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The interaction of amphetamine and eserine on the EEG
Vol . 5, pp . 1897-1902, 1966 . Life Sciences Printed in Great Britain.
Pergamon Press Ltd.
THE INIERACfION OF ~TAMtNE AND ESERIt~ ON THE EEG
Charles D. Barnes Department of Anatomy and Physiology, Indiana University Bloomington, Indiana 47401 (Received 7 June 1966 ; in îinal form 18 August 1966) AMPHETAMINE HAS been shown by mite and Boyajy (1) to antagmize the electro-
~eephalographic (EEG) synchronization produced by barbiturates, resulting in desynchronization similar to that observed in alert animals (2,3) .
White and
Daigrsesult's (4) demmstration that midbrain transactions prevent the EEG arousal produced by amp}w;tamine - whereas transaction at the ponto-eesencephalic junction does not - indicates that centers in the posterior part of the midbrain are necessary to prodi.~ce the observed effects . White and Hoyajy (1) have also shams that eserine produces desynchronization of a barbiturate synchronized EEG by exciting subcorticai center .
The
site of action of cholinergic drugs in producing desynchronizatian of the EEG, according to Rinaldi and Himwi~ (5), Sterner and Himwich (6) and I1'yuchenck and Mashkovskü (7), is at the ~sodiencephalic level . Behavioral studies m the interaction of eseri~ and amphetamine indicate that each drug does not potentiate the effects of the other, but rather antagonizes them (8) .
The present study was undertaleen to ascertain whether the
interaction of the two drugs resulted in similar effects an the EEG .
Methods Experiments were performed an 12 female mrngrel dogs and 36 female albino rabbits . Dog experiments :
Dogs were given 20 mg/kg pentobarbital sla+ly I .V .
Needle
electrodes were placed in the frontal and occipital regions of the scalp with the reference electrode in the puma of the ear . 1897
Control recordings were made
1898
Vol . 5, No . 20
DRUGS ON EEG
for 15 minutes after pentobarbital administration before additia~nal drugs weeree injected .
In six of the animals, drugs Were given I .V. in the following
sequence :
ao~hetmmine 2.5 mg/kg, eserine 1 .0 mg/kg ; in the remaining six :
eserine 1 .0 ng/kg, amphetamine 2 .5 mg/kg.
Continuous EEG recordings were made ;
a mininami of 2 minutes was allowed between injections .
The EEG activity was
analyzed for the purpose of oosparison by wanting the nasiber of spites wfiich ezoeeded an arbitrarily selected wltage in each dog per uiit length of record . Rabbit experi.aients :
Rabbits Were anesthetized with 700 ®g/kg urethane plus 15
ag/kg pentobarbital I .P . ; the skull was exposed; and electrodes were scYewed through the bme with their tips located m the dura over the left motor, the left occipital, and the right temporal areas of the cortex .
The electrodes Were
sired to a socloet ; a pedestal was formed a:vuid the electrodes, wires and soclaet vrith methyl methacrylate polymer ; and the wound was then closed aroand the pedestal .
A minims of three weeks was allowed for recovery .
On the day of the
eucperisent a catheter was inserted into the marginal ear vein for the administration of drugs .
In half of the animals, dnigs were given in the following
sealuenoe : pentobaifiital 5 mg/kg, amphetamine 2.5 mg/kg, eserine 0 .2 mK/kg, atropine 2 mg/kg, followed by another injection of atropine 2 eig/kg .
In the
remaining half of the animals the order of the amphetamine and eserine were reversed while the other dnigs retained their previous sequence . EEG recordings were made .
Continuous
A minimmn of 2 minutes was allowed between completion
of the injection of one drug and the beginning of the injection of the next . Initially a 10-minute inter-drug interval was used m three animals .
Inass.~
as the findings With this interval period were the same as those for a 2-aiauite interval and since several of the drugs being used have relatively short EEG effect, the shorter injection interval was chosen for the study. given in 0.9i saline . Polygraph.
All drugs Were
Electmenoephalogrgphic rewrdings were made on a Grass
llpprapriate control§ were nn to äeterndne length of drug EEG effect .
Blood pressure rewrdings were ~oade frog three animals ~i.le drugs were being
DRUGS ON EEG
Vol . 5, No . 20
injected.
