Effects of Psychotropic Drugs on Canine Cerebral Diazepam

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.9.838 on 1 September 1975. Downloaded from

Journal ofNeurology, Neurosurgery, and Psychiatry, 1975, 38, 838-844

Effects of psychotropic drugs on canine cerebral metabolism and circulation related to EEG diazepam, clomipramine, and chlorpromazine

ATSUO SARI', YASUO FUKUDA, TAKEFUMI SAKABE, TSUYOSHI MAEKAWA, AND TOSHIZO ISHIKAWA From the Department of Anesthesiology, Yamaguchi University School ofMedicine, Ube, Yamaguchi, Japan

SYNOPSIS The effects of diazepam, clomipramine, and chlorpromazine upon cerebral metabolism guest. Protected by copyright. and blood flow were examined separately in 18 dogs. After the administration of diazepam or clomipramine, cerebral cortical oxygen consumption (CMRO2) decreased significantly by a maximum of 17% and 13% of control within 10 minutes and 15 minutes, and returned to control at 120 minutes and 90 minutes, respectively. Chlorpromazine, however, decreased by a maximum of 10% of control, a level which continued throughout the period of observation. It was observed that reduction in CMRglucose was followed by the reduction in CMRO2 at an interval during the early stages of CMRO2 depression. Diazepam produced a significant decrease in CBF accompanied by a reduction in CMRO2, but neither clomipramine nor chlorpromazine had any effect on CBF in spite of reduction in CMRO2. Reduction in CMRO2 both with diazepam and clomipramine was accompanied by slow wave activities of EEG, but with chlorpromazine reduction in CMR02 was accompanied with less pronounced slow wave activities. It was concluded that the three drugs examined were cerebral metabolic depressants.

It has been generally assumed that the effects of 1960), where the other two drugs are concerned, psychotropic drugs upon the central nervous despite their profound effects on the central system are related to their therapeutic action in nervous system, little information has been patients with psychiatric disorder. This assump- reported regarding their effect on cerebral tion follows from extensive pharmacological, metabolism (in vivo) and circulation. It was, http://jnnp.bmj.com/ biochemical, and electrophysiological studies therefore, the purpose of the present study to obtained with these drugs. In the present study attempt to discover whether or not these drugs we examined the effect of three psychotropic produce any changes in cerebral metabolism drugs-diazepam, clomipramine, and chlor- and circulation related to EEG. promazine-on the canine cerebral metabolism A part of the study on diazepam has been and circulation. reported elsewhere (Maekawa et al., 1974). Although the effects of chlorpromazine on on September 25, 2021 by cerebral oxygen consumption have been exten- METHODS sively investigated in animals (Frowein et al., 1955) or men (Fazekas et al., 1955; Morris et al., Eighteen fasting unpremedicated dogs weighing 8 to 1955; Aizawa et al., 1956; Moyer et al., 1956; 26 kg were anaesthetized with halothane (1.0-2.0%) inspired in oxygen. The trachea was intubated with a Ehrmantraut et al., 1957; Sutherland et al., cuffed endotracheal tube with the aid of succinyl- choline and thereafter 10 mg/kg/h was given to I Address for correspondence and reprints: Dr A Sari, Department Ventilation was controlled of Anesthesiology, Yamaguchi University, School of Medicine, 1144 maintain muscle paralysis. Kogushi Ube, Yamaguchi, Japan. with an animal respirator, AR-300 (Acoma, Tokyo, (Accepted 10 March 1975.) Japan). Cannulae were placed in the femoral artery 838 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.9.838 on 1 September 1975. Downloaded from Effects ofpsychotropic drugs on canine cerebral metabolism and circulation related to EEG 839 for blood sampling and pressure determination, in one femoral vein for the reinfusion of blood, and in % Control another femoral vein for drug administration. There- after, the dog was placed in a prone position with the head supported on a block. CMRo2 The surgical preparation used in the present study for direct measurement of cerebral blood flow (CBF) was originally described in detail by Michenfelder et al. (1968). With this technique, blood flow from the s0 Diazepam sagittal sinus is diverted through a cannula to an 401 0.25 mcg/kg external reservoir at the level of the sinus, measured by timed collection, and returned by pump into the EEG 30 femoral vein. The percentage of the drained region 20 was determined by staining the veins with Sudan III I dissolved in vinyl acetate monomer injected from the 1t cannulated portion of the sagittal sinus at the completion of the study. These percentages and the indi- C25 IO5I20 30 45 60 90 120 150mh vidual brain weights of the dogs studied were used to convert unit of flow per minute to per 100 g of brain % Control weight per minute. After isolation by obliteration of the diploic veins that communicate with the sagittal CMRo2

