Epilepsia, 17:183-196, 1976.

Raven Press, New York

Biphasic Effects of Imipramine in Experimental Models of Epilepsy Stephan C. Lange, Robert M. Julien, and Glenn W. Fowler Departments of Pharmacology and Pediatrics, University o f California at Irvine, Irvine, California 9271 7 (Received March 19, 1976)

INTRODUCTION

EXPERIMENTS IN MICE

Tricyclic antidepressants suppress convulsive activity both in man (Millichap, 1965; Fromm et al., 1972) and in a variety of animal models of experimental epilepsy (Vernier, 1961; Stille and Sayers, 1964; Baker and Kratky, 1967; Fromm et al., 1972; Julien et al., 1975). Limitation t o the antiepileptic action of tricyclic antidepressants was noted in man by Fromm et al. (1972) and by Legg and Swash (1974) who reported that while low doses of imipramine (TofranilB ) or trimipramine effectively suppressed convulsive activity, higher doses exacerbated grand mal and psychomotor seizures and frequently converted the spikeand-wave discharges of petit ma1 epilepsy into bursts of polyspikes. In addition, high doses of imipramine initiated spontaneous seizure discharges both in cats (Dasberg and Feldman, 1968) Bnd in rabbits (Van Meter et al., 1959). Thus, imipramine and other tricyclic antidepressants appear to produce a biphasic effect manifested by antiepileptic properties at low doses and convulsant properties at higher doses. A more precise correlation between dosage and antiepileptic and convulsant effects has not been made, nor has the extent of imipramine’s antiepileptic action been delineated. Therefore, experiments utilizing a variety of laboratory models of experimental epilepsy were conducted in mice and cats to provide these data.

Methods

Male Swiss-Webster mice, 20-25 g, were housed in groups of 5 and allowed free access to food and water for at least 3 days prior to experimentation. All imipramine injections were made intraperitoneally in distilled water (0.1 m1/10 g body wt). Time to peak effect was determined (Goodman et al., 1953) and utilized to obtain an EDs0 of imipramine against seizures induced by maximal electroshock stimuli, for the elevation of minimal electroshock threshold, and against seizures induced by pentylenetetrazol (MetrazolB) (Millichap, 1965; Swinyard, 1972). In the maximal electroshock seizure test with 45 mice, antiepileptic protection was determined by a drug-induced block of the tonic-extensor component of the induced seizure (50 mA, 60-Hz sine waves, 0.2 sec duration, Spiegel corneal electrodes). In 45 additional mice, a minimal electroshock threshold was established for each animal by determining at 48-hr intervals the minimal current required to elicit forelimb or facial clonus (4-7 mA, 60-Hz sine waves, 0.2 sec duration). Once the threshold was determined for each animal, doses of imipramine were tested against a current 20% greater than control (Millichap, 1965; Swinyard, 1972). An effective elevation of seizure threshold was determined by the absence of forelimb or facial clonus. Finally, in 35 mice, clonic seizures were Key words: lmipramine - Anticonvulsant Cats -Mice - Afterdischarge - Electroshock - induced by subcutaneous administration of Estrogens - Penicillin pentylenetetrazol (86 mg/kg) (Goodman et al.,

