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The effect of antidepressant drugs on the convulsive excitability of brain structures
ht. 1. Neurophannacol..
1964,3, 605-609
THE EFFECT CONVULSIVE
Pergamon
Press.
Printed in tit. Britain.
13 tigs., IO refs.J
OF ANTIDEPRESSANT DRUGS ON THE EXCITABILITY OF BRAIN STRUCTURES G. STILLEand A. SAYERS
Research Institute, Dr. A. Wander S.A., Berne, Switzerland Snrnmary-The effects of antidepressant drugs on the convulsive excitability of the cortex, thalamus and hippocampus were investigated electro-encephalographically in rabbits. Imipramine, Noveril, amitriptyline and desmethylamitriptyline suppress the excitability of the cortex as opposed to the desmethyl-derivatives of imipramine and Noveril. Toxic doses of antidepressants lead to limbic convulsions. INTRODUCTION THE well
known representatives of antidepressant drugs, imipramine and amitriptyline have a distinct effect in electroshock experiments. According to FROMMEL and FLEURY (1959), 50 mg/kg imipramine se. shorten the duration of the tonic extensor phase and coma following electroshock in guinea pigs. IO-30 mg/kg imipramine S.C.administered to mice also inhibit the extensor component of the maximal electroshock seizure (SIGG, 1959). PIETTE et a/. (1963) observed a marked elevation of the electroshock threshold in rabbits following administration of imipramine but not after desmethylimipramine. Corresponding effects of amitriptyline on the electroshock have been described by VERNIER (1961) and BESENDORF et al. (1962).
The usual method of carrying out electroshock experim~xlts (for example, with cornea1 electrodes) is a very rough procedure, and does not permit the localisation of the site of action of anticonvulsant compounds in the brain. We have therefore investigated the effect of compounds used in the treatment of depressions on the electrographical seizure activity arising when various brain centres are electrically stimulated. MONNIER and KRUPP (1959) have already reported that imipramine reduces the excitability of the cortex and diencephalon. METHODS
On stimulating certain parts of the brain with an increasing voltage a threshold value is reached at which spike potentials are discharged, lasting beyond the end of stimulation, and often appearing during the stimuIation itself (afterdischarge threshold). A number of compounds used in the treatment of depression were investigated in regard to their effect on the afterdischarge threshold of the cortex, thalamus and hippocampus. The stereotaxic method as described in detail by MONNIER and GANGLOFF (1961) was used on unanaesthetized rabbits. A Grass stimulator S 4 C in conjunction with an isolation unit supplied a stimulus with an impulse frequency of 40 c/s and an impulse duration of 3 msec, the voltage being increased until an afterdischarge was obtained. The electrical brain activity was recorded from the sensory-motor and visual cortices with silver screws and from the N. caudatus, hippocampus dorsalis, thalamus medialis, and formatio reticularis with platinum needles. 605
606
G.
STLLE
and A.
SAYERS
The following compounds were examined : imipramine (Tofranila), desmethylimipramine (Pertofrans), amitriptyline (Laroxyl”. Tryptizol@), desmethylamitriptyline (Nortriptyline, Aventyl~g), trimepropimine (Surmontila), chlorprothixene (Taractan”) and a new antidepressive, developed in our laboratories, HF-1927 (Noveril@) together with its desmethyl product (HF-2132). Single doses of 20 mg:kg were adninistered S.C. RESULTS
None of the compounds investigated showed any significant effect on the convulsive excitability of the thalamus and hippocampus”. Trimepropimine, thioridazine, chlorprothixene and levomepromazine, as well as desmethylimipramine and desmethyl-Noveril also had no effect on the afterdischarge threshold of the cortex. On the other hand imipramine, Noveril, amitriptyline and desmethylamitriptyline led to an increase of the cortical afterdischarge threshold of more than 100 per cent. The effects of various compounds (average values) are presented together with the confidence limits (p=O .OS) in Fig. 1. Vo!t’
?Smglkg
20 mglkg Dasmathyllmlpramme
20mglkg Dasmathyl-Novarll
Novaril (HF 1927) SC
~c.
(HF2132) SC
“’
6
_._.-.m.