sinus, the collection and the measurement of the guest. Protected by copyright. venous drainage of a known portion of the brain provides a ready source for sampling mixed venous blood, which is exclusively representative of the brain tissue. The oxygen content of arterial and sagittal sinus blood was calculated from measurements of oxy- haemoglobin (IL 182 CO-oximeter, Instrumental EEG Laboratories, Boston, Mass., U.S.A.) and oxygen tension (IL 113 electrodes). Additional measurements included arterial pressure (strain gauge), pH and PaCO2 (electrode 37°C), and brain temperature (parietal epidural thermistor). Cerebral metabolic rate for oxygen (CMRo2) was calculated as the % Control product of CBF and arterial sagittal sinus blood 110. oxygen content difference (C(a-v)02). Blood glucose level was determined by an enzymatic method. CMRo2 ir,Ir CMRgluc se was calculated as the product of CBF and arterial sagittal sinus blood glucose difference (C(a-v)g1ucose). Cerebral vascular resistance (CVR) 90 was calculated as the ratio of the mean arterial #0 Chlorpromazine http://jnnp.bmj.com/ pressure (MAP) to the CBF. The oxygen-glucose 40 index (OGI) was calculated as described by Cohen et 0.5 mg/kg al. (1967). The EEG was recorded from the parietal EEG 30 lobes using bipolar silver-silver chloride disc electrodes and was analysed every 10 seconds with a 20 r I - i frequency analyser, MAF-5 (Nihonkoden, Tokyo, Japan) throughout the study. Every activity was I0 expressed as a percentage of on September 25, 2021 by integrated voltage of 8 5 l0152 30 45 60 (2-4 Hz), 6 (4-8 Hz), a (8-13 Hz), Pi' (13-20 Hz) and 90 12 150mm P2 (20-30 Hz) waves. FIG. 1 Effects of diazepam, clomipramine, and chlorpro- After completion of the surgical preparation, the mazine on CMRo2; and each wave activity ofEEG. Three figures represent sequential changes in CMRo2; accom- inspired halothane was maintained at 0.2% for 1 h paniedby changes in the EEG after administration ofdiaze- so that any possible effects of residual halothane on pam, clomipramine, and chlorpromazine. Key: 0: 8 wave, CMRo2, CBF or EEG could be kept constant 0: Owave, x: a wave, A::, wave, 0: 2 wave. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.9.838 on 1 September 1975. Downloaded from 840 Atsuo Sari, Yasuo Fukuda, Takefumi Sakabe, Tsuyoshi Maekawa, and Toshizo Ishikawa throughout the study. Ventilation was adjusted to tion of blood or other cerebral vascular anomalies maintain normocapnia (PaCO2 39 ± 2 mmHg). was found at necropsy. Sodium bicarbonate was given as needed to main- Statistical significance was tested by Student's t tain a normal buffer base. The epidural temperature test for paired data (P < 0.05, considered statistically was maintained at 37 ± 0.1 °C by external means, and significant). haemoglobin levels were maintained above 13 g/dl. Blood loss due to sampling was replaced by fresh RESULTS heparinized blood. Control measurements were obtained over a 30 The sequential effects of diazepam, clomi- minute period and mean values were calculated from pramine, and chlorpromazine upon cerebral five to eight consecutive determinations of CBF and haemodynamics, metabolism, and EEG are C(a -v)02 and two to three determinations of shown in Tables 1, 2, and 3, and Fig. 1. C(a -v)glucose. The dogs were divided into three groups. Five dogs received 0.25 mg/kg diazepam, CEREBRAL METABOLISM Two minutes after the five dogs received 2 mg/kg clomipramine, and eight dogs received 0.5 mg/kg chlorpromazine. All drugs administration of 0.25 mg/kg diazepam, CMRO2 was were administered intravenously. After control reduced significantly and remained de- determinations, measurements were done subse- creased over a 90 minute period. Thereafter, it quently at 2, 5, 10, 20, 30, 45, 60, 90, 120 and 150 returned to control value. Its minimum level (except for clomipramine) minutes after injection of was 84% of control at 10 minutes. OGI at two each drug. No evidence of extracerebral contamina- minutes decreased significantly to 770. guest. Protected by copyright.

