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THE EFFECTS OF SOME CENTRAL NERVOUS SYSTEM DEPRESSANTS ON CONFLICT BEHAVIOR IN DOGS
THE
EFFECTS
DEPRESSANTS
OF
SOME ON
CENTRAL
CONFLICT
NERVOUS
BEHAVIOR
SYSTEM IN DOGS
MASAAKI TAMURA Department of Pharmacology, Facultyof Medicine, University of Tokyo,Tokyo Receivedfor publicationDecember12, 1962
Conflict behavior induced by punishing the animal's approach to food has been frequently studied in cats or rats as a means for evaluating the effects of drugs upon neurotic conditions. In 1945Masserman and Yum (1) showed that alcohol prevented the development of neurotic behavior in cats and abated the neurotic behavior. A similar result was obtained by Conger (2) in rats. Jacobsen and Skaarup (3), modifying the technique described by Masserman, introduced a method which permits evaluation of drug effects upon behavior with ease. They found that benzilic acid aminoester deriva tives, especially benactyzine, have a clear-cut normalizing effect in cats. Recently Naess and Rasmussen (4), Geller and Seifter (5), and other workers proposed newer procedures which allowed more objective evaluation of drugs upon behavior. This paper describes a method for inducing conflict behavior in dogs, and the effects of some drugs upon the conflict behavior. METHODSAND MATERIALS In this series of experiments 16 adult dogs, 7 female and 9 males, ranging in weight from 6.5 to 15 kg, were used. They were fed on boiled barley containing fish meat once a day at 5 : 00 p.m.
FIG.
田村
正昭
I
Fig. 1 (A) illustrates the outline of experimental cage, 100cm wide, 120cm deep and 100 cm high. Excepting the base and the front side, all the faces were made of wire mesh fixed to the wooden frame of the cage. On the front side of the cage, a food box, 30 x 20 x 15 cm, Fig. 1 (B), and a bar were placed . When the dog pressed the bar, a buz zer signal worked automatically, and when the dog pushed the lid of the food box from the inside of cafe the animal could open it to take food in the box . The food for reward were made of 70% boiled barley and 30% finely minced fish meat . It was placed in the food box in a volume of about 4 cm'. The cage was further equipped with a bell , and two metal plates for punishing the dog by electric shock. Phenobarbital sodium (Phenobal), pentobarbital sodium (Mintal), thiopental sodium (Ravonal), chlorpromazine hydrochloride (Contomin), and benactyzine hydrochloride (Parpon) were used in diluted solution of less than 1 per cent. Ethanol was used as a 30% aqueous solution and meprobamate (Atraxin) as a 10% propylene glycol solution . All drug solutions were injected intravenously. The interval between two successive drug injections was at least one week. The experiments were undertaken 1 min after injec tion in cases of thiopental and ethanol, and 5 min after injection in cases of other drugs . CONDITIONING The they
dogs were trained
learned
box
and
food.
to push
put
buzzer
and
they
was given.
buzzer
signal
generally
the
and
training
then
They
repeated
of food-taking min.
Fig.
to obtain
after
was further
the feeding this
2 shows
the
training
a day.
became
sequence than such
the
response
repeated
cycle
more
the
when
food taking
2 to 3 hours
times,
to open
only
In the final stage
achieved
1 to 5 days,
the
the bar so as to make
food. This conditioned was
food
it to take
learned
to press
First,
lid of the
into
eat the food
signal
they learned the
the
the head
Secondly,
food box
stepwise.
of
When 10 to 15
stabilized.
of activities
100 times
in 15
FIG.
2
examples.
INDUCTION OF CONFLICT BEHAVIOR Having achieved frequently
the conditioned
over a period
this type of feeding, the punishment the electrodes had completed
attached
food-taking
of 2 to 3 months.
of the electric
to the food box (mouth)
10 feeding
response, the dogs were further
trained
When the dogs had been well accustomed to shock, 5-20 volts, was given through
and the floor (paw).
When the dogs
cycles they were given the electric shock concomitantly
with
bell signal.
After
the subsequent
10 normal
feeding cycles a second punishment
was
given, and this was repeated every 10 feeding cycles as far as the dogs continued feed ing. This punishing procedure was applied every day until -the conflict behavior deve loped. Although some individual variation in the pattern was noticed, the following behaviors were common : 1) the dogs performed only one or two, or no feeding cycle, 2) the frequencies
of behaviors
the cage, wandering considerably
such as licking and smelling the floor or the frame of
about in the experimental
increased.
