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Resolved: There exists an atropinic agent in vivo
Medical Hypotheses 6: 801-805, 1980
RESOLVED:
THERE EXISTS AN ATROPINIC AGENT IN VIVO
S. Cantor, Health Sciences Centre, Children's Hospital, 685 Bannatyne Avenue, Winnipeg, Manitoba R3E Owl
ABSTRACT It is suggested that there exists a competitive antagonist of the cholinergic system which is secreted during sleep, pregnancy, and acute stress. A biochemical model of the sleep cycle is presented. It is suggested that normally the putative cholinergic antagonist is metabolized rapidly upon being released from the cholinergic receptor. Defective metabolism of this putative cholinergic antagonist is hypothesized to be one cause of hypotonic schizophrenia. Key Words - acetylcholine; atropine; sleep; stress; pregnancy; placenta; schizophrenia. INTRODUCTION The cholinergic system is essential to life. As a result, it has presented special problems to researchers over the years. In contrast to the adrenergic system which can be easily manipulated in laboratory animals (adrenergic functioning can be augmented by as much as five times without incurring the death of laboratory animals), the cholinergic system resists manipulation (1,2), readily resulting in morbidity and mortality in the research animal. Thus far, only one cholinolytic agent, acetylcholinesterase, has been identified. It seems unlikely that a compound which is so essential and which is so carefully regulated would have only one antagonist, even though it is recognized that almost all acetylcholine is rapidly metabolized by acetylcholinesterase as soon as it comes off the cholinergic receptor. The improbability that there exists only one regulator is enhanced by the observation that the cholinergic system can be blocked by an excess of acetyl choline (as occurs in the presence of an acetylcholinesterase inhibitor), and that the depolarizing block which results from such an excess can be released only by a competitive cholinergic antagonist which displaces acetylcholine from the receptor thus enabling catabolism by acetylcholinesterase. A competitive cholinergic antagonist, such as atropine, results in only a partial block of the cholinergic system (since the antagonist and the acetylcholine compete for the cholinergic receptor). There are at least three physiologic states, during which a competitive cholinergic antagonist could have survival value: stress, sleep, and pregnancy. 801
It is widely accepted, that adrenaline is the biochemical mediator of the "fight or flight" reaction. The efficiency of this reaction could however be enhanced if at the same time as the adrenergic system is stimulated, the cholinergic system were inhibited. Indeed, many of the components of the "fight or flight" reaction are more compatible with a cholinergic inhibition. Dilated pupils, dry mouth, rapid heart beat, sudden muscle weakness are in fact much more easily induced by an atropinic agent than by an adrenergic one (3,4). Furthermore, the release of a competitive cholinergic agent, which would rapidly inhibit the vagus, could help to prevent a vagal syncopal attack which might otherwise accompany such stressful situations. It has long been recognized that acetylcholine stimulates uterine activity (5). During pregnancy, the release of an agent which would keep both uterus and fetus relaxed would certainly enhance the survival of the fetus. The production by the placenta of a competitive cholinergic antagonist would be a safe and effective way of maintaining pregnancy, especially if the competitive cholinergic antagonist in its turn was rapidly metabolized. Deep sleep, in many ways resembles a depolarizing cholinergic block. The biochemical mechanism of inducing deep sleep is not presently known. Nevertheless, the circadian endocrine secretions which are known to accompany sleep are compatible with intermittent increases in cholinergic activity during the sleep cycle. An Hypothesis: Let us assume that there exists a competitive cholinergic antagonist in vivo. Any hypothesis which proposes such an agent should also state when it would be produced, what its function would be, and when it would be metabolized. A Biochemical Model of Sleep: A competitive cholinergic antagonist should be released by cholinergic neurons whenever a depolarizing block of the cholinergic system is imminent. Let us suppose that sleep begins with the release of a "sleep factor" (many are presently being postulated in the literature) which both stimulates cholinergic neurons to release a steady and sustained increase in acetylcholine and partially inhibits the activity of acetylcholinesterase. As the increase in cholinergic activity is thus maintained, the subject descends into deeper and deeper stages of sleep until stage 4 is reached and the subject is practically comatose (6). In the midst of stage 4 a change occurs in the subject (7), as muscle activity slowly reappears and sleep lightens and the subject ascends to stage 3, stage 2, etc. This ascent from stage 4 sleep could be mediated by the release of a competitive cholinergic antagonist which slowly displaces acetylcholine from the cholinergic receptor thus releasing the "depolarizing block". REM sleep would then represent the final stage during which the cholinergic system is active although partially blocked. Certainly the primary process thinking and hallucinatory activity which is so typical of the dream process (8) is reminicent of the primary process thought and hallucinatory activity
802
As the competitive cholinergic which is seen in an atropinic delirim(3,4). antagonist is itself displaced from the cholinergic receptor by acetylcholine the subject would either descend once more into deep sleep (if the sleep factor is still present) or ascend into wakefulness. It is postulated that the cholinergic competitive antagonist is metabolized very rapidly as it is displaced from the cholinergic receptor. Any constant disruption of REM sleep, could however result in the disruption of this cycle and a state of conscious delirium (due to the maintenance of the cholinergic block as a result of interrupting the metabolism of the competitive cholinergic antagonist), Figure 1 summarizes this model of sleep.