TABLE 1 EFFECTS OF DIAZEPAM (0.25 MG/KG) ON CEREBRAL METABOLISM AND CIRCULATION

Time CMRo2 CMRglucose OGI CBF MAP C VR PaCO2 PssO2 (min) (m/l100g/min) (mglOO0g/min) (%) (ml/l00g/min) (mmHg) (mmHg/ml/ (mmHg) (mmHg) JOOg/min) Mean SE Mean SE Mean SE Mean SE Mean SE Mean SE Mean SE Mean SE Control 6.3 0.4 9.1 0.6 96 4 60 2 110 9 1.85 0.19 40.8 1.5 34 2 2 5.3 0.4* 9.4 1.2 77 5* 51 10* 98 12 1.94 0.25 41.8 1.3 33 1 10 5.2 0.4* 7.4 0.6* 100 5 53 2* 101 10 1.94 0.25 NE NE 33 1 30 5.7 0.4* 7.9 1.0 99 6 54 3 103 9 1.98 0.26 NE NE 32 3 90 5.9 0.4* 9.6 1.2 87 9 55 3 114 8 2.14 0.24 39.3 1.8 29 3 150 6.1 0.4 8.8 0.7 93 5 57 4 110 7 1.99 0.23 39.1 1.9 30 3

* Significantly different from control (P < 0.05). NE = not examined.

TABLE 2 http://jnnp.bmj.com/ EFFECTS OF CLOMIPRAMINE (2 MG/KG) ON CEREBRAL METABOLISM AND CIRCULATION

Time CMRo2 CMRglucose OGI CBF MAP C VR PaCO2 PssO2 (nin) (mi/JOOg/min) (mg/1oog/min) (%0) (ml/100g/min) (mmHg) (mmHg/mll (mmHg) (mnmHg) 1OOg/min) Mean SE Mean SE Mean SE Mean SE Mean SE Mean SE Mean SE Mean SE

Control 6.4 0.2 9.1 0.3 95 4 58 2 123 9 2.17 0.21 37.6 0.9 34 2 on September 25, 2021 by 5 6.3 0.4 9.3 0.5 90 3 59 4 112 13 1.98 0.32 38.1 0.4 34 2 10 5.8 0.3* 9.4 0.6 84 6* 55 4 96 11* 1.78 0.25* 37.6 0.4 33 3 15 5.6 0.4* 9.6 0.6 80 4* 53 4 79 12* 1.53 0.22* 38.7 0.5 33 4 30 5.9 0.3* 8.5 0.6 95 8 54 3 83 13* 1.56 0.22* 38.4 0.4 32 3 60 6.1 0.4 9.3 0.6 88 6 57 3 106 10 1.88 0.17 38.2 0.4 32 2 120 6.5 0.2 9.1 0.5 97 3 57 3 115 8 2.04 0.19 39.2 1.1 31 2

* Significantly different from control (P < 0.05). J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.9.838 on 1 September 1975. Downloaded from

Effects ofpsychotropic drugs on canine cerebral metabolism and circulation related to EEG 841