I_
2
--I
1
/
/
1
I
I
-1
0
1
2
3
r,
5
I
4
-1
0
/
1
2
/
3
1
5 hr
FIG. 1. Behaviour of cortical afterdischarge threshold in rabbits in the course of 5 hr after subcutaneous injection of imipramine, desmethylimipramine, Noveril, desmethylnoveril, amitriptyline and desmethylamitriptyline. Abscissa in hr; Ordinate in Vs. (Thin lines represent the confidence limits p=O.O5). *Since this paper was submitted for publication a significant inhibition of hippocampus excitability has been demonstrated following 40 mg/kg Noveril S.C.
Antidepressant
FR sm
607
drugs on the brain convulsive excitability
----~.L+-v--~~
-..---
4.4-
I
EMG 60 set TiST LOHz.3mwc. 6V
120 set
184set
iSCX -mJJY
Cm dexter -----+vvyk&fB~~
1
xiiLOHz.3msec
12V
FIG. 2. Spike activity in the EEG after stimulation of the cortex in unanaesthetized rabbits. At the top before treatment and at the bottom after treatment with 20 mg/kg Noveril SC. Cs==Cortex sensitivus Cm=Cortex motoricus Cl=Cortex limb&s Co = Cortex opticus NmT=N. medialis thalami CA=Cornu ammonis (Hippocampus) NCa=N. caudatus FR=Formatio reticularis EMG=~l~tromyogram
608
G. STKLE and A. SAYERS
Untreated animats examined over 4-S hr showed constant threshold values. In the untreated rabbit (Fig. 2, top) stimulation with 6 V causes an afterdischarge in the cortex and thalamus in the form of spikes, lasting over 3 min, with motor convuIsions (see EMG). Administration of 20 mg/kg Noveril S.C.to the same animal (bottom) greatly reduces this effect even following stimulation with 12 V when spikes occur for only 3 set durati on. DISCUSSION
Of the compounds used in the clinic as antidepressants, imipramine, Noveril, amitriptyline and desmethylamitriptyline reduce the cortical excitability to convulsive electrical stimulation. It is noteworthy that desmethylation of the side chain abolishes this effect in the case of irnipramine and Noveril, but not in the case of amitriptyline. With regard to the reserpine- and tetrabenazine (Nitoman~)-antagonism, however, Iesmethylimipramine is clearly superior to imipramille and desmethyl-~overil is equal to qoveril (STILLE, 1964). Evidently, there is no connection between reserpine- or tetrasenazine-antagonism and antidepressive effect on the one hand, and the suppression of the cortical excitability on the ,other hand. However, particularly in the case of the antidepressants, allowance must be made for the differences found in varying animal species (BICKEL et al. 1963). Trimepropimine, thioridazine, chlorprothixene and levomepromazine, although occasionally used in the treatment of depression, must be classified as neuroplegics, in view of their depressive qualities and the fact that they show no antagonism against reserpine and tetrabenazine. Their depressive activity is due to a suppression of the ascending reticular system rather than to a reduction of the excitability of the cortex. The effectiveness of imipramine, Noveril, amitriptyline and desmethylamitriptyline on the convulsive excitability of the cortex stands in contrast to the fact that these compounds in toxic doses themselves produce convulsions. These convulsions do not originate in the
FIG. 3. EEG of unanaesthetized rabbits after toxic doses (20 mg/kg iv.) of Noveril, showing spontaneous convulsions of the multiple spike and wave type, beginning in the ~ippocampus.
