Lithium lon이 약물에 의한 수면에 미치는 영향에 관한 뇌파학적 연구

Abstract

[영문]

Since its discovery by Arfwedson in 1818, lithium* has been tried in the treatment of various diseases, including urinary calculi, gout and epilepsy. Most of these treatments are now considered useless or contra-indicated. Through Cade's discovery of a benificial effect of lithium salts on psychotic excitement,

attention has once more become focused on the biological effects of the lithium ion. the tragic consequences, in 1949, of the indiscriminate use of lithium salts as a salt substitute have resulted in an almost complete reglect, in certain psychotic states, of this promising therapeutic agent. In recent years, however, evidence has been accumulated indicating that lithium treatment is safe and may be continued indefinitely if regular plasma-assays and careful clinical observations are done. Also, it is widely accepted that lithium ion is of definite clinical

value in the treatment of mania and that it is very useful in controlling psychotic excitement found in a variety of psychoses.

So far relatively little work has been done toward the understanding of the mechanisms whereby lithium exerts its definite clinical effects in mania and in other psychotic excitements. Generally, profound, persistent insomnia is one of the most conspicuous symptoms in mania and other psychotic excitements. such insomnia is quite often unresponsive, even to a high does of hypnotic. Sleep can be readily detected and its depth estimated accurately by electroencephalographic recording.

In view of these facts, to investigate one area of the action of the lithium ion, the author conducted electroencephalographic studies of the effects of lithium ion on drug-induced sleep.

Material and Method

1. The experimental work was done on mature rabbits of both sexes, weighing between 2.0kg and 2.8kg.

2. Grass Model 6A5 8 channel EEG and Grass E2B subdermal electrode were used in EEG recording. The active electrode was placed on the parieto-occipital region, the reference electrode near the tip of nasal bone.

3. Sleeping time was measured in minutes beginning from the time the intravenous injection was completed until the time when the animal woke up spontaneously. To avoid the interruption of post-narcotic sleep, the conventional tapping or pressing method of checking for sleep was replaced by a continuous EEG recording. The sleep stages were divided into A,B,C,D and E stages which roughly paralled Loomis' observations on human beings.

4. All intravenous injections were done into the marginal ear vein of the rabbit. 6.36% lithium chloride(LiCl) solution was injected in a designated volume at a constant rate for 1 minute. Fresh 2% solution of thiopental sodium (a thiobarbiturate) and pentobarbital sodium ( a non-thiobarbiturate) were injected in

a designated volume, at a constant rate for 2 minutes.

5. In lithium+thiopental group and lithium+pentobarbital group, lithium in a dose of 3.0Eq/kg was injected intravenously, following which thiopental and pentobarbital were given in a dose of 20 mg/kg respectively.

6. In the thiopental+lithium group and pentobarbital+lithium group, the intravenous injection of thiopental and pentobarbital were done, respectively, to induce sleep. Upon complete awakening, 3.0mEq/kg of lithium was injected intravenously.

7. In the oil group, to ensure the circulation of enough chyme, three intraperitoneal injections of oil emulsion were done prior to the experiment. Each time 3.0ml/kg of oil emulsion was injected. The interval between injections ranged from 6 to 8 hours. The oil emulsion was prepared by mixing equal parts of pure olive oil and water in a blender.

8. The plasma thiopental level was determined by Brodie et al method.

Observations and Results

The following experiments were conducted.

1. Experiment Ⅰ (Lithium alone group)

LiCl solution in 1.5mEq/kg and 3.0mEq/kg were resepectively injected intravenously to a group of rabbits. None of the rabbits fell asleep. Only motor retardation was observed. In the EEG the frequency increased markedly and the amplitude only slightly.

2. Experiment Ⅱ (Thiopental alone group)

Intravenous injections of thiopental in 10mg/kg and 20mg/kg were given respectively. The results were shown in Table 1.

Dosage(mg/kg) No.of Animals Mean Duration of sleep±S.D.(min.)

10 10 18.9±5.5

20 15 31.0±6.3

P<0.01

Table 1 Sleeping time of the group receiving thiopental alone

In the EEG of the 20mg/kg rabbits, very slow waves (0.5-3 cps) of high amplitude(150 μV range) were recorded for the first 5 to 10 minutes, a finding which was not observed in the 10 mg/kg rabbits.

3. Experiment Ⅲ (Pentobarbital alone group)

Intravenous injection of pentobarbital in a dose of 20mg/kg induced a relatively long sleep (Table 2).

Dosage(mg/kg) No.of Animals Mean Duration of sleep±S.D.(min.)

20 10 54.9±13.2

Table 2 Sleeping time of the group receiving pentobarbital alone.

In this group no part of the record contained high voltage fluctuations with frequency form 0.5 to 3cps. The record consisted only of the C.B and A strages of Loomis.

4. Experiment Ⅳ (Lithium+Thiopental group)

Interavenous injection of LiCl in a dose of 3.0mEq/kg was immediately followed by intravenous injection of thiopental, 20mg/kg, which induced significantly longer sleep than the group receiving thiopental alone (Table 3).

Group Dosage(mg/kg) No.of Animals Mean Duration of Sleep±S.D.(min.)

(A) 20 15 31.0±6.4

(B) 20 15 48.3±7.8

P<0.01

Table 3 Sleeping time of the group given thiopental alone(A), and the

Li+thiopental group (B)

In the EEg, it was found that prolongation of sleep took place in the stages of C.B. and that it did not occur in D and E stages of sleep.

5. Experiment V (Lithium+Pentobarbital Group)

LiCl, in a dose of 3.0 mEq/kg was injected intravenously, and immediately followed by 20mg/kg of pentobarbital. Sleep was significiantly longer than in the group getting pentobarbital alone (Table 4).

Group Dosage(mg/kg) No.of Animals Mean Duration of Sleep±S.D.(min.)

(C) 20 10 54.9±13.2

(D) 20 10 81.4±14.0

P<0.05

Table 4 Sleeping time of the group given only pentobarbital (C) and the

Li+pentobarbital group (D)

The EEG record showed no E and D stages of sleep. The prolongation took place in the C, B, and A stages.

6. Experiment Ⅵ(Thiopental+Lithium Group)

Thiopental, 20 mg/kg was injected intravenously to induce sleep. On spontaneous and complete wakening, LiCl in a dose of 3.0mEq/kg, was injected intravenously.

within 2 to 3 minutes all rabbits fell asleep and continued to sleep for an average of 18 minutes. In the EEG only the A and B stages of sleep were observed. On no occasion delta range waves were present. In this group the plasma thiopental level was determined from blood drawn 5 minutes after the animal fell asleep following the LiCl injection. The level was 26±9 ㎍/dl. This level of thiopental alone is insufficient to induce sleep in rabbits.

7. Experiment Ⅶ (Pentobarbital+Lithium Group)

On awakening from the pentobarbital sleep (20mg/kg) LiCl in 3.0mEq/kg of LiCl were injected intravenously. Within 2 to 3 minutes the rabbits fell asleep again and continued to sleep for an average of 36 minutes. In the EEG only the A and B stages of sleep were observed, and the burst activity was usually more marked with higher amplitude than in the thiopental+lithium group.

8. Experiment Ⅷ (Oil Group)

This group was subdivided as follows:

a) Thiopental subgroup

Thiopental, 20mg/kg was injected intravenously. The results was shown in Table 5.

In the EEG the duration of high amplitude delta range waves was shorter than in the thiopental along group. Frequently such waves were non-existent.

b) Pentobarbital subgroup

Group Dosage(mg/kg) No.of Animals Mean Duration of Sleep±D.S.(min.)

(E) 20 10 16.1±6.6

(A) 20 15 31.0±6.3

P<0.01

Table 5 Sleeping time of the "oil" thiopental subgroup (E) and the group given thiopental alone (A)

With the exception of the fact that the rabbits were injected with oil, the same procedure was performed as in the pentobarbital group. No difference was seen either in the EEG or in the sleeping time when this group was compared with the

pentobarbital group which did not receive the oil injection.

c) Lithium+Thiopental subgroup

Except for the fact that oil was injected in this group, the same procedure was performed as for the lithium+thiopental group which did not get the oil injection.

The sleeping time was significantly prolonged as compared with that of the thiopental subgroup which was given oil (Table 6). Sleep prolongation took place in the C,B and A stages.

Group Dosage(Mg/kg) No.of Animals Mean Duration of Sleep S.D.(min)

(E) 20 10 16.1±6.6

(F) 20 10 24.6±4.8

Table 6 "Oil" Thiopental subgroup (E) and "Oil" Li+Thiopental subgroup

(F)

d) Lithium+Pentobarbital subgroup

Except for the fact that the rabbits had been injected with oil, the same procedure was performed as in the lithium+pentobargital group. Both in the EEG and sleeping time no difference was noted between the two serials.

e) Thiopental+Lithium subgroup

Except for the fact that the rabbits had been injected with oil, the same procedure was performed as in the thiopental+lithium group. The rabbits slept again after the LiCl injection (iv). Upon awakening from the thiopental sleep. In the EEG of the Li-induced sleep, only the A and B stages of sleep were observed.

f) Pentobarbital+Lithium subgroup

Except for the fact that the rabbits were injected with oil the same procedure was carried out as in the pentobarbital+lithium group. Rabbits fell asleep and continued to sleep for over 20 minutes when given Li injection (iv) on awakening from the pentobarbital sleep.

In the EEG of the Li-induced sleep, only the A and B stages of sleep were observed.

Conclusion

1. Intravenous injection of LiCl alone in a dose of 3.0mEq/kg did not induce sleep in mature rabbits. Motor retardation only was observed. The EEG record showed the frequency to be increased markedly, but the amplitude only slightly.

2. The lithium ion significantly prolonged the sleeping time following thiopental sodium (a thiobarbiturate) and pentobarbital sodium (a non-thiobarbiturate). The prolongation of sleep took place in the C,B and A stages of sleep.

3. Also in the group injected with oil the lithium ion significantly prolonged the sleeping time following thiopental sodium and pentobarbital sodium. In the oil injected thiopental subgroup the period of high amplitude delta range waves was

shortened than that in the thiopental group which received no oil.

4. When injected intravenously after a complete awakening from the thiopental or pentobarbital sleep, the lithium ion induced a second sleep which continued for over 15 minutes. In the EEG of the Li-induced second sleep only the A and B stages of sleep were observed.