TABLE 3 EFFECTS OF CHLORPROMAZINE (0.5 MG/KG) ON CEREBRAL METABOLISM AND CIRCULATION

Tim1e CMIRo2 CMRglucose OGI CBF MAP C VR PaCO2 PssO2 (min) (mI/J00g/min) (m?g/IOg/mmin) (,/) (mill00g/min) (inmHg) (mmHg/ml/ (mmHg) (,nunHg) JOOg/mnin) .Mfean SE Mean SE Mean SE Mean SE Mean SE Mean SE Mean SE Mean SFE Control 6.3 0.1 8.8 0.3 97 2 60 3 94 6 1.57 0.07 39.2 0.7 35 2 5 6.3 0.1 11.5 1.0* 73 5* 58 3 90 6 1.56 0.10 39.5 0.7 34 2 10 5.8 0.2* 9.8 0.7 82 6 59 3 84 6* 1.46 0.08 39.6 0.6 34 3 30 5.8 0.2* 8.8 0.3 89 3 57 2 77 5* 1.33 0.09* 40.0 0.8 32 3 90 5.8 0.2* 8.4 0.4 93 4 53 2 74 4* 1.42 0.12 39.9 1.3 28 2 150 5.6 0.2* 8.0 0.3 93 5 49 3 70 6* 1.45 0.15 38.6 0.7 26 2

* Significantly different from control (P < 0.05).

A significant reduction in CMRO2 was ob- PaCO2 or sagittal sinus P02 (PssO2) were served between 10 and 30 minutes after admini- observed during the period of observation in all stration of 2 mg/kg clomipramine. And there- groups after the administration of each drug. after CMRO2 gradually returned to control value

during 45 to 120 minutes. The minimum level in EEG AND CMRo2 Representative EEG changes guest. Protected by copyright. CMRO2 in the clomipramine group was 87% of and corresponding values of CMRO2 of the control at 15 minutes after the injection. There three groups are illustrated in Figs 2, 3, and 4. were no significant changes in CMRglucose. The With diazepam, high voltage (100-150 .tV) slow OGI showed a transient significant decrease between 10 to 15 minutes, and thereafter returned to control. With 0.5 mg/kg chlorpromaz- CMRo2 ine, CMRO2 decreased significantly to 92% of (rn/lOOg/rnln) control 10 minutes after injection and continued to decrease throughout a 150 minute period of Control 6.12 _ observation. At five minutes, chlorpromazine briefly, but significantly, caused an increase of Diazepom (0.25mg/kg) CMRglucose while not significantly decreasing CMRO2. As a result, a significant reduction in OGI occurred.

CEREBRAL HAEMODYNAMICS A statistically sig- 0Omin 5.05 1 nificant reduction in CBF was produced at two and 10 minutes in the diazepam group, but was http://jnnp.bmj.com/ not accompanied by significant changes in MAP 30min 5.26 M or CVR. In each group that was given clomipramine or chlorpromazine, MAP started to decrease significantly at 10 minutes with a 5.75 concomitant reduction in CVR and gradually 90 mn returned to control value within 60 minutes in

the clomipramine group, but continued to de- on September 25, 2021 by crease throughout the period observed in the 150mmn 6.06 ". chlorpromazine group. There were no significant _o&vOj changes in CBF in the two groups, which indicates that CBF was maintained by a significant reduction in CVR accompanied by a consider- FIG. 2 A typical EEG tracing before and after injec- able fall in MAP. No significant changes in tion ofdiazepam with corresponding values ofCMRo2. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.9.838 on 1 September 1975. Downloaded from 842 Atsuo Sari, Yasuo Fukuda, Takefumi Sakabe, Tsuyoshi Maekawa, and Toshizo Ishikawa

CMRo2 (m/liOo/mln) CMR02 (m/IOOg/mln)

- Control 6.61 q'_ Imf Control 6.68 ^ Clormipromine (2 mg/kg) Chlorpromozine (0.5 mgAg), 5 min 6.51 < _ 5 mn 6.73 "H^A16,WjO