When these abnormal
cage, and lying or sitting down became behaviors
had been established,
the electric
shock was neglected and only the bell signal was used at the end of each 10 cycles of feeding.
Under
re-establish
these circumstances,
the normal
conditioned TABLE
This total
table numbers
it took generally
1.
shows
the
of
behaviors
food taking reaction.
Examples
avarage
of
conflict
numbers
divided
by
of
behavior
behaviors
minutes
An experiment
cycles of feeding, or when the animal
per
dogs.
minute, for
the
that
is to
say,
the
experiment.
were carried
was terminated
required
for the dogs to
Table 1 shows two examples. in
required
The dogs were not starved, and the experiments before meal at 5:00 p.m.
2 to 3 months
out in the afternoon
when the dog completed
more than 5 min to complete
50
a feeding
cycle. The following categories of behavior
were particularly
per min were recorded : feeding cycle, putting the head into the box without buzzer, smelling about in the experimental cage, licking the body or experimental scratching turning
cage,
the body, neck, head, etc., back from the food box and the bar,
extramanipulation
of the bar without
taking the food,
observed and the frequencies
lying or sitting.down, standing
still more than 30 sec.
The last two categories
were counted 2, 3, 4.and so on when the animal
remains
in the
specified states more than 1, 1.5, 2 min and so on. hesitation
of food-taking
violent behaviors
more than 5 sec after pressing
including
barking,
the bar,
biting at experimental
cage, pushing
the door
of the cage, with head or paws, falling
or tumbling,
autonomic
reaction
including
vomiting,
micturition,
defecation,
etc.
RESULTS The assessment on the temporary
of the effects of drugs on conflict behavior recovery
toward
normal
feeding cycle.
was based principally
The effect was graded as +
(marked decrease in the conflict behavior), + (moderate decrease in conflict behavior), 0 (slight or no change) according to the degree of recovery toward the pre-punishment, normal
behavior
(Table 2).
TABLE 2. The effects of phenobarbital
This
table
of behaviors
shows divided
the avarage by minutes
numbers required
of
(30 mg/kg i.v.) on conflict behavior.
behaviors
for the
per
minute,
that
is to say, the total
numbers
experiment.
Two to 3 days before as well as after the experiment with drug, the control ments (conflict behavior) were carried out with physiological saline (0.5 ml/kg) of drug solution. Table 3 shows the effects of some drugs on conflict behavior. Phenobarbital, pentobarbital, and thiopental markedly lessened the degree flict behavior and restored the inhibited food-taking response in the majority
experi instead of con of dogs
TABLE
3a.
The
effect
of
barbiturates
on
conflict
behavior.
In Table 3a, b, c, the total numbers of feeding cycle are given in columns under headings of pre-exp. control, drug i.v. and post-exp. control, and under "behavior" is given the extent of the decrease of the conflict behavior. pre-exp. control : 2-3. days before drug administration, drug i.v.: 5 min after drug administration (phenobarbital, pentobarbital, benacty zine, chlorpromazine, meprobamate), 1 min after drug administration (thiopental, ethanol), post-exp. control : 2-3 days after drug administration.
TABLE: 3b.
The effect
of benactyzine
on conflict
behavior.
(Table 3a). Severe ataxia was produced by these three drugs. conflict behavior, when large doses (40-60 mg/kg) of phenobarbital dogs frequently
failed to press the bar exactly and
buzzer
The
signal.
conditioned
even when the dogs sometimes
food taking
Before producing were administered
the the
put the head into the box without
response,
however,
was never
abolished
fell (Table 4a).
Benactyzine produced no noticeable improvement in the conflict behavior except in one dog (Table 3b). Before producing the conflict behavior, when large doses (1 mg/kg) were given the conditioned food taking response was abolished and the dogs wandered about in the experimental cage. They rarely lay or sit down, and when they lay down they stood up soon (Table 4b). Outside the experimental cage, the dogs treated with large doses (1 mg/kg) of benactyzine dropped the food out of the mouth and some of them vomited or exhibited poor appetite. Chlorpromazine exerted no marked effect on inhibited food taking response (Table 3c). Before producing conflict behavior, when large doses (1-1.5 mg/kg) were adminis tered the dogs spent a large part of time lying down in the experimental cage, but as soon as the animal heard the buzzer signal, the dog stood up and put the head into the
TABLE 3c. The effects of chlorpromazine,
TABLE
4a.