a
--NC)
u
SF-
tACH-
8 G
Depolarizing Block (Stage 4)
I_
Stage 3,2 --)
Figure 1: Proposed sleep cycle. Abbreviations: SF: sleep factor; ACH: acetylcholine; CA: competitive ztagonist; CAase: enzyme which metabolizes competitive antagonist. The Stress Reaction: At least two other functions of a competitive cholinergic antagonist could be postulated. The first would be release during periods of acute stress. This would necessitate postulating that adrenaline can stimulate cholinergic neurons to release the competitive cholinergic antagonist. It would enhance survival value during a stress reaction by preventing vagal syncope, by enhancing alertness, and by enhancing the rapid adrenergic stimulation of the heart (9). Pregnancy: A final function which is postulated for a competitive cholinergic antagonist would be during pregnancy. If the placenta was able to synthesize and release such an agent it would both inhibit uterine contraction and maintain the fetus in a state of motor laxity and semi-stupor. It would be necessary to postulate that the fetus has little or no ability to metabolize the putative competitive cholinergic antagonist. This in fact would be compatible with the theory of a partial cholinergic inhibition during REM sleep which has been proposed above since the newborn not only has over 70% REM sleep, but also demonstrates other more certain signs of cholinergic inhibition such as dilated pupils, no perspiration, and poor temperature regulation. It could be postulated that the enzymes which catalyze the metabolism of the putative competitive cholinergic compound have very low activity at birth and slowly increase in activity as the baby matures.
803
A Related Disease State: It has been stated elsewhere that hypotonic schizophrenia,could well reflect an inhibited cholinergic system (10). Postulating a failure to metabolize the competitive cholinergic agent proposed above as one of the major causes of hypotonic schizophrenia is compatible with a great deal of observed data: - Bender suggested many years ago (11) that childhood schizophrenia was a dysmaturation process. The hypotonic childhood schizophrenic in fact resembles in many ways the newborn infant (who it has been postulated lacks the enzymatic capacity to break down the putative cholinergic antagonist). Like the newborn infant, the hypotonic schizophrenic child has difficulty controlling temperature, has a soft velvety skin, dilated pupils, lax joints, very soft muscle tone, is very pale, and has a higher incidence of blue eyes than is found in the normal population (many babies are born with blue eyes which subsequently turn brown) (12). - Although sleep studies have nctyet been done on the subgroup of hypotonic schizophrenics, there is evidence that chronic schizophrenics have significantly reduced stage 3 and stage 4 sleep (13). This would also be compatible with the hypothesis of sleep proposed above, which would predict that an excess of the cholinergic antagonist would prevent descent into deep sleep (a depolarizing block of the cholinergic system could not occur in the presence of such an antagonist). - Decompensation into schizophrenia in females commonly occurs postpartum. If there is a competitive cholinergic antagonist secreted by the placenta during the pregnancy it could well be that its persistence postpartum helps precipitate the psychotic episode. It would of course then be necessary to postulate that the hormones which are elevated during the pregnancy somehow mask the effects of this competitive cholinergic antagonist during the pregnancy (perhaps by stimulating its breakdown), but as the hormones rapidly drop postpartum the subject is no longer protected from the higher level of partial cholinergic inhibitionwhich has prevailed during the pregnancy. Many clinicians have observed that females are especially vulnerable to psychosis during low levels of estrogen and progesterone (such as postpartum, during menses, and post menopause). There is presently no satisfactory explanation for this phenomenon. - Finally, the well known schizophrenic susceptibility to stress could be a function of stress-induced increases of the putative cholinergic antagonist followed by inadequate metabolism of the antagonist. CONCLUSIONS It has been postulated that there exists in vivo a competitive cholinergic antagonist whose function it is: (a) protect the body against a depolarizing block of the cholinergic system during sleep; (b) to partially
804
inhibit the cholinergic system during stress reactions; and (c) to help maintain pregnancy. It has further been postulated that inadequate breakdown of this competitive cholinergic antagonist is one of the causes of hypotonic schizophrenia. REFERENCES 1.