609
Antidepressant drugs on the brain convulsive excitability cortex, picture
however, but in the limbic structures, as can be seen in the typical electrographic (multiple spikes and waves) Fig. 3. STEINER and HIMWICH (1963) even regard the spike-like dysrhythmia and seizure activity of the limbic structures as one of the typical symptoms of antidepressant drugs. R&sum&L’effet des antidCpresseurs sur l’excitatilitk convulsive du cortex, du thalamus et de l’hippocampe a cte Ctudit sur I’EEG du lapin. L’imipramine, le Noveril, l’amitriptyline et led~mcthylamitriptyline,contrairementauxdCrivts dtmethvlCs de l’imioramine et du Noveril, inhikent l’excitabilitk corticale. Des doses toxiques- de ces substances entrafnent une tendance accrue aux convulsions limbiques. Zusammenfassung-Es wurde beim Kaninchen die Wirkung von Antidepressiva auf die Kramferregtarkeit von Cortex, Thalamus und Hippokarrpus elektro-enzephalographisch untersucht. Imipramin, Noveril, Amitriptylin und Desmethylamitriptylin, jedoch nicht die Desmethylderivate von lmipramin und Noveril, dampfen die Erregtarkeit der Hirnrinde. Dieser Wirkung steht eine gesteigerte rhinenzephale Krampfneigung in toxischen Dosen der Antidepressiva gegeniiber,. REFERENCES
BICKEL, M. H., SULSER, F. and BRODIE, B. B. (1963). Conversion of tranquilizers to antidepressants by removal of one N-methyl group. Life Sciences, 4: 247-253. BESENDORF,H., STEINER,F. A., and H~~RLIMANN,A. (1962). “Laroxyl”, ein neues Antidepressivum mit sedierender Wirkung. Schweiz.med. Ws chr. 92: 244-246. FROMMEL.E. and FLEURY. C. (1959). De la uharmacodvnamic diffkrentielle du Tofranil d‘avec la chlorpromazine. Med.exp. ‘1: 284-268. . MONNIER, M. and KRUPP, P. (1959). Elektrophysiologische Analyse der Wirkung-verschiedener Neuroleptica (Chlorpromazin, Reserpin, Tofranil, Meprotamat). Schweiz.med. Wschr. 89: 430-433. MONNIER,M. and GANGLOFF,H. (1961) Atlas for Stereotaxic Brcin Research . Elsevier, Amsterdam. PIETTE,Y., DELALJNOIS, A. L., DE SCHAEPDRYVER, A. F. and HBYMANS, C. (1963). Imipramine andelectroshock threshold. Arch.internat.Pharmacodyn 144: 293-297. SIGG, E. B. (1959). Pharmacological studies with Tofranil. Canad.pyschiatr.Assoc.J. 4: 75-85. STEINER,W. G. and HIMWICH,H. E. (1963). Effects of antidepressant drugs on limbic structures of rabbit. J.nerr.ment.Dis.
137: 277-284.
STILLE,G. (1964). Zur pharmakologischen Arzneim.-Forsch.
Priifung von Antifepressiva
am Beispiel eines Dibenzodiazepins.
14: 534537.
VERNIER,V. G. (1961). The pharmacology
of antidepressant
agents. Dis.Nerv.Syst.
22: l-7.
1964,3, 605-609
THE EFFECT CONVULSIVE
Pergamon
Press.
Printed in tit. Britain.
13 tigs., IO refs.J
OF ANTIDEPRESSANT DRUGS ON THE EXCITABILITY OF BRAIN STRUCTURES G. STILLEand A. SAYERS
Research Institute, Dr. A. Wander S.A., Berne, Switzerland Snrnmary-The effects of antidepressant drugs on the convulsive excitability of the cortex, thalamus and hippocampus were investigated electro-encephalographically in rabbits. Imipramine, Noveril, amitriptyline and desmethylamitriptyline suppress the excitability of the cortex as opposed to the desmethyl-derivatives of imipramine and Noveril. Toxic doses of antidepressants lead to limbic convulsions. INTRODUCTION THE well
known representatives of antidepressant drugs, imipramine and amitriptyline have a distinct effect in electroshock experiments. According to FROMMEL and FLEURY (1959), 50 mg/kg imipramine se. shorten the duration of the tonic extensor phase and coma following electroshock in guinea pigs. IO-30 mg/kg imipramine S.C.administered to mice also inhibit the extensor component of the maximal electroshock seizure (SIGG, 1959). PIETTE et a/. (1963) observed a marked elevation of the electroshock threshold in rabbits following administration of imipramine but not after desmethylimipramine. Corresponding effects of amitriptyline on the electroshock have been described by VERNIER (1961) and BESENDORF et al. (1962).
The usual method of carrying out electroshock experim~xlts (for example, with cornea1 electrodes) is a very rough procedure, and does not permit the localisation of the site of action of anticonvulsant compounds in the brain. We have therefore investigated the effect of compounds used in the treatment of depressions on the electrographical seizure activity arising when various brain centres are electrically stimulated. MONNIER and KRUPP (1959) have already reported that imipramine reduces the excitability of the cortex and diencephalon. METHODS
On stimulating certain parts of the brain with an increasing voltage a threshold value is reached at which spike potentials are discharged, lasting beyond the end of stimulation, and often appearing during the stimuIation itself (afterdischarge threshold). A number of compounds used in the treatment of depression were investigated in regard to their effect on the afterdischarge threshold of the cortex, thalamus and hippocampus. The stereotaxic method as described in detail by MONNIER and GANGLOFF (1961) was used on unanaesthetized rabbits. A Grass stimulator S 4 C in conjunction with an isolation unit supplied a stimulus with an impulse frequency of 40 c/s and an impulse duration of 3 msec, the voltage being increased until an afterdischarge was obtained. The electrical brain activity was recorded from the sensory-motor and visual cortices with silver screws and from the N. caudatus, hippocampus dorsalis, thalamus medialis, and formatio reticularis with platinum needles. 605
606
G.
