Brain Research, 88 (1975) 141-144
141
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
Blockade of tardive seizures in rats by electroconvulsive shock
R. G. BABINGTON AND P. W. WEDEKING Department of Pharmacology, The Squibb Institute Jbr Medical Research, Princeton, N.J. 08540 (U.S.A.)
(Accepted January 14th, 1975)
Electroconvulsive therapy is a widely used and effective form of psychiatric treatment, particularly for endogenous depression, yet it is basically an empirical method of therapy. Numerous theories, both physiological and psychological, have been put forth to explain the therapeutic effects of electroconvulsions 4,9 but, unfortunately, the animal models used to screen compounds for antidepressive activity do not lend themselves to experimentation with electroconvulsions. Supportive evidence for any of the theoretical mechanisms is still wanting. We reported recently3,15 that certain CNS-active agents were capable of suppressing the tardive seizures that are 'kindled '5 by brief daily presentations of low-intensity electrical stimulation to selected brain sites. In particular, antidepressive agents exerted a preferential blockade of seizures originating from the amygdala. Because the tardive seizure model readily accommodates electroconvulsive shock (ECS) testing, experiments were carried out to determine whether the pharmacological effects of the antidepressives could be mimicked with ECS. The procedure for establishing tardive seizures has been documented in detail3,1% but the basic steps will be described. Rats were implanted with a stainless steel bipolar electrode in the centro-medial amygdala or septum or, epidurally, on the sensorimotor cortex. Each animal was subsequently stimulated electrically once daily for 1 rain with a 50-#A, 60-Hz constant current sine wave. During the first few sessions, none of the animals exhibited seizures, but after 4-7 days, bilateral clonic seizures began to develop. Once seizures appeared during stimulation, the current was shut off and the duration of the seizure was measured. Within 3-4 weeks, sensitization progressed so that, according to the individual animal, 5-7 sec of stimulation elicited seizures that lasted 45-75 sec. In the first experiment, tardive seizures were established before the animals were used. On the test day, two control measurements were made 15 min apart. I f the seizures did not vary in duration by more than 1 0 ~ , the pair of control values was averaged to serve as the baseline value; otherwise, the rat was not used. Each animal was then given a single ECS treatment consisting of a 0.25-sec transspinal train of 60Hz current at 50 ~ 2 mA. This current was sufficient to produce tonic extension of the limbs. Separate groups of 8 rats were then challenged at various time intervals
142
7+
I00
Z O
~-
75
rY D bJ n,N
~
5o
d 0 b-Z 0
u
25
0
F I I
I
i
15 50 60
120
i
180
i
i
240
TIME AFTER ECS
560 (MIN)
Fig. I. Effect of a single electroconvulsive shock (ECS) on the d u r a t i o n o f tardive seizures elicited
from the amygdala (O), neocortex (A) or septum (11). Separate groups of 8 rats were tested at various times after ECS. The duration of post-ECS seizures is expressed as a percentage of baseline duration.
after ECS with each animal receiving brain stimulation of the same duration as had been needed to produce the control seizures. Fig. 1 presents the effects of a single ECS treatment on the duration of tardive seizures elicited from the amygdala, septum, or cortex. As was the case with tricyclic antidepressive drugs ~,15, the most profound effect of ECS was on the amygdatoidinduced response; seizures elicited from septum or cortex showed less of a reduction, not only in magnitude of the response, but also in duration of the suppression. The durations of seizures originating in the amygdala were still slightly depressed 5-6 h after ECS treatment. In the second experiment, only rats with electrodes implanted in the amygdala were used, and tardive seizures were not established prior to ECS treatment. The parameters for both tardive seizures and ECS were the same as in the first experiment. The procedure was to administer ECS at: (a) 30 min prior to electrical stimulation of the amygdala; (b) 5 min after cessation of the 1-min stimulation period (or in those cases where short periods of seizures were evoked, 5 min after cessation of the seizures); or (c) 4 h after amygdaloid stimulation. On day 20, ECS treatment was terminated. Fig. 2 illustrates the results of administration of ECS during the sensitization process. ECS treatment 30 min prior to stimulation of the amygdala completely blocked establishment of tardive seizures, but as soon as ECS was terminated, the sensitization process proceeded in normal fashion. The results with ECS cannot merely be ascribed to the postictal depression associated with electroconvulsions. Administration of ECS approximately 24 h prior to sensitization, although not as effective as the other two ECS schedules, certainly had a profound effect on the
143 80
I I
70 60 50
IZ:
I
40
2 50-
J
20
J
I0 0 5
I0
15
20
, 25
4 30
DAYS
Fig. 2. Prevention by electroconvulsive shock of development of tardive seizures in the amygdala. ECS was administered 30 rain ([1), 20 h (A) or 24 h (O) prior to amygdaloid stimulation with the same stimulus parameters as control (Q). ECS treatment was terminated at day 20 (dashed line). Each plot represents a group of 8 animals.
