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Effects of psychotropic drugs on hamster hibernation—pilot study
prog. Printed
Nemo-PsychophannacoZ. in Crest Britain.
All
EFFECTS
PETER
ZVOLSKY,
03G4-7722/81/06059?-04$03.00/O
1981, vo1.5, pp.599-602 rights reserved.
Copyright
OF PSYCHOTROPIC HIBERNATION-PILOT
DRUGS ON HAMSTER STUDY
LIBOR
JANSKY,
JANA
VYSKOCILOVA,
01331
PAUL
Pergamon
Press
Ltd.
GROF
Psychiatric Unit and Department of Biology, Charles University, Prague, Czechoslovakia, and Department of Psychiatry, M&aster University, Hamilton, Ontario, Canada. Research
(Final
Form - April
1981)
Abstract 1. 2. 3.
4.
The desynchronization of circadian and circannual rhythms may play an important role in primary affective disorders. Interesting biochemical as well as anatomical parallels have been found between primary affective disorders and hibernation. Hibernation is a periodic circannual event which is determined mainly by internal and hereditary factors, and influenced also by environmental stimuli. We employed hibernation as an animal model of periodic events and studied the effect of psychotropic drugs on hibernation in the golden hamster. In this paradigm imlpramine clearly interfered with the hibernating process and caused significant prolongation of the prehibernation period. The results of lithium trial could not be interpreted because of methodological problems.
Key Words: disorders.
golden
hamster,
hibernation,
imipramine,
lithium
chloride,
primary
affective
Introduction In the course of 24 hours many functions of the human body undergo regular rhythmic fluctuations. These daily cycles are called "circadian" rhythms, and can be seen as a biological clock. It seems certain that there are at least two distinct internal circadian oscillators in the human body. These oscillators are capable of desynchronizing either from each other and/or from the environment (Aschoff, 1969; Pittendrigh, 1974, Jenner et al., When two distinct circadian osclllators produce differing circadian frequencies in (1979). various body functions, the alternating coordination and interference between the two oscillators is called a beat phenomenon, by analogy to the audible beat produced between two tuning forks of slightly different frequency. There are some authors (Kripke, et al., 1978) who believe that primary affective disorders could be caused simply by such a desynchronization of various body functions, for instance of temperature, pulse, hormone metabolism, etc. Hypotheses which consider possible relations between disorders of circadian and circannual rhythms and the development of primary affective dlsorders are attractive especially from the point of view of some clinical expressions of mood disorders, such as early morning awakening, the morning worsening of mood, and seasonal occurrence of the disease with some patients. It would be worthwhile to test the hypotheses. Alas, In contrast to the world of physics, the periodic events of living matter are more difficult to define, to determine and to study. Nevertheless, because of our interest in the influence of psycbopharmaca on periodic events other than primary affective disorder we were looking for some regular periodic changes in behaviour and became attracted by hibernation. This is a circannual event which is probably determined by endogenous factors and is Influenced also by exogenous conditions. Hibernation is governed mainly by the hypothalamus, serotonergic system, and the pineal gland. All these systems are thought to play an important part also in primary affective disorders. 599
600
.
Because of the striking analogies thought that it would be interesting of the golden hamster.
P. Zvolsky
et
al.
end similarities between hibernation and depression we to find out how psychopharmacs would effect hibernation
Nterial
and methods
Animals. Experiments were performed on 80 golden old and weighing 100 g, on the average.
hamsters
Drugs. Imipramine (Melipramin) 8 mg./kg./day and lithium given in the food to groups of experimental animals.
(Mesocricetus chloride,
auratus),
40 mmol./kg./day
60 days were
The experiment took place in a room especially equipped for hibernation, and the golden hamsters were kept in plastic cages. The control group comprised 40 animals (20 males, 20 females). Twenty male hamsters were given imipramine and twenty male hamsters were administered lithium chloride. Both drugs were applied in food. The level The animals were observed for 60 days and the results were recorded every day. of lithium in serum was examined after one week of lithium application and then before the end of the trial. The estimation was done by standard flamephotometric method with randomly cboeen animals. After one week of the experiment the average of lithium serum of the chosen animals was 0.8 mEq/L. In the second examination at the end of the experiment the level of lithium in serum was equal to zero. For the description of the results we used the following terms: by the time from the beginning of the experiment to the observation nation (in days). The symbol I150 denotes the period in which half hibernating.