STLLE
and A.
SAYERS
The following compounds were examined : imipramine (Tofranila), desmethylimipramine (Pertofrans), amitriptyline (Laroxyl”. Tryptizol@), desmethylamitriptyline (Nortriptyline, Aventyl~g), trimepropimine (Surmontila), chlorprothixene (Taractan”) and a new antidepressive, developed in our laboratories, HF-1927 (Noveril@) together with its desmethyl product (HF-2132). Single doses of 20 mg:kg were adninistered S.C. RESULTS
None of the compounds investigated showed any significant effect on the convulsive excitability of the thalamus and hippocampus”. Trimepropimine, thioridazine, chlorprothixene and levomepromazine, as well as desmethylimipramine and desmethyl-Noveril also had no effect on the afterdischarge threshold of the cortex. On the other hand imipramine, Noveril, amitriptyline and desmethylamitriptyline led to an increase of the cortical afterdischarge threshold of more than 100 per cent. The effects of various compounds (average values) are presented together with the confidence limits (p=O .OS) in Fig. 1. Vo!t’
?Smglkg
20 mglkg Dasmathyllmlpramme
20mglkg Dasmathyl-Novarll
Novaril (HF 1927) SC
~c.
(HF2132) SC
“’
6
_._.-.m.
I_
2
--I
1
/
/
1
I
I
-1
0
1
2
3
r,
5
I
4
-1
0
/
1
2
/
3
1
5 hr
FIG. 1. Behaviour of cortical afterdischarge threshold in rabbits in the course of 5 hr after subcutaneous injection of imipramine, desmethylimipramine, Noveril, desmethylnoveril, amitriptyline and desmethylamitriptyline. Abscissa in hr; Ordinate in Vs. (Thin lines represent the confidence limits p=O.O5). *Since this paper was submitted for publication a significant inhibition of hippocampus excitability has been demonstrated following 40 mg/kg Noveril S.C.
Antidepressant
FR sm
607
drugs on the brain convulsive excitability
----~.L+-v--~~
-..---
4.4-
I
EMG 60 set TiST LOHz.3mwc. 6V
120 set
184set
iSCX -mJJY
Cm dexter -----+vvyk&fB~~
1
xiiLOHz.3msec
12V
FIG. 2. Spike activity in the EEG after stimulation of the cortex in unanaesthetized rabbits. At the top before treatment and at the bottom after treatment with 20 mg/kg Noveril SC. Cs==Cortex sensitivus Cm=Cortex motoricus Cl=Cortex limb&s Co = Cortex opticus NmT=N. medialis thalami CA=Cornu ammonis (Hippocampus) NCa=N. caudatus FR=Formatio reticularis EMG=~l~tromyogram
608
G. STKLE and A. SAYERS
Untreated animats examined over 4-S hr showed constant threshold values. In the untreated rabbit (Fig. 2, top) stimulation with 6 V causes an afterdischarge in the cortex and thalamus in the form of spikes, lasting over 3 min, with motor convuIsions (see EMG). Administration of 20 mg/kg Noveril S.C.to the same animal (bottom) greatly reduces this effect even following stimulation with 12 V when spikes occur for only 3 set durati on. DISCUSSION
Of the compounds used in the clinic as antidepressants, imipramine, Noveril, amitriptyline and desmethylamitriptyline reduce the cortical excitability to convulsive electrical stimulation. It is noteworthy that desmethylation of the side chain abolishes this effect in the case of irnipramine and Noveril, but not in the case of amitriptyline. With regard to the reserpine- and tetrabenazine (Nitoman~)-antagonism, however, Iesmethylimipramine is clearly superior to imipramille and desmethyl-~overil is equal to qoveril (STILLE, 1964). Evidently, there is no connection between reserpine- or tetrasenazine-antagonism and antidepressive effect on the one hand, and the suppression of the cortical excitability on the ,other hand. However, particularly in the case of the antidepressants, allowance must be made for the differences found in varying animal species (BICKEL et al. 1963). Trimepropimine, thioridazine, chlorprothixene and levomepromazine, although occasionally used in the treatment of depression, must be classified as neuroplegics, in view of their depressive qualities and the fact that they show no antagonism against reserpine and tetrabenazine. Their depressive activity is due to a suppression of the ascending reticular system rather than to a reduction of the excitability of the cortex. The effectiveness of imipramine, Noveril, amitriptyline and desmethylamitriptyline on the convulsive excitability of the cortex stands in contrast to the fact that these compounds in toxic doses themselves produce convulsions. These convulsions do not originate in the
FIG. 3. EEG of unanaesthetized rabbits after toxic doses (20 mg/kg iv.) of Noveril, showing spontaneous convulsions of the multiple spike and wave type, beginning in the ~ippocampus.