development of tardive seizures; and ECS 4 h after (or 20 h prior to) the kindling experience was as effective as ECS 30 min prior to kindling stimulation. Again, sensitization proceeded rapidly once ECS was stopped. Thus, ECS has profound effects on established tardive seizures as well as on the development of those seizures. In particular, ECS, like antidepressive agents, exerts a selective effect on seizures arising from the amygdala. In fact, the amygdaloid specificity of ECS was greater than that seen with drugs. Some investigators have pointed out a relationship between the antidepressive activity of some drugs and their influence on the amygdala. For example, antidepressives block limbic system afterdischarges elicited from the amygdala s,1°,13 and suppress local evoked potentials and spontaneous E E G activity in the amygdaloid complex 6 of cats. A strong case has been made that the antidepressive blockade of muricidal behavior in rats involves an amygdaloid effect s. Even though antianxiety agents do not exhibit a predilection for the amygdala, they are quite potent and active in blocking amygdaloid tardive seizures 3,15. The amygdaloid activity might explain the observation of several investigators that, in patients with mixed symptoms of anxiety and depression, an anxiolytic, rather than a tricyclic, is the drug of choice 7,11,12. Due to the difficulty of measuring ECS effects in the usual animal models employed for determining antidepressive effects, little evidence is available linking ECS and the amygdala. Vogel and Haubrich 14, however, found that multiple ECS treatments, like antidepressive drugs s, blocked muricidal behavior in rats. In man, bilateral electroconvulsive therapy (ECT) is more effective than unilateral ECT, a result that was long attributed merely to the effect of bilateral stimulation p e r se 1.
144 A b r a m s and T a y l o r ~, however, found that the classical bilateral EC'I- ~va.-. n.~rc effective than a n t e r i o r bifrontal ECT. The single crucial factor for effective E ( I t r e a t m e n t , then, is the r e q u i r e m e n t that the current pass t h r o u g h the t e m p o r a l lobes (amygdala?), A l t h o u g h our results do not explain the m ech an i sm by which E C T produces its t h erap eu t i c effects, they do reinforce the co n cep t t h a t the a m y g d a l a might be inw~tved in depression and that successful t r e a t m e n t o f depression requires an effect on that structure.