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(7 animals); and (3) electrically induced cortical afterdischarge duration (12 animals) and threshold (8 animals). All animals were initially anesthetized with halothane; the trachea and the femoral artery and vein were cannulated. The animal was placed in a stereotactic machine with care taken t o insure that only minimal pressure was present. Skin and muscle overlying the skull were reflected. EEG screws were located over anterior and posterior suprasylvian gyri bilaterally with a ground screw in frontal sinus. Following completion of surgical procedures, all exposed wound margins were locally anesthetized with 20% benzocaine powder Results (Demetrescu and Julien, 1974). The animals In preliminary electroshock experiments in were paralyzed with d-tubocurarine (0.45 27 mice, imipramine (5-35 mg/kg) exerted mg/kg/hr) and artificially ventilated to an maximal antiepileptic action 30 min after end-tidal COz of 3.0-3.4%. Body temperature intraperitoneal administration. Using this time was maintained at 37.5"C via a servo-controlled to peak effect, the EDs0 and 95% confidence heating pad. The EEG, tracheal COz, and limits (Litchfield and Wilcoxin, 1947) for arterial blood pressure were continuously imipramine to block the tonic extensor recorded on a polygraph (Grass model 78). The component of the maximal electroshock seizure experiments were initiated no earlier than 1.5 hr following discontinuation of halothane. was 21.0 (17.5-25.2) mg/kg. Penicillin-Znduced Activity. Under general In additional mice, an electroshock threshold which would induce forelimb or facial anesthesia the left sensorimotor cortex was clonus in each animal was determined. In these exposed, dura reflected, and EEG recording animals, imipramine (5-50 mg/kg) exerted no electrodes located as discussed above. Control effect on electroshock threshold. Similarly, EEG records were obtained at 1.5 hr after imipramine (5-50 mg/kg) in 3 5 mice failed to discontinuation of halothane, and 5,000 units prevent seizures produced by pentylenetetrazol of potassium penicillin in 0.05 ml distilled (86 mg/kg, s.q.). Doses above 50 mg/kg were water was injected subpially. Epileptiform not attempted because neurological deficits activity was allowed t o develop over a period of were noted at such doses. Neurotoxicity not less than 6 0 min (Julien and Halpern, consisted of loss of hindlimb placing, staggered 1972). Cumulative doses of imipramine (2.5 gait, widened stance, and loss of the righting mg/kg, i.v.) were then administered at 30-min reflex. At doses of 70 mg/kg or above, animals intervals and effects recorded. Conjugated Estrogen-Znduced Activity. In also exhibited Straub tails, tremors, and generalized clonic convulsions. The TDS was this series of seven experiments, two 6 X 8 mm pads of filter paper saturated with a 2% calculated t o be 71.0 (65.7-76.7) mg/kg. aqueous solution of conjugated estrogen (hemarin@) were placed bilaterally over EXPERIMENTS IN CATS exposed sensorimotor cortex after discontinuation of halothane and recording of the control Methods EEG. Cumulative doses of imipramine were administered and the drug's effects recorded. Experiments performed on 2 3 cats (2.5-4.2 Afterdischarge Duration and Threshold. kg, both sexes) evaluated the antiepileptic After surgical exposure of the suprasylvian gyri action of imipramine against four models of bilaterally, halothane was discontinued and an experimental epilepsy: (1) penicillin-induced electrocorticogram was recorded utilizing two epileptiform discharge (4 animals); (2) con- silver-silver chloride electrodes placed over the jugated estrogen-induced spike-wave discharge left suprasylvian gyrus. Following collection of 1953; Millichap, 1965). In imipramine-treated mice, absence of seizure activity over a 30-min period of observation was considered an effective block. Neurotoxicity of imipramine was evaluated by examination of the hindlimb placing response, righting reflex, gait and stance, and equilibrium tests (Swinyard, 1972). In addition, animals were observed for signs of tremulousness, Straub tails, and spontaneous seizure activity. A TDSo (toxic dose for 50% of the animals) was then calculated according to the method of Litchfield and Wilcoxin (1947).

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control records, the homotopic area of the contralateral gyrus was stimulated once every 1 0 min with a 5-sec train of monophasic square waves (0.5 msec, 100 Hz). For the afterdischarge duration series, a control voltage was established which initiated an afterdischarge persisting for 30 to 50 sec following cessation of the stimulus train. Imipramine was administered intravenously in cumulative doses at 30-min intervals and the electrical stimulation was repeated at predrug control voltage at 10-min intervals. In the afterdischarge threshold series, a voltage was found that would induce an afterdischarge of 2-5 sec duration. Cumulative 2.5 mg/kg doses of imipramine were then administered at 30-min intervals and alterations in threshold measured by the change in stimulus voltage required to maintain the 2-5 sec afterdischarge. These alterations in afterdischarge threshold were plotted as a percent of predrug control voltage. Results