609
Antidepressant drugs on the brain convulsive excitability cortex, picture
however, but in the limbic structures, as can be seen in the typical electrographic (multiple spikes and waves) Fig. 3. STEINER and HIMWICH (1963) even regard the spike-like dysrhythmia and seizure activity of the limbic structures as one of the typical symptoms of antidepressant drugs. R&sum&L’effet des antidCpresseurs sur l’excitatilitk convulsive du cortex, du thalamus et de l’hippocampe a cte Ctudit sur I’EEG du lapin. L’imipramine, le Noveril, l’amitriptyline et led~mcthylamitriptyline,contrairementauxdCrivts dtmethvlCs de l’imioramine et du Noveril, inhikent l’excitabilitk corticale. Des doses toxiques- de ces substances entrafnent une tendance accrue aux convulsions limbiques. Zusammenfassung-Es wurde beim Kaninchen die Wirkung von Antidepressiva auf die Kramferregtarkeit von Cortex, Thalamus und Hippokarrpus elektro-enzephalographisch untersucht. Imipramin, Noveril, Amitriptylin und Desmethylamitriptylin, jedoch nicht die Desmethylderivate von lmipramin und Noveril, dampfen die Erregtarkeit der Hirnrinde. Dieser Wirkung steht eine gesteigerte rhinenzephale Krampfneigung in toxischen Dosen der Antidepressiva gegeniiber,. REFERENCES
BICKEL, M. H., SULSER, F. and BRODIE, B. B. (1963). Conversion of tranquilizers to antidepressants by removal of one N-methyl group. Life Sciences, 4: 247-253. BESENDORF,H., STEINER,F. A., and H~~RLIMANN,A. (1962). “Laroxyl”, ein neues Antidepressivum mit sedierender Wirkung. Schweiz.med. Ws chr. 92: 244-246. FROMMEL.E. and FLEURY. C. (1959). De la uharmacodvnamic diffkrentielle du Tofranil d‘avec la chlorpromazine. Med.exp. ‘1: 284-268. . MONNIER, M. and KRUPP, P. (1959). Elektrophysiologische Analyse der Wirkung-verschiedener Neuroleptica (Chlorpromazin, Reserpin, Tofranil, Meprotamat). Schweiz.med. Wschr. 89: 430-433. MONNIER,M. and GANGLOFF,H. (1961) Atlas for Stereotaxic Brcin Research . Elsevier, Amsterdam. PIETTE,Y., DELALJNOIS, A. L., DE SCHAEPDRYVER, A. F. and HBYMANS, C. (1963). Imipramine andelectroshock threshold. Arch.internat.Pharmacodyn 144: 293-297. SIGG, E. B. (1959). Pharmacological studies with Tofranil. Canad.pyschiatr.Assoc.J. 4: 75-85. STEINER,W. G. and HIMWICH,H. E. (1963). Effects of antidepressant drugs on limbic structures of rabbit. J.nerr.ment.Dis.
137: 277-284.
STILLE,G. (1964). Zur pharmakologischen Arzneim.-Forsch.
Priifung von Antifepressiva
am Beispiel eines Dibenzodiazepins.
14: 534537.
VERNIER,V. G. (1961). The pharmacology
of antidepressant
agents. Dis.Nerv.Syst.
22: l-7.