An analysis of tranquilizers in chronically electrode implanted cat

In?. J. NelWOPklMcZCO~, 1962, 1,49-53.

Perffamon Press. Priited io Gt. Britain. II table, 2 fi+~s.,10 tefs.

AN ANALYSIS OF TRANQUILIZERS IN CHRONICALLY ELECTRODE IMPLANTED CAT R. KIDQ and K. ~~~~TU Shionogi Reseamb Laboratory, Osaka, Japan Snmmary-Experiments were performed to analyse the characteristics of tranquilizers and barbiturates both electrographically and behaviourally using chronically electrode-implanted cats. In the chlorpromazine and reserpine-treated cat, such characteristics in EEG and behaviour as moderately fall in the neocortical and the thaiannc activities. marked fall in the amygdaloid and the hippocampal activities dissociated from the neocorti& activities, unwoncerned posture to the Circumstance changes of various autonomic funGtkn3~non-hypnotic action by large dose of the drug* were observed. Also, “Vage-like behaviour” caused by chlorpromazine were analysed. On the contrary, characteristic of ERG in p~nob~bi~-Na treatment was mostly observed as a fall of neocortical and thalamic activities with anesthetization. Meprobamate seems to act intermediately between chlorpromazine and phenobarbitalNa. INTRODUCTION 2%~ purpcrse of the present study was the comparison between the differences of central e%%Xsoftransfers such as ~~~~~GM~~, reseqine and meprobamate and barbiturates

both efectroence~halo~aphicafly cats.

and behaviouralty using chronicafly el~tr~e-im~Ianted

MBTHODS Experiments were performed using 20 chronic cats with a cross-over design of 3 weeks interval. The im~~antrne~t technique and inserted points of electrode in chronic cat have already been described ~A~~TU, 1959). Dosage of each drug, administered intravenously, was classified into three levels from the behaviour as shown befow. In order to analyse the site of action of the drugs, effect of drugs on EEG arousal reaction and behavioural attention reaction caused by various external stimulations and also on behaviour changes elicited by electrical stimulation of various areas of the brain such as anterior-, posterior part of the hypothalamus, the midbra,iu recticular formation and the amygdala were examined.

After injection of ~~~~rorna~ne (0*2, I-5, 15 mgjkg), the eat took a drowsy to lightsleeping posture. Characteristic ofEEG patterns were irreguIar slow waves in the neocortex and low voltage, fast waves in the amygdala (Fig. IA). On the other hand, in site of the arousal waves that were seen in the neocortex, hippocampal arousal waves were completely blocked (Fig. IB). Namely, “ dissocation” of EEG patterns (TOXUZANE:et al., 1960) between the neocortex and the ~ppo~arn~us was induced. Narcosis was never 49

50

R. KIDO and K. YAMAMOTO

FIG. 1. EEG patterns before and after administration of chlorpromazine in a chronic cat. The upper two pictures show normal alert and drowsy pattern. (A): 64 min after administration of 5 mg/kg of chlorpromazine, the cat took a relaxed posture; irregular slow waves in the sensory areas of the neocortex and in the centremedian nucleus of the thalamus and desynchronized pattern in the amygdala were seen. (B): 280 min after, the cat has been taking the same posture continuously; in spite of the arousal pattern which was seen in the neocortex, thalamus and the amygdala, blocking of the hippocampal arousal wave was observed. LCM : left centremedian nucleus of the thalamus, L.AMY: amygdala, L.HIP: hippocampus, L.ANT.SIG : anterior sigmoid gyrus, L.ECT.SYL: ectosylvian gyrus, L.LAT: lateral gyrus.

seen even with large dose of chlorpromazine ,and the main consciousness level remained a drowsy or light sleeping state, however, EEG arousal reaction and behavioural attention reaction almost disappeared. Also, after injection of chlorpromazine (1-5 mg/kg), the cats which were taking a sleeping posture suddenly jumped up and scratched the cage or bit the lead wire (Fig. 2). This abnormal behaviour, which was called “rage-like behaviour” and resembled the complex behaviour of “sham rage” and “chewing response”, was repeatedly seen in almost all cats treated with chlorpromazine within about 6 hr after injection. In order to analyse this behaviour, the following stimulation experiments were performed and the elevation of thresholds was compared. As definitely shown in Table 1, the thresholds of the anterior hypothalamic and the reticular stimulation were elevated after injection of chlorpromazine. On the contrary, the thresholds of “sham rage” caused by the posterior hypothalamic stimulation and “chewing response” caused by the amygdaloid stimulation were not affected. These unbalances of the threshold elevation could be one of the mechanisms of the “rage-like behaviour” caused by administration of chlorpromazine.

FIG. 2. 50 min after chlorpromazine 5 mg/kg I.V. (Cat No. 43, 3.5 kg 3). “Rage-like behaviour” induced by intravenous injection of chlorpromazine (I-5 mgfkg). The cat which was taking a sleeping posture, suddenly jumps up and scratches the cage or bites the lead wire. This abnormal behaviour, which resembled the complex behaviour of sham rage and chewing response, was repeatedly seen in almost all cats treated with chlorpromazine within about six hours after injection. Characteristic of EEG during this paroxysm was arousal pattern in the hippocampus and slow waves in the neocortex and the thalamus.

f. p, SO

51

An analysis of tranquilizers TABLE. 1. EFFECT OF CHLORPROMAZINE, MEPROBAMATE AND BEHAVIOUR CHANGES ELICTED BY RETICULAR, HYPOTHALAMIC IN CHRONIC CATS

Parameters

Behaviour

Anterior hypothalamus

100 c/s 1 msec 2.5-7 .O V

Mydriasis Olfactory response Searching response

Posterior hypothalamus

100 c/s

Searching response

Sham rage

lmsec 2.0-7.0 V Reticular formation

Amygdala

100 c/s 2 .O-3 a5 V

Mydriasis Piloerection Somatic movement

40 c/s 3 msec 1 G-5 .O V

Olfactory response Chewing response Salivation

lIllSl?C

-

: O-25%,

f

PHENOBARBITAL-NA AND AMYGDALoID

ON VARIOUS STIMULATION

PhenoChlorproMeprobarbital-Na mazine bamate 3-5mg/kg i.v. 30 mg/kg i.v. 30 mg/kg iv.

f

80%

f

50%

f

67%

-

6%

f

46%

f

41%

-

4%

f

65%

f

60%

38%

f

32%

f

75%

7%

f

30%

f

63%

f

-

:26-100%

This experiment was carried out to analyse the mechanism of “rage-like behaviour” which was elicited by administration of chlorpromazine. The unbalance of the threshold elevation between the anterior hypothalamus-reticular formation and the posterior hypothalamusamygdala was pointed out as a mechanism of occurrence of this abnormal behaviour. Arrow showed a grade of threshold elevation.

2.

Reserpine

Reserpine (0.03, 0.1-0.3, 1.5 mg/kg) caused rigidity of the skeletal muscle, frequent respiration, ptosis, myosis and diarrhoea. These effects reached a peak within 2448 hr and continued for 100 hr. Rhythmical slow waves of about 12 c/s were continuously seen in the neocortex and the thalamus, while the amygdala and the hippocampus showed arousal pattern. Within 2448 hr after administration of reserpine, in spite of the arousal pattern seen in the neocortex, the limbic system, especially the amygdala, showed a deep sleep-like pattern taking a sedate behaviour. At this time, normal EEG arousal reaction of the neocortex and “arousal pattern in lower level” (TOKIZANE et al., 1960) of the amygdala was observed, but behavioural attention reaction disappeared. 3. Meprobamate Meprobamate (6, 30-60, 120 mg/kg) caused the appearance of rhythmical 14 to 20 c/s waves in the neocortex and the thalamus. Spike discharges in the amygdala, characteristic 25 c/s of high voltage waves were seen in the hippocampus at higher dose of meprobamate, and consciousness level from the behaviour showed drowsy to deep sleep. Behavioural attention reaction remained normal even with large doses of meprobamate.

52

R. KIDOand K. YAMAMOTO

4. Phenobarbital-Na Phenobarbital-Na (6, 30-60, 120 mg/kg) caused sedation, sleep and narcosis. High voltage slow waves in the neocortex and the thalamus, multiple spikes in the amygdala and low voltage fast waves in the hippocampus were observed. Disappearance of EEG arousal reaction usually progressed in parallel with the one of the behavioural attention reaction, and “arousal pattern in lower level” was sometimes observed in the neocortex and the thalamus. DISCUSSION TOKIZANEet al (1960) clarified the existence of the “hypothalamic activating system” on the paleo- and the archicortex. The results obtained with chlorpromazine and reserpine, from this point of view, seem to suggest that each drug inlluenced both activating systems. KAWAMURAet al (1961) showed that chlorpromazine was more depressive on the hypothalamic activating system than on the reticular activating system in acute cats, electrographically. YOKOTA(1959) in chronic cats and MONNIER(1957) in rabbits also showed the depressive effect of chlorpromazine on the reticular activating system. On the other hand, since the desynchronization of amygdaloid lead and the blocking of hippocampal arousal wave, as above mentioned, were usually obtained as a result of activation of the preoptic region (TOKIZANEet al., 1960) or the septum one of the effects of chlorpromazine might be activation for the inhibitory area of the hippocampus as described by PRESTON(1956). Also, a mechanism of “rage-like behaviour” caused by chlorpromazine, was presumed as the unbalance in the elevation of the stimulation thresholds in the central nervous system, KAADAand BRULAND(1960) described the same result on the posterior hypothalamic threshold to the behaviour in chlorpromazine treated cats. The neocortical and thalamic slow waves caused by reserpine might suggest the effect of the drug on the neocortical system as described by MONNIER(1957). On the contrary, behavioural sedativeness and electrographical deep sleep-like pattern in the amygdala, dissociated from the neocortical arousal pattern later, seems to suggest the one of the sites of action of the drug being on the limbic system. KIKUCHI(1961) pointed out, electrographitally, that the site of action was in areas others than the neocortical system in reserpine treated rabbits. After administration of meprobamate, characteristic EEG pattern appeared in all leads, however, specific effect of the drug on the thalamus, as shown by HENDLEYet al. (1957), was not noticed. EEG change in the limbic system, the result of Table 1 and RANDALL’Sdescription (1961) might suggested that site of action of meprobamate exists not only neocortical system but also limbic system. Evident changes in EEG caused by phenobarbital-Na were seen in the neocortical and the thalamic leads. And these were confirmed as a fall of function in the reticular activating system behaviourally (RANDALL,1961) (also as shown in Table 1) and electrographically. As above mentioned, differences between tranquilizers and barbiturates were markedly recognized and meprobamate seems to exist intermediately between chlorpromazine and phenobarbital-Na. RksumL-Sur des chats, porteurs d’Clectrodes chroniques on a fait des expkiences pour analyser les caracttristiques des tranquillisants et des barbituriques, sur Mectroenctphalogramme et sur le comportement des animaux.

53

An analysis of tranquilizers Chez les chats trait& a la chlorpromazine et a la reserpine, on a pu observer, dam l’electroencephalogramme, une diminution mod&&s des activites neocorticales et thalamiques, une diminution nette des activites amygdaliennes et hippocampiques dissociQ des activites necortitales, une posture inadapt&e aux circonstances, des modifications de certaines fonctions De plus, on a autonomes et un effet non hypnotique de fortes doses des meclicaments. observe un “comportement rabique” cause par la chlorpromazine. D’autre part, le traitement par le phenobarbital sodique a fait apparaitre le plus souvent dans l%lectro-encephalogramme, une diminution des activites neocorticales et thalamiques ainsi qu’un effet anesthesiant. Le meprobamate parait occuper une place intermediaire entre la chlorpromazine et le phenobarbital sodique. Zusammenfassung-An Katzen als chronischen Elektroden-Tragern wurden Versuche durchgefiihrt, urn den Einfluss von Tranquillizern und Barbituraten auf EEG und Verhalten zu studieren. Bei den mit Chlorpromazin und Reserpin behandelten Katzen kommen im EEG und im Verhalten ein mksiger Abfall der neokortikalen und thalamischen Aktivitlt, ein deutlicher Abfall der amygdaloiden und hippokampalen Aktivitat unabhlngig von der neokortikalen Aktivitlt, eine den Umstanden unangebrachte Haltung, Veranderungen verschiedener autonomer Funktionen und eine nicht-hypnotische Wirkung grosser Dosen der Medicamente zur Beobachtung. Ausserdem wurde unter Chlorpromazin-Wirkung ein tollwut-artiges Verhalten festgestellt. Demgegntiber wurden Besonderheiten des EEG bei mit Phenobarbital-Natrium behandelten Tieren meist in Form eines Rtickgangs der neokortikalen und thalamischen Aktivitat samt einem Narkose-Effekt beobachtet. Meprobamat scheint sich wirkungsmassig in dieser Beziehung zwischen Chlorpromazin und Phenobarbital-Natrium einordnen zu lassen. Author’s address-K. YAMAMOTO, Division of Neuropharmacology, Shionogi Research Laboratory,Shionogi & Co., Ltd. Fukushima-ku, OSAKA, Japan

REFERENCES HENDLEY,C. D., LYNES,T. E. and BERGER,F. M. (1957). Effect of meprobamate on electrical activity of thalamus and other subcortical areas. Tranquilizing Drugs. Publication No. 46 of the American Association for the Advancement of Science, Washington, D.C., 35-46. KAADA, B. R. and BRULAND,H. (1960). Effects of chlorpromazine on the “attention” (orienting), fight and anger responses elicited by cerebral stimulation. Acta Physio. &and. 50: suppl. 175, 81. H., NAKAMURA,Y. and TOIUZANE,T. (1961). Effect of acute brain stem lesions electrical activities of the limbic system and neocortex. Jap. J. Physiof. 11: X4-575.

KAWAMIJRA,

on the

KIKUCHI,T. (1961). Electroencephalographic studies on the action of reserpine in the rabbit and combined action of reserpine and methamphetamine. Folia Pharm. Jap. 57: 173492. MONNIER,M. (1957). Topic action of psychotropic drugs on the electrical activity of cortex, rhinencephalon and mesodiencephalon. Psychotropic Drugs. Elsevier, New York. 217-234. PRESTON, J. B. (1956). Effect of chlorpromazine

on the central nervous system of the cat; a possible neural basis for action. J. Pharmacol. 118: 100-115. RANDALL,L. D. (1961). Pharmacology of chlordiazepoxide (Librium). Dis. Nerv. Syst. 22: 7-15. TOKIzANE,T., KAWAMURA,H. and IMAMURA,G. (1960). Hypothalamic activation upon electrical activities of Paleo-and Archicortex. Neurologia, Medico-chirurgica. 2: 63-76. YAMAMOTO, K. (1959). Studies on the normal EEG of the cat. Comparison between the EEG of fixed cats and unfixed cats seen from the skull and subcortical leads in various consciousness levels and the corresponding behaviour. Annual Reports of Shionogi Research Laboratory, Osaka, Japan. 9: 1125. -1164. YOKOTA, S. (1959). The effect of chlorpromazine on the electrical activity of the brain in the conscious cat by the implanted electrode method. Folia Pharm. Jap. 55: 966980.