In total
The
Table numbers
effects
of
phenobarbital
4a, b,
c the
avarage
of
behaviors
divided
on
numbers by
meprobamate,
conditioned
of
minutes
ethanol on couflict behavior.
food
behaviors
per
required
for
taking
response
minute, the
that
experiment
and
on
is to
say,
behavior.
the
are showed.
TABLE 4b.
TABLE
4c.
The
The
effects
effects
of
of benactyzine
chlorpromazine
box to eat food, and then repeated experimental
on conditioned
on
conditioned
food taking
food
response
taking
response
and on behavior .
and
on
behavior
two or three feeding cycles (Table 4c) . Outside
.
the
cage, the dogs had a good appetite.
Meprobamate toward normal
improved
the conflict behavior
very much
and temporary
recovery
was seen in most of dogs . Severe ataxia was seen in all. Ethanol also improved the conflict behavior and the inhibited food-taking response , but the effect seemed less obvious than those of barbiturates and meprobamate (Table 3c).
Ataxia Fasting
feeding activity
was considerable
(Table 4c).
of 48 to 72 hours caused no remarkable
change
in conflict behavior .
DISCUSSION
Jacobsen and Skaarup (6) set the switch for signal on the opposite side of the food box in their apparatus. In the present experiments, the bar for buzzer signal and the
food box were set on the same side so that the frequency of turning back from the food box or the bar might be taken as one of abnormal behaviors. The behavioral effects of chlorpromazine in dogs was discriminated from these of benactyzine by the experi ments in which this arrangement was used. In this experimental series once the conflict behavior had been established, most of the dogs performed only one or two, or no feeding cycle, so the improvement of the conflict behavior by drugs is independent of the change in pain threshold. Dogs were used in this experiment. The dog might be too large for the laboratory animal in this type of experiment but is very convenient in some respects : 1) the be haviors are observed in detail ; 2) the dog learns conditioned food taking process easily and the experiments can be carried out without fasting. Since the present study was primarily qualitative, no attempts were made to compare the potency of meprobamate with those of barbiturates. Although the effects of mepro bamate and barbiturates were differentiated from those of chlorpromazine and benac tyzine. In comparison of the results obtained with cats or rats by Masserman, Conger, Jacobsen, etc. (1-9), and results with dogs by this author, there are some similarities as well as differences according to drugs. Regardless of the animal species barbiturates and meprobamate had clear-cut normaliz_neffects on the conflict behavior. Ethanol also possessed a normalizing effect on the conflict behavior, although the effect was not so obvious as that of barbiturates or meprobamate. Chlorpromazine, regardless of animal species, had no effect on the inhibited food taking response. The effect of benactyzine varied with the species of animals, and the results obtained in the dogs were more closely resembling those in rats rather than those in cats. SUMMARY The effects of some central nervous system depressants upon conflict behavior in dogs were studied. Phenobarbital, pentobarbital, thiopental, meprobamate and ethanol restored the in hibited food taking response, but benactyzine and chlorpromazine did not produce the restoring effect. Before inducing conflict behavior, phenobarbital did not abolish the conditioned food taking response even in such large doses as caused severe ataxia and sometimes falling, although the dogs frequently failed to press the bar exactly. Benactyzine and chlorpromazine abolished the conditioned food taking response, and in the doses almost abolishing the conditioned food taking response, the former caused dogs to walk about in the experimental cage and the latter to lie down. Acknowledgement : The author is much indebted to Prof. Dr. H. Kumagai, Dr. F. Sakai, Dr. A. Sakuma and Dr. T. Fukuhara for valuable suggestions and advices.
REFERENCES 1) MASSERMAN,J.H. AND YuM, K.S. : Psychosom.Med. 8, 36 (1946) 2) CONGER,J.J. : Quart. J. Stud. Alc. 12, 1 (1951) 3) JACORSEN,E. AND SKAARUP,Y.: Acta pharm. tox. Kbh. 11, 125 (1955) 4) NAESE,K. AND RASMUSSEN,W.: Ibid. 15, 99 (1958) 5) GELLER, I. AND SEIFTER,J. : Psychopharmacologia1, 482 (1960) 6) JACOBSEN,E. AND SKAARUP,Y.: Acta pharm. tox. Kbh. 11, 117 (1955) 7) MASSERMAN,J.H. AND SIEVER,P.W. : Psychosom.Med. 6, 7 (1944) 8) BAILEY,C.J. AND MILLER, N.E.: J. comp.physiol. Psychol. 45, 205 (1952) 9) MASSERMAN, J.H.:
Amer. J. Psychiat. 101, 389 (1944)
EFFECTS
DEPRESSANTS
OF
SOME ON
CENTRAL
CONFLICT
NERVOUS
BEHAVIOR
SYSTEM IN DOGS
MASAAKI TAMURA Department of Pharmacology, Facultyof Medicine, University of Tokyo,Tokyo Receivedfor publicationDecember12, 1962
Conflict behavior induced by punishing the animal's approach to food has been frequently studied in cats or rats as a means for evaluating the effects of drugs upon neurotic conditions. In 1945Masserman and Yum (1) showed that alcohol prevented the development of neurotic behavior in cats and abated the neurotic behavior. A similar result was obtained by Conger (2) in rats. Jacobsen and Skaarup (3), modifying the technique described by Masserman, introduced a method which permits evaluation of drug effects upon behavior with ease. They found that benzilic acid aminoester deriva tives, especially benactyzine, have a clear-cut normalizing effect in cats. Recently Naess and Rasmussen (4), Geller and Seifter (5), and other workers proposed newer procedures which allowed more objective evaluation of drugs upon behavior. This paper describes a method for inducing conflict behavior in dogs, and the effects of some drugs upon the conflict behavior. METHODSAND MATERIALS In this series of experiments 16 adult dogs, 7 female and 9 males, ranging in weight from 6.5 to 15 kg, were used. They were fed on boiled barley containing fish meat once a day at 5 : 00 p.m.
FIG.
田村
正昭
I
Fig. 1 (A) illustrates the outline of experimental cage, 100cm wide, 120cm deep and 100 cm high. Excepting the base and the front side, all the faces were made of wire mesh fixed to the wooden frame of the cage. On the front side of the cage, a food box, 30 x 20 x 15 cm, Fig. 1 (B), and a bar were placed . When the dog pressed the bar, a buz zer signal worked automatically, and when the dog pushed the lid of the food box from the inside of cafe the animal could open it to take food in the box . The food for reward were made of 70% boiled barley and 30% finely minced fish meat . It was placed in the food box in a volume of about 4 cm'. The cage was further equipped with a bell , and two metal plates for punishing the dog by electric shock. Phenobarbital sodium (Phenobal), pentobarbital sodium (Mintal), thiopental sodium (Ravonal), chlorpromazine hydrochloride (Contomin), and benactyzine hydrochloride (Parpon) were used in diluted solution of less than 1 per cent. Ethanol was used as a 30% aqueous solution and meprobamate (Atraxin) as a 10% propylene glycol solution . All drug solutions were injected intravenously. The interval between two successive drug injections was at least one week. The experiments were undertaken 1 min after injec tion in cases of thiopental and ethanol, and 5 min after injection in cases of other drugs . CONDITIONING The they
dogs were trained
learned
box
and
food.
to push
put
buzzer
and
they
was given.
buzzer
signal
generally
the
and
training
then
They
repeated
of food-taking min.
Fig.
to obtain
after
was further
the feeding this
2 shows
the
training
a day.
became
sequence than such
the
response
repeated
cycle
more
the
when
food taking
2 to 3 hours
times,
to open
only
In the final stage
achieved
1 to 5 days,
the
the bar so as to make
food. This conditioned was
food
it to take
learned
to press
First,
lid of the
into
eat the food
signal
they learned the
the
the head
Secondly,
food box
stepwise.
of
When 10 to 15
stabilized.
of activities
100 times
in 15
FIG.
2
examples.
INDUCTION OF CONFLICT BEHAVIOR Having achieved frequently
the conditioned
over a period
this type of feeding, the punishment the electrodes had completed
attached
food-taking
of 2 to 3 months.
of the electric
to the food box (mouth)
10 feeding
response, the dogs were further
trained
When the dogs had been well accustomed to shock, 5-20 volts, was given through
and the floor (paw).
When the dogs
cycles they were given the electric shock concomitantly
with
bell signal.
After
the subsequent
10 normal
feeding cycles a second punishment
was
given, and this was repeated every 10 feeding cycles as far as the dogs continued feed ing. This punishing procedure was applied every day until -the conflict behavior deve loped. Although some individual variation in the pattern was noticed, the following behaviors were common : 1) the dogs performed only one or two, or no feeding cycle, 2) the frequencies
of behaviors
the cage, wandering considerably
such as licking and smelling the floor or the frame of
about in the experimental
increased.