1 ABRAMS, R., Recent clinical studies of ECT, Semin. Psychiatry, 4 (1972) 3-12. 2 ABRAMS, R., AND TAYLOR, M. A., Anterior bifrontal ECT: a clinical trial, Brit. J. Psychiat., 122 (1973) 587-590. 3 BABINGTON,R. G., AND WEDEKING,P. W., The pharmacology of seizures induced by sensitization with low-intensity brain stimulation, Pharmacol. Biochem. Behav., 1 (1973) 461-467. 4 FLEMING, T. C., An inquiry into the mechanism of action of electric shock treatments, J. ~erv. ment. Dis., 124 (1956) 440450. 5 GODDARD, G. V., MclNTVRE, D. C., AND LEECH, C. K., A permanent change in brain function resulting from daily electrical stimulation, Exp. Neurol. 25 (1969) 295-330. 6 GUERRERO-FIGUEROA,R., AND GALLANT, D. M., Effects of pinoxepin and imipramine on the mesencephalic reticular formation and amygdaloid complex in the cat: neurophysiological and clinical correlations in human subjects, Curr. ther. Res., 9 (1967) 387-403. 7 HOLLISTER,L. E., OVERALL,J. E., POKORNY,A. D., AND SHELTON,J,, Acetopbenazine and diazepam in anxious depression, Arch. gen. Psychiat. (Chic.), 24 (1971) 273-278. 8 HoRovrrz, Z. P., The anaygdala and depression. In S. GARATTIMAND M. N. G. DUKES(Eds.), First Int. Syrup. Antidepressant Drugs, Milan, Excerpta Medica ICS No. 122, Excerpta Medica, Amsterdam, 1966, pp. 121 - 129. 9 MmLER, E., Psychological theories of E.C.T.: a review, Brit. d. Psychiat., 113 (1967) 301-31 I. 10 PENALOZA-ROJAS,J. H., BACH-Y-RITA,G., RUBIO-CHERANNIES,H. F., AND HERNANDEZ-PEON, R., Effects of imipramine upon hypothalamic and amygdaloid excitability, Exp. Neurol., 4 (1961) 205-213. l I RASKIN, A., A guide for drug use in depressive disorders, Amer. J. Psychiat., 13l (1974) 181-185. 12 RASKIN, A., SCHULTERBRANDT,J. G., REATIG, N., CROOK, T. H., AND ADLE, D., Depression subtypes and response to phenelzine, diazepam, and a placebo, Arch. gen. P~vchiat. (Chh'.J, 30 (1974) 66-75. 13 SCHMITT, H., ET SCRMITT, H., Action de l'imipramine, de I'amitriptyline et de leurs derives monod6m~thyl6s sur les post d6charges provoqu6es par l'excitation de certaines structures rhin6ncephaliques chez le lapin, Th~rapie, 21 (1966) 675-684. 14 VOGEL, J. R., AND HAUBRICH, D. R., Chronic administration of electroconvulsive shock effects on mouse-killing activity and brain monoamines in rats, Physiol. Behav., 11 (1973) 725-728. 15 WEDEKING,P. W., AND BABINC;TON,R. G., Effects of neurological agents on seizures elicited by low-intensity brain stimulation in rats, Pharmacologist, I1 (1969) 279.
141
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
Blockade of tardive seizures in rats by electroconvulsive shock
R. G. BABINGTON AND P. W. WEDEKING Department of Pharmacology, The Squibb Institute Jbr Medical Research, Princeton, N.J. 08540 (U.S.A.)
(Accepted January 14th, 1975)
Electroconvulsive therapy is a widely used and effective form of psychiatric treatment, particularly for endogenous depression, yet it is basically an empirical method of therapy. Numerous theories, both physiological and psychological, have been put forth to explain the therapeutic effects of electroconvulsions 4,9 but, unfortunately, the animal models used to screen compounds for antidepressive activity do not lend themselves to experimentation with electroconvulsions. Supportive evidence for any of the theoretical mechanisms is still wanting. We reported recently3,15 that certain CNS-active agents were capable of suppressing the tardive seizures that are 'kindled '5 by brief daily presentations of low-intensity electrical stimulation to selected brain sites. In particular, antidepressive agents exerted a preferential blockade of seizures originating from the amygdala. Because the tardive seizure model readily accommodates electroconvulsive shock (ECS) testing, experiments were carried out to determine whether the pharmacological effects of the antidepressives could be mimicked with ECS. The procedure for establishing tardive seizures has been documented in detail3,1% but the basic steps will be described. Rats were implanted with a stainless steel bipolar electrode in the centro-medial amygdala or septum or, epidurally, on the sensorimotor cortex. Each animal was subsequently stimulated electrically once daily for 1 rain with a 50-#A, 60-Hz constant current sine wave. During the first few sessions, none of the animals exhibited seizures, but after 4-7 days, bilateral clonic seizures began to develop. Once seizures appeared during stimulation, the current was shut off and the duration of the seizure was measured. Within 3-4 weeks, sensitization progressed so that, according to the individual animal, 5-7 sec of stimulation elicited seizures that lasted 45-75 sec. In the first experiment, tardive seizures were established before the animals were used. On the test day, two control measurements were made 15 min apart. I f the seizures did not vary in duration by more than 1 0 ~ , the pair of control values was averaged to serve as the baseline value; otherwise, the rat was not used. Each animal was then given a single ECS treatment consisting of a 0.25-sec transspinal train of 60Hz current at 50 ~ 2 mA. This current was sufficient to produce tonic extension of the limbs. Separate groups of 8 rats were then challenged at various time intervals
142
7+
I00
Z O
~-
75
rY D bJ n,N
~
5o
d 0 b-Z 0
u
25
0
F I I
I
i
15 50 60
120
i
180
i
i
240
TIME AFTER ECS
560 (MIN)
Fig. I. Effect of a single electroconvulsive shock (ECS) on the d u r a t i o n o f tardive seizures elicited
from the amygdala (O), neocortex (A) or septum (11). Separate groups of 8 rats were tested at various times after ECS. The duration of post-ECS seizures is expressed as a percentage of baseline duration.