15min 6.38 J 10 min 6.12

30 nm 6.12 AM 0kA,/\b ywo 30 min 5.46

60 mn 6.32 2 90 min 5.79 guest. Protected by copyright. 120min 6.60 150 min 5.68

1 5O.uV I 5OpV 19 I 5

FIG. 3 A typical EEG tracing before and after injec- FIG. 4 A typical EEG tracing before and after injection of clomipramine with corresponding values of tion of chlorpromazine with corresponding values of CMRo2. CMRo2.

wave activity (8) predominated within two DISCUSSION minutes after the injection with a concomitant decrease in fast waves. These EEG changes were In dosage similar to that used in clinical prac- statistically significant and thereafter gradually tice, diazepam, clomipramine, and chlorpro- returned to control levels over a 20 to 30 minute mazine cause a significant reduction in CMR02 period. Such predominant increases in slow in dogs. wave activity corresponded with the decreases in Reduction in CMR02 with diazepam accom- CMRO2 (Fig. 2). With clomipramine, slow wave panied by a concomitant reduction in CBF http://jnnp.bmj.com/ (8) activities showed a tendency to increase, and occurred within two minutes after the injection. fast wave activities decreased within five minutes The appearance of the effect of diazepam on after injection and reached their lowest value CMRO2 was faster than either clomipramine or within 15 to 30 minutes, corresponding to a chlorpromazine, which possibly indicates that reduction in CMRO2 (Fig. 3). These EEG diazepam can pass the blood-brain barrier changes with clomipramine gradually returned faster than the other two. This is in agreement

to control levels within 90 to 120 minutes after with findings reported by Kleijn (1969) that upon September 25, 2021 by injection. Chlorpromazine showed different take of [14C]diazepam in the mouse brain EEG changes from the two former drugs; reaches its maximum about one minute after significant increases in 8 and a wave activities intravenous injection. In vitro, Davis et al. were observed from 30 minutes and 10 minutes (1971) demonstrated a reduction in oxygen after injection, respectively, accompanied by a consumption in rat brain mitochondria. significant reduction in fl2 waves (Fig. 4). There has been no available report concerning J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.9.838 on 1 September 1975. Downloaded from Effects ofpsychotropic drugs on canine cerebral metabolism and circulation related to EEG 843

the effect of clomipramine or other types of and chlorpromazine is due to disproportional antidepressant drugs on cerebral oxygen con- change in CMRglucose to a reduction in CMRO2. sumption in vivo. However, in vitro, Ernsting et This was also suggestive in the chlorpromazine al. (1960) investigated the effect of several group at 10 minutes. Our findings showed that psychotropic drugs on the oxygen consumption the changes in CMRgIucOse were slower than in rat brain and concluded that imipramine those of CMRO2 at early states of their altera- reduced oxygen consumption significantly. Di tion. This delayed change in CMRglu0ose was Mascio et al. (1964) found the tricyclic anti- probably due to differences in equilibration of depressants, imipramine or desipramine, pro- oxygen and glucose metabolism. Chlorpromazine duced hypnotic-like action in normal men. The produced a significant increase in CMRglucose at present study indicated that their hypnotic-like five minutes. Aizawa et al. (1956) found an action may be related to decrease in CMRO2. increase in CMRglucose 30 minutes after injection of chlorpromazine in man that was probably In the dog, Frowein et al. (1955) could not due to a rise in glucose level in the blood, but the observe any significant changes in CMRO2 and blood glucose level was not mentioned. In the CBF after the injection of 2-10 mg/kg chlor- present study, a transitory but significant in- promazine. CMRO2 in man (Fazekas et al., crease in CMRglucose was not accompanied by an 1955; Morris et al., 1955; Aizawa et al., 1956; elevated blood glucose level. This finding is Moyer et al., 1956; Ehrmantraut et al., 1957; contrary to Sutherland et al., 1960) also, showed no changes previous reports (Norman and