The symbol Bl is defined of the first hiberof the animals were
Results The results
are presented
in Table
1.
In the group of hamsters on imipramine there was an impressive prolongation of the prehibernation period. The percentage of hibernating animals decreased considerably. In was comparison with the controls in whom El was 11 days, the El in the group on imipramine 28 days. The time of prehibernation period was prolonged from 31 to 36 days in the control Finally, in contrast to 77% of hibernating group. groups, and to 52 days in the imipramine males and 81% of hibernating females in the control group, only 33% of the animals were hibernating in the imipramine group. The mortality in the control and imipramine groups were similar (10 - 15%).
Effects
of
psychoactive
drugs
on
hamster
Table The effect on hibernation
Hxper Group
.
N
of
imipramine of golden
hibernation
- pilot
601
study
1 and lithium hamster.
Hl
chloride
Worta1ity (X)
Prehibernation (days)
H50
(days)
(days)
Hibernating animals (Xl
Control (male>
20
10
36.7
11
25
77.7
Control (female)
20
15
31.7
11
40
81.2
Imipramine
20
10
52.5
28
33.3
20
50
21.0
11
40.0
Lithium
Chloride
In contrast there was a very high mortality in it reached 50% of all animals in this group. This the intoxication of animals in the lithium treated and were not eating, their serum level of lithium to zero. Behavioural signs of intoxication were results in the lithium group therefore cannot be little is known in pharmacology about the proper hamsters.
the
group of hamsters treated high mortality was apparently group as the animals became by the and of the wperiment also obsenred in these hamsters. interpreted. We should mention dosage of drugs for experiments
by
lithium: due to intoxicated decreased The that very in golden
Discussion The etiology of primary affective disorders is not known. Neither do we know the However, for years there mechanisms of therapeutic effect of lithium salts or imipramine. have been concentrated efforts to explore the role of biogenic amines in these disorders. The psychopharmaca are believed to exercise their therapeutic effect in functional Imipramine inhibits the reuptake psychoses by influencing the turnover of catecholamines. The mechanism of the effect of lfthium has not been of serotonin and noradrenaline. elucidated either in acute treatment or in prophylactic use. In addition to its effect on neme cell membranes, lithium can also influence the metabolism of noradrenaline and serotonin in the brain. While comparing hibernation with primary affective disorders, it is useful to quote Jansky’s hypothesis, which takes into consideration the time sequence of particular events following one another during hibernation. We underline especially those events vhich are conspicuous from the point of view of the hypothetical mechanisms of manic depressive disease. After the inhibition of the satiety center, which is probably determined by endogsnous and hereditary factors, the intake of tryptophan in food increases. This stimulates the turnover of serotonin in serotonergic pathways of the brain stem, which induces tirthervarious changes and decreases the activity of the hypophyseal-adrenocortical axis. nnre, a mechanism in piaeal gland is also put into action. With the shortened interval of daylight the transformation of serotonin to melatonin is increased. Malatonin inhibits sexual activity and the hypophyseal-adrenocortical axis. When we compare these observed facts and the hypotheses, we find certain parallels. The main role in the regulation of both events - mood as well as hibernation - belongs to the hypothalamus, vith possible participation of the serotonergic system. One can imagine also that the study of the function of pineal gland and its change after experimental manipulatton could help to clarify some etiopathogenetic problems of primary affective disorders.
P. Zvolsky
602
et al.