Penicillin-Induced Epileptiform Discharge. Within 1 hr after the subpial injection of 5,000 units of penicillin, epileptiform discharges consisted of bursts of high-voltage repetitive spikes separated by periods of quiescence (Fig. 1, control). Cumulative doses of imipramine (2.5 mg/kg) reduced the frequency of such bursts as the total dose was increased from 2.5 t o 17.5 mg/kg (Fig. 1). In only 1 of the 4 animals was the spike amplitude depressed. In contrast t o this reduction in ictal discharges, interictal discharges (which are absent in control records) progressively increased in frequency with increasing doses of imipramine. In doses of 22.5 mg/kg, interictal spikes increased in amplitude and were frequently interrupted by bursts of repetitive spikes; such bursts, however, occurred less than in preimipramine control records.

FIG. 1. Effect of imipramine on penicillin-induced epileptiform discharge. Data obtained from a locally anesthetized, paralyzed cat. Pairs of traces were recorded between anterior and posterior suprasylvian gyrus leads over left (upper) and right (lower) hemispheres before and following imipramine (2.5 - 22.5 mg/kg, i.v.) in 2.5 mg/kg increments.

Conjugated Estrogen-Indu ced Epilep tiform Discharge. Epileptiform activity following the topical application of conjugated estrogen to sensory-motor cortex was characterized by spike-and-slow wave discharge recurring at a frequency of 2-2.5 Hz (Fig. 2, control). Imipramine (in 5 mg/kg increments, i.v.) in doses to 1 5 mg/kg progressively decreased both the frequency and the amplitude of estrogen-induced epileptiform discharge. In contrast, at doses of 20 mg/kg and above, electrographic activity was characterized by repetitive trains of high-amplitude 5 to 8-Hz spikes with some spike-and-wave discharge. Paroxysmal epileptiform activity consisting of polyspike (8-12 Hz) discharges followed by postictal quiescence was recorded in 3 of the 7 animals with estrogen-induced foci following doses of imipramine in excess of 20 mg/kg. Afterdischarge Duration and Threshold. In the afterdischarge duration experiments, low doses of imipramine (2.5-10 mg/kg) shortened the duration of electrically induced afterdischarges. An example is illustrated in Fig. 3. In this figure, a 32-sec afterdischarge was recorded from the suprasylvian gyrus following cessation of the 5-sec stimulation applied to the contralateral homotopic cortex. Fifteen minutes after imipramine (2.5 mg/kg, i.v.), afterdischarge duration was reduced by 40%. After a total dose of 7.5 mg/kg, afterdischarge was further reduced. With an increase of cumulative dose to 22.5 mg/kg, the afterdischarge (although less than predrug control duration) was longer than that elicited after lower doses of imipramine (Fig. 3, 7.5 mg/kg). After a cumulative dose of 22.5 mg/kg, afterdischarge amplitude increased and was greater than that recorded either prior to drug administration or following lower doses. In addition, only after doses of 22.5 mg/kg was the afterdischarge response followed by a period of postictal depression. In the afterdischarge threshold experiments, imipramine was administered in 2.5 mg/kg increments at 30-min intervals and the stimulus voltage adjusted to maintain a “threshold” afterdischarge of preimipramine duration (2-5 sec). The results of these eight experiments are illustrated in Fig. 4. Imipramine in doses of 2.5-10 mg/kg produced a dose-related elevation of afterdischarge threshold t o 70% above control at doses of 1 0 mg/kg. Higher doses

EFFECTS OF IMPRAMINE IN EPILEPSY MODELS

187

FIG. 2. Effect of imipramine on conjugated estrogen-induced epileptiform discharge. Traces labeled “control” are monopolar recordings obtained 1 hr following topical application of a 2% solution of conjugated estrogens to sensorimotor cortex. Imipramine was administered in increments of 5 mg/kg, i.v. at 20-min intervals to a total dose of 20 mg/kg. Note the change in amplitude calibration in the bottom set of traces (20 mg/kg).