1899
No significant correlation was found between changes in blood pres
sure and EEG changes related to dnig injection .
Four additiaial blood pressure
control animals were run in which neostigmine was substituted for eserine, two in the eserine-amphetamine sequence and two in the amphetamine-eserine sequence . In all four of these animals, no change in the EEG similar to that found in eserine was exhibited; however, the blood pressure changes with the neostigmine were similar to those seen with eserine .
Results Dog experiments : barbital alone .
In all animals the EEG pattern was synchronous after pento The subsequent administration of amphetamine or eserine
brought about EEG desynchranizatian.
Restlessness was often abser~ned following
the amphetamine injection but not after the eserine .
N
Pentobarbital
Panloborbilol
+Amphatomina
+ Esarina
After rcoeiving the *hind
+ Esarina
+Mipf»~~mina
FIG. 1 The top series of EEG patterns is from a rabbit which had received in strmssim pentobarbital, amphetamine, and eserine. The halloo series is from a rabbit which had received pentobarbital, eserine, and aphetaoine . About 3 adautes has elapsed between each 1 seared long pattern . Calibration : 50 vV .
1900
DgfTG3 ON EEG
Vol . 5, Ro . 20
drug - whether eserine or amphetamine depending upon which drug had Previously been glum - the EEG tended to shift back towards synchronization .
Even in
those aniaals in which the EEG had seemed to oscillate between synchronization and desynchrauzatian, the mean effect was towards synchronization . Rabbit experiments :
though smaller doses
of pentobarbital and eserine were used can caNrRO~
rabbits than an dogs the EEG results are in general the same .
In each animal,
whether the drug sequence was p~tobarPElROaAMITAL
bital-amphetamine-eserine or pentobarbital -eserine-amphetamine, the EEG pattern was farad to be synchronized by pentobarbital
ESERINE
and desynchraiized by amphetamine or eserine.
The EEG pattern then exhibited
a tendency to shift back towards synchronization (be less desynchronized) with AYPNETAYNiE
administration of the third drug (FIG . 1) . In both dru$ SegUBnce gI'OUpS the first 2 mg/kg dose of atropine would, in
ATROPINE
effect, rescue the synchronizing tendency of the nest recently given drug by causing desynrhronizatim .
The second 2 mg/
kg dose of atropine resulted in a synATROPINE
chronized EEG pattern, often of greater
FIG. 2 A series of EEG patterns from a rabbit showing the effect of drugs injected serially at 3 minute intervals. Order of injectim is from top to bottom. Fach pattern is 1 second tang . Calibration:' 50 yV.
al~plitude than that produced originally by the pentobarbital (FIG . 2) .
Vol .
5, Ro . 20
1901
DRIIGS ON EDG
Discissim Either amphetamine or eserine antagonize the synchronous EEG pattern pro doted by pentobarbital .
However, when both amphetamine and eserine are given,
the antagonism to pentobarbital produced EEG synchronization is reduced froe that of the single drug .
M apparent amphetamine-eserine antagonism is further
demonstrated by the fact that the administration of low doses of atropine, which would counteract the es~erine before the amphetamine due to the lower da~se of eserine (4), to aninaLs having received both drugs results in a reversed shift in the EEG pattern towards the desynchroadzatian which was present during amphetamine of eserine alone . It has been reported by Longo and Silvestrini (3) and I1'yuchenck and Mashkovskhü(7) that eserine and amphetamine act m different cells to produce their characteristic EEG desynchronization . The opposing effects of adrenergic and cholinergic agents applied to same cells in the midbrain have been described by Bradley and Wolstencroft (9) and Courville et al . (10) .
The latter
interpret their data as indicating that the retiailar formatiam east contain two antagonistic ascending systems:
one adrenergic, the other cholinergic.
The present results are interpreted as supporting the concept that eserine and amphetamine act m separate neuronal pools, the activity of either one resulting in antagonism of the EEG synchraiizatian following pentobarbital .
However,
eserine, either directly or indirectly through those cells activated by it, seems to have an inhibitory influence on the a~hetamine activated neuron pool . Likewise, amphetamine exhibits an inhibitory influence an the eserine activated neuron pool .
The existence of such an inhibitory system would help
to explain
such findings as those of Carlton and Didaeb (11) who demonstrated that doses of atropine, which itself produces no effect, markedly augment an increased response rate in an operant, shock-avoidance situation observed after the infection of amphetamine.
1902
Vol . 5, No . 20
DRIIG3 ON EEG
Both eserine and a~hetamine given separately produce desynchronizatirn of the electioencephalographic pattern produced by pentobarbital in dogs and rabbits . The EEG alerting effect of the two dnigs acting simultaneously is less than that of either aie acting singly.
Shall doses of atropine given when both
asQhetamir~e and eserine are acting cause the EEG pattern to rorort to the less synchronous pattern seen after only amphetaaine or eserine . The ascending roticular forsatian may, theroforo, contain separate neuronal pools, one adronoroceptive and one cholinoroceoptive .
The two systess may,
however, inhibit one another either diroctly or indirectly through cells activated by each . Referonoes 1.
R. P. 1YFIITE and L. C. BOYAJY, Proc . Soc. FScp . Biol . Med. 102 , 479 (1959) .
2.
J. ELKS, C. ELIG?S and P. B. BRADLEY, J . Ment . Sci. 100, 125 (1954) .
3.
V. G. LINGO and B. SILVESIRLNI, J. Pharmeaol. F.xp. Ther . 120, 160 (1957) .
4.
R. P. ~iITE and E. A. MIGNEAULT, J. Phareiacol . Exp. Ther. 125, 339 (1959) .
5.
F. RINALDI and H. E . HIMWIaI, Arch . Neurol . Psychiat . 73, 387 (1955) .
6.
W. G. STEINER and H . E. HIMYICH, Science 1 873 (1962) . R. Y. IL'YIJC{~IIX and M. D. MA.9iICWSFCII, Fiziol zh . S.S .S .R . ~ 1352 (1961) .
7. 8.
C. D. BARNES and F. H. MEYERS, Science 144, 1221 (1964) .
9.
P. B . BRADLEY and J. H. IYIXSIINN(:ImFT, Nature 196, 840 (1962) .
10 .
J. OOURVILLE, J. lYAL9-1, and J. P. CORDEfW, Science 138, 973 (1962) .
11 .
P. L . CARTQN and P . DIMbD, J . Pharmacol. Exp. Ther . 134, 91 (1961) .
Pergamon Press Ltd.
THE INIERACfION OF ~TAMtNE AND ESERIt~ ON THE EEG
Charles D. Barnes Department of Anatomy and Physiology, Indiana University Bloomington, Indiana 47401 (Received 7 June 1966 ; in îinal form 18 August 1966) AMPHETAMINE HAS been shown by mite and Boyajy (1) to antagmize the electro-
~eephalographic (EEG) synchronization produced by barbiturates, resulting in desynchronization similar to that observed in alert animals (2,3) .
White and
Daigrsesult's (4) demmstration that midbrain transactions prevent the EEG arousal produced by amp}w;tamine - whereas transaction at the ponto-eesencephalic junction does not - indicates that centers in the posterior part of the midbrain are necessary to prodi.~ce the observed effects . White and Hoyajy (1) have also shams that eserine produces desynchronization of a barbiturate synchronized EEG by exciting subcorticai center .
The
site of action of cholinergic drugs in producing desynchronizatian of the EEG, according to Rinaldi and Himwi~ (5), Sterner and Himwich (6) and I1'yuchenck and Mashkovskü (7), is at the ~sodiencephalic level . Behavioral studies m the interaction of eseri~ and amphetamine indicate that each drug does not potentiate the effects of the other, but rather antagonizes them (8) .
The present study was undertaleen to ascertain whether the
interaction of the two drugs resulted in similar effects an the EEG .
Methods Experiments were performed an 12 female mrngrel dogs and 36 female albino rabbits . Dog experiments :
Dogs were given 20 mg/kg pentobarbital sla+ly I .V .
Needle
electrodes were placed in the frontal and occipital regions of the scalp with the reference electrode in the puma of the ear . 1897
Control recordings were made
1898
Vol . 5, No . 20
DRUGS ON EEG
for 15 minutes after pentobarbital administration before additia~nal drugs weeree injected .
In six of the animals, drugs Were given I .V. in the following
sequence :
ao~hetmmine 2.5 mg/kg, eserine 1 .0 mg/kg ; in the remaining six :
eserine 1 .0 ng/kg, amphetamine 2 .5 mg/kg.