The idea that functional disorders of mood could be an evolutionary relic of photoperiodic activity of man has been expressed already by Lange in 1928. Unlike his ancestors, man no longer harmonizes his life activities according to the daylight and seasonal cycles. Thanks to artifical light and other advantages of civilization he has to readjust his biological cycles to socially induced schedules. One can speculate than, that some fragile, genetically predisposed subjects cannot tolerate well this continuous and steady activity and may develop desynchronization of basic physiologlcal function which could lead to an affective disorder. There are of course, dangers in making parallels between the inhibitions caused by hibernation and phasic depression. Gn the one side, we have a physiological state, which contributes to the adaption of the animal and helps him overcome difficult environmental On the other side, we are dealing with depression, which could only harm man's conditions. adaptation. Nevertheless, hibernation represents a rare biologic model of a periodic event and it seems worthwhile to study the effects of psychopharmaca on its course. Conclusion We observed in this pilot study a definite effect of tricyclic antidepressant, imlpramine on hibernation of the golden hamster. Imipramine prolongs significantly the prehibernation period. Hibernation appears to be a valuable model of a circannual periodic event which should be further explored. Such investigations could be useful for studies of the mechanisms involved in primary affective disorders as well as in the effect of psychotropic drugs. References ASCHOm, J. (1969). Desynchronization and resynchronization of human circadian rhythms. Aerospace Med. 40: 844. JANSKY, L. (19771, Ekologicka fysiologie zivocichu a cloveka. SPN, Prague. JENNER, F.A. and DAMAS-MORA, J. (1979). Cyclic processes and abnormal behaviour. In: Handbook of Biological Psychiatry, Part 1, H.M. van Praag, M.H. Lader, O.J.Fafaelsen and E.J. Sachar (Eds.), Marcel Dekker, New York and Basel, pp. 229-271. RRIPICE, D.S., MDLLANE, D.J., ATKINSON, M. and Wolf, S. (1978). Circadian rhythm disorders in manic depressive. Biologic Psychiatry, 13: 335-351. PITTENDRIGH, C.S. (1974). Circadian oscillation in cells and the circadian organization of multicellular systems. In: The Neurosciences: Third Study Program: Schmitt, F.O., and Worden, F.G. (Eds.), MIT Press, Cambridge, MASS. p. 437. Inquiries
and reprint
Dr. Peter Zvolsky P.O. Box 585 Hamilton, Ontario. L8N 3K7
requests
should
be addressed
to:
Nemo-PsychophannacoZ. in Crest Britain.
All
EFFECTS
PETER
ZVOLSKY,
03G4-7722/81/06059?-04$03.00/O
1981, vo1.5, pp.599-602 rights reserved.
Copyright
OF PSYCHOTROPIC HIBERNATION-PILOT
DRUGS ON HAMSTER STUDY
LIBOR
JANSKY,
JANA
VYSKOCILOVA,
01331
PAUL
Pergamon
Press
Ltd.
GROF
Psychiatric Unit and Department of Biology, Charles University, Prague, Czechoslovakia, and Department of Psychiatry, M&aster University, Hamilton, Ontario, Canada. Research
(Final
Form - April
1981)
Abstract 1. 2. 3.
4.
The desynchronization of circadian and circannual rhythms may play an important role in primary affective disorders. Interesting biochemical as well as anatomical parallels have been found between primary affective disorders and hibernation. Hibernation is a periodic circannual event which is determined mainly by internal and hereditary factors, and influenced also by environmental stimuli. We employed hibernation as an animal model of periodic events and studied the effect of psychotropic drugs on hibernation in the golden hamster. In this paradigm imlpramine clearly interfered with the hibernating process and caused significant prolongation of the prehibernation period. The results of lithium trial could not be interpreted because of methodological problems.
Key Words: disorders.