FIG. 3. Effect of imipramine o n afterdischarge duration. In the control, a 5-sec train of 4 V, 0.5 msec, 100-Hz pulses t o suprasylvian cortex initiated a 32-sec afterdischarge recordable from contralateral cortex. Imipramine (2.5 - 7.5 mg/kg, i.v.) reduced afterdischarge duration, whereas cumulative dose of 22.5 mg/kg was less effective than lower doses in reducing afterdischarge duration. Note the increase in the amplitude of the afterdischarge response and the period of postictal silence in the higher dose.

EFFECTS OF IMIPRAMINE IN EPILEPSY MODELS

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FIG. 4. Effect of imipramine on afterdischarge threshold. Data obtained from observations in 8 cats with averages and standard deviations shown. Voltage adjustments required to elicit an afterdischarge of 2 - 5 sec duration expressed as a percent of the control voltage required to elicit a similar response before drug administration. Note the biphasic effect of imipramine on afterdischarge threshold. The dotted line is for base-line reference only.

caused a progressive reduction of threshold. After a cumulative dose of 20 mg/kg, afterdischarge fell to approximately 40% below predrug control. Spontaneous Imipmmine-Induced Epileptiform Discharges. Concomitant with the reduction of afterdischarge threshold illustrated in Fig. 4,spontaneous epileptiform episodes were observed; the record from one such animal is illustrated in Fig. 5. These spontaneous episodes occurred in 2 of the 8 animals at doses of 17.5 and 27.5 mg/kg, and in both cases were observed within 10 min of drug injection. In Fig. 5, a 23.5-min recording of the EEG pattern following a cumulative dose of 17.5 mg/kg in one animal is illustrated. As shown, there was a progressive increase in EEG amplitude with appearance of spontaneous spike discharges.

Such activity increased until high-voltage repetitive spike sequences of 15-20 sec duration occurred. Such episodes recurred at approximately 2-min intervals over a period of 1 t o 2 hr. In both animals, the amplitude and frequency of this epileptiform activity was depressed by diazepam (1.0 mg/kg, i.v.).

DISCUSSION Imipramine and other tricyclic antidepressants have been reported to possess both antiepileptic and proconvulsant properties both in man (Table 1) and in a variety of laboratory models of epilepsy (Table 2). The present report has verified in the cat and mouse that imipramine indeed possesses both convulsant

FIG. 5. A 23.5-min recording of EEG activity from a cat following a cumulative dose of imipramine of 1 7 . 5 mg/kg. The EEG shows progressive increase in amplitude with the appearance of spontaneous spike discharges. Spike activity increases in frequency and culminates in 15 - 20-sec bursts of repetitive spikes.

EFFECTS OF IMIPRAMINE IN EPILEPSY MODELS

191

TABLE 1. Clinical investigations of tricyclic antidepressants in epilepsy ~

Drug

Dose

Effect ~

Imipramine

60 mg/day, p.0.

Imipramine Imipramine Trimipramine Desipramine

75 mg, i.v. 400 mg/day, p.0. 20 mg, p.0. 200 mg/day, p.0.

Reduction of minor motor seizures; conversion of minor motor to major motor seizures Activation of EEG Convulsions Convulsions Antiepileptic

and antiepileptic effects and that the drug exerts a biphasic effect on brain excitability with antiepileptic actions occurring at low doses of the drug and convulsant effects occurring at higher doses, Concerning the antiepileptic properties of imipramine, the present results indicate that the drug is most effective against those models of experimental epilepsy which correlate drug effectiveness with the clinical treatment of major motor seizures (maximal electroshock seizures in mice, penicillin-induced epileptiform activity in cats, and afterdischarge duration in cats). Imipramine was less effective as an antiepileptic agent in those models of experimental epilepsy which correlate drug effectiveness with clinical utility in the treatment of minor motor seizures. Such laboratory models of minor motor seizures include tests such as the minimal electroshock threshold and pentylenetetrazol-seizures in mice aFd conjugated estrogen-induced spikeand-wave discharges in cats (Sorel, 1961; Chen et al., 1968; Swinyard, 1969; Julien et al.,

1975). In contrast to imipramine’s antiepileptic properties at doses of 2.5-15 mg/kg, i.v., in cats and 17-25 mg/kg, i.p., in mice, convulsant effects were noted at higher doses. In the mouse, doses of 70 mg/kg induced Straub tails, tremors, and generalized chronic convulsions. In the cat, doses of 20-22.5 mg/kg, i.v., intensified penicillin and estrogen-induced epileptiform discharge (which is reduced at lower doses of imipramine) and lowered afterdischarge threshold to 40% below predrug control (Fig. 4 ) with the appearance of spontaneous episodes of repetitive spiking (Fig.

5).

Reference

~~

Fromm e t al. (1972)

Kiloh et al. (1961) Delay and Deniker (1959) Legg and Swash (1974) Pineda and Russel (1974)

The mechanism responsible for imipramine’s biphasic action on the CNS is a matter of speculation. That an action on brain catecholamines may be involved in the low-dose antiepileptic effects of imipramine can be postulated from several observations. Imipramine blocks the active reuptake of brain norepinephrine both in uitro (Glowinski and Axelrod, 1964) and in uiuo (Ross et al., 1971). Jobe et al. (1973) correlated this imipramine-induced inc&ase in brain norepinephrine with the drug’s depressant action on audiogenic seizures in the rat and postulated that norepinephrine exerts an inhibitory effect on the brain which tends to limit the spread of seizure discharge. In addition to its action on brain catecholamines, imipramine exerts a stabilizing effect on excitable membranes, an effect whikh may represent a mechanism of anticonvulsant action (Woodbury and Fingl, 1975). Imipramine possesses local anesthetic properties (Domenjoz and Theobald, 1959) and exerts direct depressant effects on both peripheral nerve (Chang and Chuang, 1972; Seemen et al., 1974) and muscle (Abood et al., 1963; Langslet et al., 1971). This effect may be due to a reversible depression of sodium and potassium conductances (Schauf et al., 1975) similar to that exerted by other anticonvulsants including lidocaine (Ritchie and Cohen, 1975), diphenylhydantoin (Lipicky et al., 1972) and carbamazepine (Schauf et al., 1974). Less clear are the mechanisms responsible for the convulsant effects of imipramine observed at high doses of the drug. It can be noted, however, that local anesthetics exert a similar biphasic effect on brain excitability (Julien, 1973). The convulsant effects of local

Mouse Mouse Mouse Mouse Mouse

Mouse Mouse Mouse Mouse Mouse Mouse Rabbit

Cat Mouse Cat Rabbit

Max. electroshock Max. electroshock Max. electroshock Max. electroshock Max. electroshock Max. electroshock Pentylenetetrazol Pentylenetetrazol Pentylenetetrazol Pentylenetetrazol Electroshock threshold Electroshock threshold Afterdischarge

Strychnine focus Strychnine Spontaneous EEG Spontaneous EEG

Rat

Species

Model 34.7 i.p. 11.6 i.p. 25.0 s.q. 30.0 s.q. 30.0 i.p. 14.0 i.p. 30.0 i.p. 32.0 i.p. 13.2 i.p. 50.0 i.p. 40.0 i.p. 16.0 i.p. 20.0 s.q.

Imipramine Amitriptyline Imipramine Amitriptyline Imipramine Imipramine Imipramine Imipramine Amitriptyline Imipramine Imipramine Amitriptyline Imipramine, ami triptyline Imipramine Imipramine Imipramine Imipramine 11.8 i.v. 50 i.p. 8 i.v. 50 i.v.