Continuous EEG recordings were made ;
a mininami of 2 minutes was allowed between injections .
The EEG activity was
analyzed for the purpose of oosparison by wanting the nasiber of spites wfiich ezoeeded an arbitrarily selected wltage in each dog per uiit length of record . Rabbit experi.aients :
Rabbits Were anesthetized with 700 ®g/kg urethane plus 15
ag/kg pentobarbital I .P . ; the skull was exposed; and electrodes were scYewed through the bme with their tips located m the dura over the left motor, the left occipital, and the right temporal areas of the cortex .
The electrodes Were
sired to a socloet ; a pedestal was formed a:vuid the electrodes, wires and soclaet vrith methyl methacrylate polymer ; and the wound was then closed aroand the pedestal .
A minims of three weeks was allowed for recovery .
On the day of the
eucperisent a catheter was inserted into the marginal ear vein for the administration of drugs .
In half of the animals, dnigs were given in the following
sealuenoe : pentobaifiital 5 mg/kg, amphetamine 2.5 mg/kg, eserine 0 .2 mK/kg, atropine 2 mg/kg, followed by another injection of atropine 2 eig/kg .
In the
remaining half of the animals the order of the amphetamine and eserine were reversed while the other dnigs retained their previous sequence . EEG recordings were made .
Continuous
A minimmn of 2 minutes was allowed between completion
of the injection of one drug and the beginning of the injection of the next . Initially a 10-minute inter-drug interval was used m three animals .
Inass.~
as the findings With this interval period were the same as those for a 2-aiauite interval and since several of the drugs being used have relatively short EEG effect, the shorter injection interval was chosen for the study. given in 0.9i saline . Polygraph.
All drugs Were
Electmenoephalogrgphic rewrdings were made on a Grass
llpprapriate control§ were nn to äeterndne length of drug EEG effect .
Blood pressure rewrdings were ~oade frog three animals ~i.le drugs were being
DRUGS ON EEG
Vol . 5, No . 20
injected.
1899
No significant correlation was found between changes in blood pres
sure and EEG changes related to dnig injection .
Four additiaial blood pressure
control animals were run in which neostigmine was substituted for eserine, two in the eserine-amphetamine sequence and two in the amphetamine-eserine sequence . In all four of these animals, no change in the EEG similar to that found in eserine was exhibited; however, the blood pressure changes with the neostigmine were similar to those seen with eserine .
Results Dog experiments : barbital alone .
In all animals the EEG pattern was synchronous after pento The subsequent administration of amphetamine or eserine
brought about EEG desynchranizatian.
Restlessness was often abser~ned following
the amphetamine injection but not after the eserine .
N
Pentobarbital
Panloborbilol
+Amphatomina
+ Esarina
After rcoeiving the *hind
+ Esarina
+Mipf»~~mina
FIG. 1 The top series of EEG patterns is from a rabbit which had received in strmssim pentobarbital, amphetamine, and eserine. The halloo series is from a rabbit which had received pentobarbital, eserine, and aphetaoine . About 3 adautes has elapsed between each 1 seared long pattern . Calibration : 50 vV .
1900
DgfTG3 ON EEG
Vol . 5, Ro . 20
drug - whether eserine or amphetamine depending upon which drug had Previously been glum - the EEG tended to shift back towards synchronization .
Even in
those aniaals in which the EEG had seemed to oscillate between synchronization and desynchrauzatian, the mean effect was towards synchronization . Rabbit experiments :
though smaller doses
of pentobarbital and eserine were used can caNrRO~
rabbits than an dogs the EEG results are in general the same .
In each animal,
whether the drug sequence was p~tobarPElROaAMITAL
bital-amphetamine-eserine or pentobarbital -eserine-amphetamine, the EEG pattern was farad to be synchronized by pentobarbital
ESERINE
and desynchraiized by amphetamine or eserine.
The EEG pattern then exhibited
a tendency to shift back towards synchronization (be less desynchronized) with AYPNETAYNiE
administration of the third drug (FIG . 1) . In both dru$ SegUBnce gI'OUpS the first 2 mg/kg dose of atropine would, in
ATROPINE
effect, rescue the synchronizing tendency of the nest recently given drug by causing desynrhronizatim .