golden
hamster,
hibernation,
imipramine,
lithium
chloride,
primary
affective
Introduction In the course of 24 hours many functions of the human body undergo regular rhythmic fluctuations. These daily cycles are called "circadian" rhythms, and can be seen as a biological clock. It seems certain that there are at least two distinct internal circadian oscillators in the human body. These oscillators are capable of desynchronizing either from each other and/or from the environment (Aschoff, 1969; Pittendrigh, 1974, Jenner et al., When two distinct circadian osclllators produce differing circadian frequencies in (1979). various body functions, the alternating coordination and interference between the two oscillators is called a beat phenomenon, by analogy to the audible beat produced between two tuning forks of slightly different frequency. There are some authors (Kripke, et al., 1978) who believe that primary affective disorders could be caused simply by such a desynchronization of various body functions, for instance of temperature, pulse, hormone metabolism, etc. Hypotheses which consider possible relations between disorders of circadian and circannual rhythms and the development of primary affective dlsorders are attractive especially from the point of view of some clinical expressions of mood disorders, such as early morning awakening, the morning worsening of mood, and seasonal occurrence of the disease with some patients. It would be worthwhile to test the hypotheses. Alas, In contrast to the world of physics, the periodic events of living matter are more difficult to define, to determine and to study. Nevertheless, because of our interest in the influence of psycbopharmaca on periodic events other than primary affective disorder we were looking for some regular periodic changes in behaviour and became attracted by hibernation. This is a circannual event which is probably determined by endogenous factors and is Influenced also by exogenous conditions. Hibernation is governed mainly by the hypothalamus, serotonergic system, and the pineal gland. All these systems are thought to play an important part also in primary affective disorders. 599
600
.
Because of the striking analogies thought that it would be interesting of the golden hamster.
P. Zvolsky
et
al.
end similarities between hibernation and depression we to find out how psychopharmacs would effect hibernation
Nterial
and methods
Animals. Experiments were performed on 80 golden old and weighing 100 g, on the average.
hamsters
Drugs. Imipramine (Melipramin) 8 mg./kg./day and lithium given in the food to groups of experimental animals.
(Mesocricetus chloride,
auratus),
40 mmol./kg./day
60 days were
The experiment took place in a room especially equipped for hibernation, and the golden hamsters were kept in plastic cages. The control group comprised 40 animals (20 males, 20 females). Twenty male hamsters were given imipramine and twenty male hamsters were administered lithium chloride. Both drugs were applied in food. The level The animals were observed for 60 days and the results were recorded every day. of lithium in serum was examined after one week of lithium application and then before the end of the trial. The estimation was done by standard flamephotometric method with randomly cboeen animals. After one week of the experiment the average of lithium serum of the chosen animals was 0.8 mEq/L. In the second examination at the end of the experiment the level of lithium in serum was equal to zero. For the description of the results we used the following terms: by the time from the beginning of the experiment to the observation nation (in days). The symbol I150 denotes the period in which half hibernating.
The symbol Bl is defined of the first hiberof the animals were
Results The results
are presented
in Table
1.
In the group of hamsters on imipramine there was an impressive prolongation of the prehibernation period. The percentage of hibernating animals decreased considerably. In was comparison with the controls in whom El was 11 days, the El in the group on imipramine 28 days. The time of prehibernation period was prolonged from 31 to 36 days in the control Finally, in contrast to 77% of hibernating group. groups, and to 52 days in the imipramine males and 81% of hibernating females in the control group, only 33% of the animals were hibernating in the imipramine group. The mortality in the control and imipramine groups were similar (10 - 15%).
Effects
of
psychoactive
drugs
on
hamster
Table The effect on hibernation
Hxper Group
.
N
of
imipramine of golden
hibernation
- pilot
601
study
1 and lithium hamster.
Hl
chloride
Worta1ity (X)
Prehibernation (days)
H50
(days)
(days)
Hibernating animals (Xl
Control (male>
20
10
36.7
11
25
77.7
Control (female)
20
15
31.7
11
40
81.2
Imipramine
20
10
52.5
28
33.3
20
50
21.0
11
40.0
Lithium
Chloride
In contrast there was a very high mortality in it reached 50% of all animals in this group. This the intoxication of animals in the lithium treated and were not eating, their serum level of lithium to zero. Behavioural signs of intoxication were results in the lithium group therefore cannot be little is known in pharmacology about the proper hamsters.