after ECS with each animal receiving brain stimulation of the same duration as had been needed to produce the control seizures. Fig. 1 presents the effects of a single ECS treatment on the duration of tardive seizures elicited from the amygdala, septum, or cortex. As was the case with tricyclic antidepressive drugs ~,15, the most profound effect of ECS was on the amygdatoidinduced response; seizures elicited from septum or cortex showed less of a reduction, not only in magnitude of the response, but also in duration of the suppression. The durations of seizures originating in the amygdala were still slightly depressed 5-6 h after ECS treatment. In the second experiment, only rats with electrodes implanted in the amygdala were used, and tardive seizures were not established prior to ECS treatment. The parameters for both tardive seizures and ECS were the same as in the first experiment. The procedure was to administer ECS at: (a) 30 min prior to electrical stimulation of the amygdala; (b) 5 min after cessation of the 1-min stimulation period (or in those cases where short periods of seizures were evoked, 5 min after cessation of the seizures); or (c) 4 h after amygdaloid stimulation. On day 20, ECS treatment was terminated. Fig. 2 illustrates the results of administration of ECS during the sensitization process. ECS treatment 30 min prior to stimulation of the amygdala completely blocked establishment of tardive seizures, but as soon as ECS was terminated, the sensitization process proceeded in normal fashion. The results with ECS cannot merely be ascribed to the postictal depression associated with electroconvulsions. Administration of ECS approximately 24 h prior to sensitization, although not as effective as the other two ECS schedules, certainly had a profound effect on the
143 80
I I
70 60 50
IZ:
I
40
2 50-
J
20
J
I0 0 5
I0
15
20
, 25
4 30
DAYS
Fig. 2. Prevention by electroconvulsive shock of development of tardive seizures in the amygdala. ECS was administered 30 rain ([1), 20 h (A) or 24 h (O) prior to amygdaloid stimulation with the same stimulus parameters as control (Q). ECS treatment was terminated at day 20 (dashed line). Each plot represents a group of 8 animals.
development of tardive seizures; and ECS 4 h after (or 20 h prior to) the kindling experience was as effective as ECS 30 min prior to kindling stimulation. Again, sensitization proceeded rapidly once ECS was stopped. Thus, ECS has profound effects on established tardive seizures as well as on the development of those seizures. In particular, ECS, like antidepressive agents, exerts a selective effect on seizures arising from the amygdala. In fact, the amygdaloid specificity of ECS was greater than that seen with drugs. Some investigators have pointed out a relationship between the antidepressive activity of some drugs and their influence on the amygdala. For example, antidepressives block limbic system afterdischarges elicited from the amygdala s,1°,13 and suppress local evoked potentials and spontaneous E E G activity in the amygdaloid complex 6 of cats. A strong case has been made that the antidepressive blockade of muricidal behavior in rats involves an amygdaloid effect s. Even though antianxiety agents do not exhibit a predilection for the amygdala, they are quite potent and active in blocking amygdaloid tardive seizures 3,15. The amygdaloid activity might explain the observation of several investigators that, in patients with mixed symptoms of anxiety and depression, an anxiolytic, rather than a tricyclic, is the drug of choice 7,11,12. Due to the difficulty of measuring ECS effects in the usual animal models employed for determining antidepressive effects, little evidence is available linking ECS and the amygdala. Vogel and Haubrich 14, however, found that multiple ECS treatments, like antidepressive drugs s, blocked muricidal behavior in rats. In man, bilateral electroconvulsive therapy (ECT) is more effective than unilateral ECT, a result that was long attributed merely to the effect of bilateral stimulation p e r se 1.