The second 2 mg/
kg dose of atropine resulted in a synATROPINE
chronized EEG pattern, often of greater
FIG. 2 A series of EEG patterns from a rabbit showing the effect of drugs injected serially at 3 minute intervals. Order of injectim is from top to bottom. Fach pattern is 1 second tang . Calibration:' 50 yV.
al~plitude than that produced originally by the pentobarbital (FIG . 2) .
Vol .
5, Ro . 20
1901
DRIIGS ON EDG
Discissim Either amphetamine or eserine antagonize the synchronous EEG pattern pro doted by pentobarbital .
However, when both amphetamine and eserine are given,
the antagonism to pentobarbital produced EEG synchronization is reduced froe that of the single drug .
M apparent amphetamine-eserine antagonism is further
demonstrated by the fact that the administration of low doses of atropine, which would counteract the es~erine before the amphetamine due to the lower da~se of eserine (4), to aninaLs having received both drugs results in a reversed shift in the EEG pattern towards the desynchroadzatian which was present during amphetamine of eserine alone . It has been reported by Longo and Silvestrini (3) and I1'yuchenck and Mashkovskhü(7) that eserine and amphetamine act m different cells to produce their characteristic EEG desynchronization . The opposing effects of adrenergic and cholinergic agents applied to same cells in the midbrain have been described by Bradley and Wolstencroft (9) and Courville et al . (10) .
The latter
interpret their data as indicating that the retiailar formatiam east contain two antagonistic ascending systems:
one adrenergic, the other cholinergic.
The present results are interpreted as supporting the concept that eserine and amphetamine act m separate neuronal pools, the activity of either one resulting in antagonism of the EEG synchraiizatian following pentobarbital .
However,
eserine, either directly or indirectly through those cells activated by it, seems to have an inhibitory influence on the a~hetamine activated neuron pool . Likewise, amphetamine exhibits an inhibitory influence an the eserine activated neuron pool .
The existence of such an inhibitory system would help
to explain
such findings as those of Carlton and Didaeb (11) who demonstrated that doses of atropine, which itself produces no effect, markedly augment an increased response rate in an operant, shock-avoidance situation observed after the infection of amphetamine.
1902
Vol . 5, No . 20
DRIIG3 ON EEG
Both eserine and a~hetamine given separately produce desynchronizatirn of the electioencephalographic pattern produced by pentobarbital in dogs and rabbits . The EEG alerting effect of the two dnigs acting simultaneously is less than that of either aie acting singly.
Shall doses of atropine given when both
asQhetamir~e and eserine are acting cause the EEG pattern to rorort to the less synchronous pattern seen after only amphetaaine or eserine . The ascending roticular forsatian may, theroforo, contain separate neuronal pools, one adronoroceptive and one cholinoroceoptive .
The two systess may,
however, inhibit one another either diroctly or indirectly through cells activated by each . Referonoes 1.
R. P. 1YFIITE and L. C. BOYAJY, Proc . Soc. FScp . Biol . Med. 102 , 479 (1959) .
2.
J. ELKS, C. ELIG?S and P. B. BRADLEY, J . Ment . Sci. 100, 125 (1954) .
3.
V. G. LINGO and B. SILVESIRLNI, J. Pharmeaol. F.xp. Ther . 120, 160 (1957) .
4.
R. P. ~iITE and E. A. MIGNEAULT, J. Phareiacol . Exp. Ther. 125, 339 (1959) .
5.
F. RINALDI and H. E . HIMWIaI, Arch . Neurol . Psychiat . 73, 387 (1955) .
6.
W. G. STEINER and H . E. HIMYICH, Science 1 873 (1962) . R. Y. IL'YIJC{~IIX and M. D. MA.9iICWSFCII, Fiziol zh . S.S .S .R . ~ 1352 (1961) .
7. 8.
C. D. BARNES and F. H. MEYERS, Science 144, 1221 (1964) .
9.
P. B . BRADLEY and J. H. IYIXSIINN(:ImFT, Nature 196, 840 (1962) .
10 .
J. OOURVILLE, J. lYAL9-1, and J. P. CORDEfW, Science 138, 973 (1962) .
11 .
P. L . CARTQN and P . DIMbD, J . Pharmacol. Exp. Ther . 134, 91 (1961) .