the
group of hamsters treated high mortality was apparently group as the animals became by the and of the wperiment also obsenred in these hamsters. interpreted. We should mention dosage of drugs for experiments
by
lithium: due to intoxicated decreased The that very in golden
Discussion The etiology of primary affective disorders is not known. Neither do we know the However, for years there mechanisms of therapeutic effect of lithium salts or imipramine. have been concentrated efforts to explore the role of biogenic amines in these disorders. The psychopharmaca are believed to exercise their therapeutic effect in functional Imipramine inhibits the reuptake psychoses by influencing the turnover of catecholamines. The mechanism of the effect of lfthium has not been of serotonin and noradrenaline. elucidated either in acute treatment or in prophylactic use. In addition to its effect on neme cell membranes, lithium can also influence the metabolism of noradrenaline and serotonin in the brain. While comparing hibernation with primary affective disorders, it is useful to quote Jansky’s hypothesis, which takes into consideration the time sequence of particular events following one another during hibernation. We underline especially those events vhich are conspicuous from the point of view of the hypothetical mechanisms of manic depressive disease. After the inhibition of the satiety center, which is probably determined by endogsnous and hereditary factors, the intake of tryptophan in food increases. This stimulates the turnover of serotonin in serotonergic pathways of the brain stem, which induces tirthervarious changes and decreases the activity of the hypophyseal-adrenocortical axis. nnre, a mechanism in piaeal gland is also put into action. With the shortened interval of daylight the transformation of serotonin to melatonin is increased. Malatonin inhibits sexual activity and the hypophyseal-adrenocortical axis. When we compare these observed facts and the hypotheses, we find certain parallels. The main role in the regulation of both events - mood as well as hibernation - belongs to the hypothalamus, vith possible participation of the serotonergic system. One can imagine also that the study of the function of pineal gland and its change after experimental manipulatton could help to clarify some etiopathogenetic problems of primary affective disorders.
P. Zvolsky
602
et al.
The idea that functional disorders of mood could be an evolutionary relic of photoperiodic activity of man has been expressed already by Lange in 1928. Unlike his ancestors, man no longer harmonizes his life activities according to the daylight and seasonal cycles. Thanks to artifical light and other advantages of civilization he has to readjust his biological cycles to socially induced schedules. One can speculate than, that some fragile, genetically predisposed subjects cannot tolerate well this continuous and steady activity and may develop desynchronization of basic physiologlcal function which could lead to an affective disorder. There are of course, dangers in making parallels between the inhibitions caused by hibernation and phasic depression. Gn the one side, we have a physiological state, which contributes to the adaption of the animal and helps him overcome difficult environmental On the other side, we are dealing with depression, which could only harm man's conditions. adaptation. Nevertheless, hibernation represents a rare biologic model of a periodic event and it seems worthwhile to study the effects of psychopharmaca on its course. Conclusion We observed in this pilot study a definite effect of tricyclic antidepressant, imlpramine on hibernation of the golden hamster. Imipramine prolongs significantly the prehibernation period. Hibernation appears to be a valuable model of a circannual periodic event which should be further explored. Such investigations could be useful for studies of the mechanisms involved in primary affective disorders as well as in the effect of psychotropic drugs. References ASCHOm, J. (1969). Desynchronization and resynchronization of human circadian rhythms. Aerospace Med. 40: 844. JANSKY, L. (19771, Ekologicka fysiologie zivocichu a cloveka. SPN, Prague. JENNER, F.A. and DAMAS-MORA, J. (1979). Cyclic processes and abnormal behaviour. In: Handbook of Biological Psychiatry, Part 1, H.M. van Praag, M.H. Lader, O.J.Fafaelsen and E.J. Sachar (Eds.), Marcel Dekker, New York and Basel, pp. 229-271. RRIPICE, D.S., MDLLANE, D.J., ATKINSON, M. and Wolf, S. (1978). Circadian rhythm disorders in manic depressive. Biologic Psychiatry, 13: 335-351. PITTENDRIGH, C.S. (1974). Circadian oscillation in cells and the circadian organization of multicellular systems. In: The Neurosciences: Third Study Program: Schmitt, F.O., and Worden, F.G. (Eds.), MIT Press, Cambridge, MASS. p. 437. Inquiries
and reprint
Dr. Peter Zvolsky P.O. Box 585 Hamilton, Ontario. L8N 3K7
requests
should
be addressed
to: