e s s (Fig. 3). C o n v e r s e l y ,
a m p h e t a m i n e was c h a r a c t e r i z e d by definite selectivity of its
effect. It was f a r m o r e s u c c e s s f u l in s u p p r e s s i n g inhibition
f r o m the v e n t r o - l a t e r a l part. With this location of the s t i m u lating e l e c t r o d e s inhibition was m o r e often c o n v e r t e d into facilitation although the initial intensity of inhibition was 1.5
t i m e s higher than during stimulation of the d o r s o - m e d i a l p a r t
of the head. This tendency for caffeine and a m p h e t a m i n e was
found not only on aggregating the r e s u l t s of s e v e r a l e x p e r i m e n t s but also in a single e x p e r i m e n t using a multiple e l e c t r o d e by m e a n s of which 6 o r 7 points of the c a u date nucleus f r o m above downward could be tested consecutively (at intervals of 0.5-1 m m ) [5].

The d r u g s tested, in p s y c h o s t i m u l a n t doses, thus had a s i m i l a r effect on the spontaneous activity of


the s e n s o m o t o r c o r t i c a l units and produced s i m i l a r changes in m o s t indices of inhibition evoked by s t i m u lation of the caudate nucleus, w h e r e a s they differed in t h e i r effectiveness depending on the origin of the
caudate influences. It can accordingly be postulated, first, that the weakening of the inhibitory m e c h a n i s m s
of the caudate nucleus plays an important role in p h a r m a c o l o g i c a l psychostimulation and, second, that the
d i s t u r b a n c e of c a u d a t e - c o r t i c a l relationships a r i s e s in different ways. Caffeine does this chiefly by d i r e c t
excitation of the cortex, but a m p h e t a m i n e by i n t e r f e r e n c e with the function of the n e o s t r i a t u m . This is conf i r m e d to s o m e extent by the ability shown by caffeine in these e x p e r i m e n t s to weaken inhibition of the c o r tical neurons during stimulation of o t h e r c o r t i c a l s t r u c t u r e s (the l a t e r a l preoptic region, the mesencephalic
r e t i c u l a r formation), w h e r e a s a m p h e t a m i n e does not p o s s e s s this p r o p e r t y .
LITERATURE
1.
2.
3.
4.
5.

E.B.
E.B.
E.B.
E.B.
E.B.

Arushanyan, F a r m a k o l . i Toksikol., No. 4, 481 (1973).


Arushanyan and Yu. A. B e l o z e r t s e v , Byull. ]~ksperim. Biol. i Med., No. 4, 75 (1970).
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Arushanyan and Yu. A. B e l o z e r t s e v , F a r m a k o l . i Toksikol., No. 3, 263 (1971).
Arushanyan, Yu. A. B e l o z e r t s e v , and B. A. Tolpyshev, Zh. Vyssh. Nerv. Deyat., No. 2, 361

(1972).
778

CITED

6.
7.
8.
9.
10.

E . B . Arushanyan, G. V. Stolyarov, and B. A. Tolpyshev, Zh. Nevropat. i Psikhiat., No. 9, 1384 (1970).
E. Grastyan, K. Lissak, and L. Molnar, Acta Physiol. Acad. Sci. Hung., 4, 262 (1953).
C . D . Hull, N. A. Buchwald, and J. Vieth, Brain Res., 6, 12 (1967).
M . R . Klee and H. D. Lux, Electroenceph. Clin. Neurophysiol., 19, 194 (1965).
S . L . Liles and G. D. Davis, J. Neurophysiol., 322, 574 (1969).

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