When these abnormal
cage, and lying or sitting down became behaviors
had been established,
the electric
shock was neglected and only the bell signal was used at the end of each 10 cycles of feeding.
Under
re-establish
these circumstances,
the normal
conditioned TABLE
This total
table numbers
it took generally
1.
shows
the
of
behaviors
food taking reaction.
Examples
avarage
of
conflict
numbers
divided
by
of
behavior
behaviors
minutes
An experiment
cycles of feeding, or when the animal
per
dogs.
minute, for
the
that
is to
say,
the
experiment.
were carried
was terminated
required
for the dogs to
Table 1 shows two examples. in
required
The dogs were not starved, and the experiments before meal at 5:00 p.m.
2 to 3 months
out in the afternoon
when the dog completed
more than 5 min to complete
50
a feeding
cycle. The following categories of behavior
were particularly
per min were recorded : feeding cycle, putting the head into the box without buzzer, smelling about in the experimental cage, licking the body or experimental scratching turning
cage,
the body, neck, head, etc., back from the food box and the bar,
extramanipulation
of the bar without
taking the food,
observed and the frequencies
lying or sitting.down, standing
still more than 30 sec.
The last two categories
were counted 2, 3, 4.and so on when the animal
remains
in the
specified states more than 1, 1.5, 2 min and so on. hesitation
of food-taking
violent behaviors
more than 5 sec after pressing
including
barking,
the bar,
biting at experimental
cage, pushing
the door
of the cage, with head or paws, falling
or tumbling,
autonomic
reaction
including
vomiting,
micturition,
defecation,
etc.
RESULTS The assessment on the temporary
of the effects of drugs on conflict behavior recovery
toward
normal
feeding cycle.
was based principally
The effect was graded as +
(marked decrease in the conflict behavior), + (moderate decrease in conflict behavior), 0 (slight or no change) according to the degree of recovery toward the pre-punishment, normal
behavior
(Table 2).
TABLE 2. The effects of phenobarbital
This
table
of behaviors
shows divided
the avarage by minutes
numbers required
of
(30 mg/kg i.v.) on conflict behavior.
behaviors
for the
per
minute,
that
is to say, the total
numbers
experiment.
Two to 3 days before as well as after the experiment with drug, the control ments (conflict behavior) were carried out with physiological saline (0.5 ml/kg) of drug solution. Table 3 shows the effects of some drugs on conflict behavior. Phenobarbital, pentobarbital, and thiopental markedly lessened the degree flict behavior and restored the inhibited food-taking response in the majority
experi instead of con of dogs
TABLE
3a.
The
effect
of
barbiturates
on
conflict
behavior.
In Table 3a, b, c, the total numbers of feeding cycle are given in columns under headings of pre-exp. control, drug i.v. and post-exp. control, and under "behavior" is given the extent of the decrease of the conflict behavior. pre-exp. control : 2-3. days before drug administration, drug i.v.: 5 min after drug administration (phenobarbital, pentobarbital, benacty zine, chlorpromazine, meprobamate), 1 min after drug administration (thiopental, ethanol), post-exp. control : 2-3 days after drug administration.
TABLE: 3b.
The effect
of benactyzine
on conflict
behavior.
(Table 3a). Severe ataxia was produced by these three drugs. conflict behavior, when large doses (40-60 mg/kg) of phenobarbital dogs frequently
failed to press the bar exactly and
buzzer
The
signal.
conditioned
even when the dogs sometimes
food taking
Before producing were administered
the the
put the head into the box without
response,
however,
was never
abolished
fell (Table 4a).
Benactyzine produced no noticeable improvement in the conflict behavior except in one dog (Table 3b). Before producing the conflict behavior, when large doses (1 mg/kg) were given the conditioned food taking response was abolished and the dogs wandered about in the experimental cage. They rarely lay or sit down, and when they lay down they stood up soon (Table 4b). Outside the experimental cage, the dogs treated with large doses (1 mg/kg) of benactyzine dropped the food out of the mouth and some of them vomited or exhibited poor appetite. Chlorpromazine exerted no marked effect on inhibited food taking response (Table 3c). Before producing conflict behavior, when large doses (1-1.5 mg/kg) were adminis tered the dogs spent a large part of time lying down in the experimental cage, but as soon as the animal heard the buzzer signal, the dog stood up and put the head into the
TABLE 3c. The effects of chlorpromazine,
TABLE
4a.
In total
The
Table numbers
effects
of
phenobarbital
4a, b,
c the
avarage
of
behaviors
divided
on
numbers by
meprobamate,
conditioned
of
minutes
ethanol on couflict behavior.
food
behaviors
per
required
for
taking
response
minute, the
that
experiment
and
on
is to
say,
behavior.
the
are showed.
TABLE 4b.
TABLE
4c.
The
The
effects
effects
of
of benactyzine
chlorpromazine
box to eat food, and then repeated experimental
on conditioned
on
conditioned
food taking
food
response
taking
response
and on behavior .
and
on
behavior
two or three feeding cycles (Table 4c) . Outside
.
the
cage, the dogs had a good appetite.
Meprobamate toward normal
improved
the conflict behavior
very much
and temporary
recovery
was seen in most of dogs . Severe ataxia was seen in all. Ethanol also improved the conflict behavior and the inhibited food-taking response , but the effect seemed less obvious than those of barbiturates and meprobamate (Table 3c).
Ataxia Fasting
feeding activity
was considerable
(Table 4c).
of 48 to 72 hours caused no remarkable
change
in conflict behavior .
DISCUSSION
Jacobsen and Skaarup (6) set the switch for signal on the opposite side of the food box in their apparatus. In the present experiments, the bar for buzzer signal and the
food box were set on the same side so that the frequency of turning back from the food box or the bar might be taken as one of abnormal behaviors. The behavioral effects of chlorpromazine in dogs was discriminated from these of benactyzine by the experi ments in which this arrangement was used. In this experimental series once the conflict behavior had been established, most of the dogs performed only one or two, or no feeding cycle, so the improvement of the conflict behavior by drugs is independent of the change in pain threshold. Dogs were used in this experiment. The dog might be too large for the laboratory animal in this type of experiment but is very convenient in some respects : 1) the be haviors are observed in detail ; 2) the dog learns conditioned food taking process easily and the experiments can be carried out without fasting. Since the present study was primarily qualitative, no attempts were made to compare the potency of meprobamate with those of barbiturates. Although the effects of mepro bamate and barbiturates were differentiated from those of chlorpromazine and benac tyzine. In comparison of the results obtained with cats or rats by Masserman, Conger, Jacobsen, etc. (1-9), and results with dogs by this author, there are some similarities as well as differences according to drugs. Regardless of the animal species barbiturates and meprobamate had clear-cut normaliz_neffects on the conflict behavior. Ethanol also possessed a normalizing effect on the conflict behavior, although the effect was not so obvious as that of barbiturates or meprobamate. Chlorpromazine, regardless of animal species, had no effect on the inhibited food taking response. The effect of benactyzine varied with the species of animals, and the results obtained in the dogs were more closely resembling those in rats rather than those in cats. SUMMARY The effects of some central nervous system depressants upon conflict behavior in dogs were studied. Phenobarbital, pentobarbital, thiopental, meprobamate and ethanol restored the in hibited food taking response, but benactyzine and chlorpromazine did not produce the restoring effect. Before inducing conflict behavior, phenobarbital did not abolish the conditioned food taking response even in such large doses as caused severe ataxia and sometimes falling, although the dogs frequently failed to press the bar exactly. Benactyzine and chlorpromazine abolished the conditioned food taking response, and in the doses almost abolishing the conditioned food taking response, the former caused dogs to walk about in the experimental cage and the latter to lie down. Acknowledgement : The author is much indebted to Prof. Dr. H. Kumagai, Dr. F. Sakai, Dr. A. Sakuma and Dr. T. Fukuhara for valuable suggestions and advices.
REFERENCES 1) MASSERMAN,J.H. AND YuM, K.S. : Psychosom.Med. 8, 36 (1946) 2) CONGER,J.J. : Quart. J. Stud. Alc. 12, 1 (1951) 3) JACORSEN,E. AND SKAARUP,Y.: Acta pharm. tox. Kbh. 11, 125 (1955) 4) NAESE,K. AND RASMUSSEN,W.: Ibid. 15, 99 (1958) 5) GELLER, I. AND SEIFTER,J. : Psychopharmacologia1, 482 (1960) 6) JACOBSEN,E. AND SKAARUP,Y.: Acta pharm. tox. Kbh. 11, 117 (1955) 7) MASSERMAN,J.H. AND SIEVER,P.W. : Psychosom.Med. 6, 7 (1944) 8) BAILEY,C.J. AND MILLER, N.E.: J. comp.physiol. Psychol. 45, 205 (1952) 9) MASSERMAN, J.H.:
Amer. J. Psychiat. 101, 389 (1944)