Dose

Drug

Suppression of discharge Potentiation of seizure Epileptiform pattern Epileptiform pattern

Seizure block Seizure block Seizure block Seizure block Seizure block Seizure block Seizure block Seizure block Seizure block Potentiation of seizure Seizure block Seizure block Increased threshold

Effect

TABLE 2 . Effects o f tricyclic antidepressants in laboratory models o f epilepsy

Baker and Kratky (1967) Theobald et al. (1968) Dasberg and Feldman (1968) Van Meter e t al. (1959)

Vernier (1961) Vernier (1961) Ogusa and Kimishiwa (1972) Ogusa and Kimishiwa (1972) Sigg (1959) Theobald et al. (1968) Sigg (1959) Vernier (1961) Vernier (1961) Theobald et al. (1968) Chen e t al. (1968) Chen e t al. (1968) Stille and Sayers (1964)

Reference

EFFECTS O F IMIPRAMINE IN EPILEPSY MODELS anesthetics may be related to a depression of central inhibitory pathways (Tanaka and Yamasaki, 1966; de Jong e t al., 1969) although similar studies involving imipramine have not been reported. Such mechanisms are a matter for additional study. It is probable, however, that this biphasic action of imipramine limits the drug's clinical utility for the treatment of seizure disorders, a limitation noted by Fromm et al. (1972).

193

Glowinski J and Axelrod J. Inhibition of uptake of tritiated noradrenaline in the intact rat brain by imipramine and strucNature turally related compounds. 204:1318-1319,1964. Goodman LS, Grewal MS, Brown WC, and Swinyard EA. Comparison of max. seizures evoked by pentylenetetrazol (Metrazol) and electroshock in mice, and their modification by anticonvulsants. J Pharmacol Exp Ther 108:168-176, 1953. Jobe PC, Picchioni AL, and Chin L. Role of brain norepinephrine in audiogenic seizure in the rat. J Pharmacol E x p Ther 184:l-9, 1973. ACKNOWLEDGMENT Julien RM. Lidocaine in experimental epilepsy: Correlation of anticonvulsant effect with This study was supported by USPHS grant blood concentrations. Electroencephalogr #NS-09835 and by a grant from the Rebecca Clin Neurophysiol 34 :639-645, 1973. Julien RM, Fowler GW, and Danielson MG. The Payne Livingston Foundation. effects of antiepileptic drugs on estrogen-induced electrographic spike-wave discharge. J Pharmacol Exp Ther 193:647-656, 1975. REFERENCES Julien RM and Halpern LM. Effects of diphenylhydantoin and other antiepileptic Abood LG, Kimizuka H, Rogeness G, and Biel drugs on epileptiform activity and Purkinje JH. Some antidepressant drugs and their cell discharge rates. Epilepsia 13:387-400, mechanism of action on excitable mem1972. brane. A n n N Y Acad Sci 107:1139-1146, Kiloh LG, Davison K, and Osselton JW.An 1963. of the electroencephalographic study Baker WW and Kratky M. Acute effects of analeptic . effects of imipramine. Electroenchlorpromazine and imipramine on hippocephalogr Clin Neurophysiol 13:216-223, campal foci. Arch Int Pharmacodyn Ther 1961. 165 :265-275, 1967. Chang CC and Chuang S. Effects of desipramine Langslet A, Johansen WG, Ryg M, Skomedal T, and Oye L. Effects of dibenzepine and and imipramine on the nerve, muscle and imipramine on the isolated rat heart. Eur J synaptic transmission of rat diaphragms. Pharmacol 14:333-339, 1971. Neuropharmacology 11:777-788, 1972. Chen G, Ensor CR, and Bohner B. Studies of Legg NJ and Swash M. Clinical note: Seizures and EEG acthation after trimipramine. drug effects on electrically induced extensor Epilepsia 15:131-135, 1974. seizures and clinical implications. Arch Int Lipicky RJ, Gilbert DL, and Stillman IM. Pharmacodyn Ther 172:183-218, 1968. Diphenylhydantoin inhibition of the sodium Dasberg H and Feldman J. Effect of imipraconductance in squid giant axon. Proc Nut mine, physostigmine, and amphetamine on Acad Sci USA 69:1758-1760, 1972. the electrical activity of the brain in the cat. Litchfield JT and Wilcoxin F. A simplified Psychopharmacologia 13:129-139, 1968. method of evaluating dose-effect experiDeJong RH, Robles R, and Corbin RW. Central ments. J Pharmacol E x p Ther 96:99-113, actions of lidocaine-synaptic transmission. Anesthesiology 30:19-23, 1969. 1947. Delay J and Deniker P. Efficacy of tofranil in Millichap JG. Anticonvulsant drugs. In: WS Root and FG Hofman (Eds), Physiological the treatment of various types of depression: Pharmacology: A Comprehensive Treatise, A comparison with other antidepressant Vol. 11, Part B. Academic Press, New York, drugs. Can Psychiatr Assoc J 4 : s 100-112, 1965, pp 97-174. 1959. Demetrescu M and Julien RM. Local anesthetics Ogusa C and Kimishiwa K. Central nervous actions and screening methods of antidepresand experimental epilepsy. Epilepsia sants. Folia Psychiatr Neurol Jap 15:235-248, 1974. 26:291-317, 1972. Domenjoz R and Theobald W. Zur pharmakologie des tofranil (N43-dirnethyl- Pineda MR and Russell SC. The use of a tricyclic antidepressant in epilepsy. Dis Neru aminopropyl-iminodibenzyl hydrochloride). Arch Int Pharmacodyn Ther 120:450-489, Syst 35:322-323, 1974. Ritchie J M and Cohen PJ. Cocaine, procaine 1959. and other synthetic local anesthetics. In: LS Fromm GH, Amores. CY, and Thies W. Goodman and A Gilman (Eds), The Imipramine in epilepsy. Arch Neurol Pharmacologica 1 Basis of Therapeutics. 27~198-204,1972. '

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Macmillan, New York, 1975, pp 379-403. Ross SB, Renyi AL, and Agren SO. A comparison of the inhibitory activities of iprindole and imipramine on the uptake of 5-hydroxytryptamine and noradrenalin in brain slices. Life Sci 10:1267-1277, 1971. Schauf CL, Davis FA, and Marder J. Effects of carbamazepine on the ionic conductances of myxicola giant axons. J Pharmacol E x p Ther 189~538-543, 1974. Schauf CL, Davis FA, and Kesler RL. Actions of the antidepressant drug imipramine on the voltage-clamped myxicola giant axon. J Pharmacol E x p Ther 193:669-675, 1975. Seeman P, Staiman A, and Chan-Wong M. The nerve impulse-blocking action of tranquilizers and the binding of neuroleptics to synaptosome membranes. J Pharmacol E x p Ther 190:123-130, 1974. Sigg EB. Pharmacological studies with tofranil. Can Psychiatr Assoc J 4 : S 75-85, 1959. Sore1 L. Research on epileptic drugs. Epilepsia 2:270-290, 1961. Stille G and Sayers A. The effect of antidepressant drugs on the convulsive excitability of brain structures. Int J Neuropharmacol 3:605-609, 1964. Swinyard EA. Laboratory evaluation of antiepileptic drugs: Review of laboratory methods. Epilepsia 10:107-119, 1969. Swinyard EA. Electrically induced convulsions. In: DP Purpura, J K Penry, D Tower, DM Woodbury, and R Walter (Eds), Experimental Models of Epilepsy - A Manual f o r the Laboratory Worker. Raven Press, New York, 1972, pp 433-458. Tanaka K and Yamasaki M. Blocking action of cortical inhibitory synapses by intravenous lidocaine. Nature 209:207-208, 1966. Theobald W, Wilhelmi G, and Krupp P. Analgesic and anticonvulsant activity of derivatives of dibenz(b,f)azepine. In: Proceedings o f the International Symposium on Pain. Academic Press, New York, 1968, pp 239-249. Van Meter WG, Owens HF, and Himwich HE. Effects of tofranil, an. antidepressant drug, on electrical potentials of rabbit brain. Can Psychiatr Assoc J 4 : S 113-118,1959. Vernier VG. The pharmacology of antidepressive agents. Dis Nerv Syst 22:s 7-13, 1961. Woodbury DM and Fingl E. Drugs effective in the therapy of the epilepsies. In: LS Goodman and A Gilman (Eds), The Pharmacological Basis of Therapeutics. Macmillan, New York, 1975, pp 201-226.

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biphasic action on the CNS as manifested by antiepileptic properties at low doses and convulsant effects at higher doses. In mice, imipramine (17.5-25 mg/kg, i.p.) blocks maximal electroshock seizures while exerting little or no effect on pentylenetetrazol-induced seizures. In cak, imipramine (2.5-15 mg/kg, i.v.) reduces penicillin and estrogen-induced epileptiform discharge, shortens afterdischarge duration, and elevates afterdischarge threshold. Higher doses in mice induce neurotoxicity, including clonic seizures. In cats, doses above 20 mg/kg intensify chemically and electrically induced seizures and induce spontaneous epileptiform episodes. Such a biphasic action of imipramine may limit the drug’s clinical utility as an antiepileptic agent and may provide an interesting tool for studies of catecholamines and brain excitability.

RESUMEN En diversos modelos de epilepsia experimental la imipramina ejerce una acci6n bifasica sobre el SNC que se manifiesta por propiedades antiepilkpticas a dosis reducidas y por efectos convulsivos a dosis m h elevadas. En ratones la imipramina (17,5-25 mg/kg i.v.) bloquea las convulsiones del electroshock miximo mientras que produce poco o ningun efecto sobre 10s ataques inducidos por el pentilentetrazol. En gatos la imipramina (2,5-15 mg/kg i.v.) reduce las descargas inducidas por la penicilina y 10s estr6genos, acorta la duraci6n de las postdescargas y eleva el umbra1 de las postelevadas, descargas. En ratones, dosis &s induce cierta neurotoxicidad incluyendo convulsiones cl6nicas. En gatos, dosis por encima de 20 mg/kg intensifican 10s ataques inducidos quimica o elhctricamente y desencadenan episodios epileptiformes espontaneos. Esta acci6n bifisica de la imipramina puede limitar la utilizaci6n clinica de esta medicaci6n como agente antiepilkptico y puede representar un excelente instrumento para 10s estudios de las catecolaminas y la excitabilidad cerebral.

(A. Portera, Madrid)

SUMMARY

ZUSAMMENFASSUNG

In a Variety of laboratory models of experimental epilepsy, imipramine exerts a

Bei einer Vielzahl von Labormodellen fur die experimentelle Epilepsie wirkt Imipramin biphasisch auf das ZNS : Antiepileptisch in

195 niedrigen Dosen, krampferregend in hoheren Anfalle. Bei Katzen verstarken Dosen uber 20 Dosen. Bei Mausen blockiert Imipramin mg/kg chemisch und elektrisch ausgeloste (17,5-25 mg/kg, i.p.) die maximalen Elektro- Anfalle und induzieren spontane epileptiforme schockkrampfe, wahrend es wenig oder keinen Episoden. Solche biphasische Wirkung des Effekt auf die pentylentetrazol-induzierten Imipramin kann den klinischen Nutzen als Krampfe ausubt. Bei Katzen reduziert Imipra- antiepileptisches Medikament begrenzen und min (2,5-15 mg/kg i.v.) die durch Penicillin und konnte weiterhin ein interessantes Hilfsmittel Ostrogen induzierten epileptiformen Entla- fur Untersuchungen der Catecholamine und der dungen, verkiirzt die Dauer der Nachentladun- Hirnexitabilitat darstellen. gen und erhoht die Schwelle fur Nachentladungen. Hohere Dosen fuhren bei Mausen zur (D. Scheffner, Heidelberg) Neurotoxizitat einschliesslich klonischer