144 A b r a m s and T a y l o r ~, however, found that the classical bilateral EC'I- ~va.-. n.~rc effective than a n t e r i o r bifrontal ECT. The single crucial factor for effective E ( I t r e a t m e n t , then, is the r e q u i r e m e n t that the current pass t h r o u g h the t e m p o r a l lobes (amygdala?), A l t h o u g h our results do not explain the m ech an i sm by which E C T produces its t h erap eu t i c effects, they do reinforce the co n cep t t h a t the a m y g d a l a might be inw~tved in depression and that successful t r e a t m e n t o f depression requires an effect on that structure.
1 ABRAMS, R., Recent clinical studies of ECT, Semin. Psychiatry, 4 (1972) 3-12. 2 ABRAMS, R., AND TAYLOR, M. A., Anterior bifrontal ECT: a clinical trial, Brit. J. Psychiat., 122 (1973) 587-590. 3 BABINGTON,R. G., AND WEDEKING,P. W., The pharmacology of seizures induced by sensitization with low-intensity brain stimulation, Pharmacol. Biochem. Behav., 1 (1973) 461-467. 4 FLEMING, T. C., An inquiry into the mechanism of action of electric shock treatments, J. ~erv. ment. Dis., 124 (1956) 440450. 5 GODDARD, G. V., MclNTVRE, D. C., AND LEECH, C. K., A permanent change in brain function resulting from daily electrical stimulation, Exp. Neurol. 25 (1969) 295-330. 6 GUERRERO-FIGUEROA,R., AND GALLANT, D. M., Effects of pinoxepin and imipramine on the mesencephalic reticular formation and amygdaloid complex in the cat: neurophysiological and clinical correlations in human subjects, Curr. ther. Res., 9 (1967) 387-403. 7 HOLLISTER,L. E., OVERALL,J. E., POKORNY,A. D., AND SHELTON,J,, Acetopbenazine and diazepam in anxious depression, Arch. gen. Psychiat. (Chic.), 24 (1971) 273-278. 8 HoRovrrz, Z. P., The anaygdala and depression. In S. GARATTIMAND M. N. G. DUKES(Eds.), First Int. Syrup. Antidepressant Drugs, Milan, Excerpta Medica ICS No. 122, Excerpta Medica, Amsterdam, 1966, pp. 121 - 129. 9 MmLER, E., Psychological theories of E.C.T.: a review, Brit. d. Psychiat., 113 (1967) 301-31 I. 10 PENALOZA-ROJAS,J. H., BACH-Y-RITA,G., RUBIO-CHERANNIES,H. F., AND HERNANDEZ-PEON, R., Effects of imipramine upon hypothalamic and amygdaloid excitability, Exp. Neurol., 4 (1961) 205-213. l I RASKIN, A., A guide for drug use in depressive disorders, Amer. J. Psychiat., 13l (1974) 181-185. 12 RASKIN, A., SCHULTERBRANDT,J. G., REATIG, N., CROOK, T. H., AND ADLE, D., Depression subtypes and response to phenelzine, diazepam, and a placebo, Arch. gen. P~vchiat. (Chh'.J, 30 (1974) 66-75. 13 SCHMITT, H., ET SCRMITT, H., Action de l'imipramine, de I'amitriptyline et de leurs derives monod6m~thyl6s sur les post d6charges provoqu6es par l'excitation de certaines structures rhin6ncephaliques chez le lapin, Th~rapie, 21 (1966) 675-684. 14 VOGEL, J. R., AND HAUBRICH, D. R., Chronic administration of electroconvulsive shock effects on mouse-killing activity and brain monoamines in rats, Physiol. Behav., 11 (1973) 725-728. 15 WEDEKING,P. W., AND BABINC;TON,R. G., Effects of neurological agents on seizures elicited by low-intensity brain stimulation in rats, Pharmacologist, I1 (1969) 279.