Hiestand, 1955; Ryall, 1956; Bonaccorsi et al., guest. Protected by copyright. under chlorpromazine. However, in the present 1964; Bachelard and Lindsay, 1966), which sug- study, the reduction in CMRO2 observed within gest hyperglycaemia with this drug. However, 10 minutes after the injection of 0.5 mg/kg Norman and Hiestand (1955) found a profound chlorpromazine continued throughout the period species variation in hyperglycaemic response to of observation. This reduction in CMRO2 lasted chlorpromazine. At the present, it is difficult to much longer than with the two other drugs. evaluate the significance of the increase in Cassano et al. (1965) demonstrated the distribu- CMRglucose with chlorpromazine. tion of chlorpromazine in cat brain using an Changes in CMRO2 were paralleled by slow autoradiographic technique and showed that wave activities in the EEG (Fig. 1). During a retention of this agent in the cortex was reduced period of reduction in CMRO2 by both diazepam four hours later. Although many of the reports and clomipramine, slow wave activities were cited above are contrary to our findings, a pos- predominant and returned to control levels sible explanation for this discrepancy could be when CMRO2 did. With chlorpromazine, how- the difference in the methods used for measuring ever, an increase in slow wave activity was not so CBF. The above-mentioned studies determined marked, whereas a decrease in fast wave activity CBF by the nitrous oxide method of Kety and was significant. Gleichmann et al. (1962) and Schmidt (1948), while, in our study, CBF was Ingvar et al. (1962) demonstrated a correlation determined by the direct measurement method between cortical oxygen consumption and EEG http://jnnp.bmj.com/ described originally by Michenfelder et al. (1968). pattern. The correlation which they found con- Theye and Michenfelder (1968) pointed out sisted of findings of predominant fast waves greater values for CMRO2 in their method than with high oxygen consumption and high voltage those generally observed in whole brain studies. slow waves with low oxygen consumption. How- The direct method is valid for a portion of the ever, we found that chlorpromazine showed a cerebral cortex, not the whole brain. Therefore, different pattern of EEG from the other our findings indicate that chlorpromazine may changes

two drugs, even though there was considerably on September 25, 2021 by reduce CMRO2 in the cortex and is in agreement less reduction in CMRO2 than the other two; with the results of electrophysiological studies by less pronounced slow wave activities. The reduc- Gangloff and Monnier (1957), who demon- tion in CBF in the diazepam group was about strated that chlorpromazine does affect the the same magnitude as the reduction in CMRO2, cerebral cortex. agreeing with the finding that PssO2 remained The decrease in OGI observed with diazepam unchanged. After administration of either J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.9.838 on 1 September 1975. Downloaded from 844 Atsuo Sari, Yasuo Fukuda, Takefumi Sakabe, Tsuyoshi Maekawa, and Toshizo Ishikawa clomipramine or chlorpromazine, CBF did not y-aminobutyric acid and glutamic acid in brain tissue. Journal of Neurochemistry, 5, 121-127. change significantly but roughly paralleled a Fazekas, J. F., Albert, S. N., and Alman, R. W. (1955). reduction in CMRO2, resulting again in un- Influence of chlorpromazine and alcohol on cerebral changed PssO2. Therefore, these changes in CBF hemodynamics and metabolism. American Journal of Medical Sciences, 230, 128-132. seem to be mostly metabolic dependent. Frowein, R. A., Hirsch, H., Kayser, D., and Krenkel, W. From these results, it was concluded that (1955). Sauerstoffverbrauch, Durchblutung und Vulner- abilitat des Warmblutergehirns unter Megaphen (Chlor- diazepam and chlorpromazine are cerebral promazin). Archiv fur Experimentelle Pathologie und cortical metabolic depressants. This evidence Pharmakologie, 226, 62-68. suggests that the reduction in cerebral cortical Gangloff, H., and Monnier, M. (1957). Topic action of reserpine, serotonin, and chlorpromazine on the un- oxygen consumption may play an important role anesthetized rabbit's brain. Helvetica Physiologica Acta, in their therapeutic action in psychiatric patients. 15, 83-104. 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