Giarman NJ, Pepeu G. Drug Induced Changes in Brain Acetylcholine. Br. J. of Pharm. 19:226 (1962).
2.
Richter D, Crossland J. Variation in Acetylcholine Content of the Brain with Physiological States. Amer. J. of Phys. 159:247 (1949).
3.
Longo VG. Behavioural and Electroencephalographic Effects of Atropine and Related Compounds. Pharm. Rev. 18(2):965 (1966).
4.
Eger EK. Atropine, Scopalamine, and Related Compounds. Anesthesiology 23(3):365 (1962).
5.
Goodman LS, Gilman A. The Pharmacological Basis of Therapeutics 4th Ed. The MacMillan Co. N.Y., N.Y. (1970).
6.
Williams RL, Karacan I, Hursch CJ. EEG of Human Sleep: Clinical Applications. John Wiley and Sons, New York, N.Y. (1974).
7.
Hobson JA, Spagna T, Malenka R. Ethology of Sleep Studied with TimeLapse Photography: Postural Immobility and Sleep-Cycle Phase in Humans. Science 201:1251 (1978).
8.
Freud S. The Interpretation of Dreams. Standard Edition, Vol IV and V. Hogarth Press, London, England 1958.
9.
Evans DE, Gillis RA. Reflex Mechanisms Involved in Cardiac Arrhythmias Induced by Hypothalamic Stimulation. Amer. J. of Physiol. 234(2): H199 (1978).
10.
Cantor Ss Trevenen C, Postuma R, Dueck R, Fjeldsted B. Is Childhood Schizophrenia a Cholinergic Disease? Arch. of Gen. Psych. to be published 1980.
11.
Bender L. Childhood Schizophrenia: Clinical Study of 100 Schizophrenic Children. Amer. J. Orthopsychiat. 17:40 (1947).
12..
Cantor S, Inayatulla M, Villafana P. The Subgroup of Hypotonic Childhood Schizophrenics. In Preparation.
13.
Caldwell DF, Domino EF. EEG and Eye Movement Patterns During Sleep in Chronic Schizophrenic Patients. EEG and Clinical Neurophys. 22:414 (1967).
805
RESOLVED:
THERE EXISTS AN ATROPINIC AGENT IN VIVO
S. Cantor, Health Sciences Centre, Children's Hospital, 685 Bannatyne Avenue, Winnipeg, Manitoba R3E Owl
ABSTRACT It is suggested that there exists a competitive antagonist of the cholinergic system which is secreted during sleep, pregnancy, and acute stress. A biochemical model of the sleep cycle is presented. It is suggested that normally the putative cholinergic antagonist is metabolized rapidly upon being released from the cholinergic receptor. Defective metabolism of this putative cholinergic antagonist is hypothesized to be one cause of hypotonic schizophrenia. Key Words - acetylcholine; atropine; sleep; stress; pregnancy; placenta; schizophrenia. INTRODUCTION The cholinergic system is essential to life. As a result, it has presented special problems to researchers over the years. In contrast to the adrenergic system which can be easily manipulated in laboratory animals (adrenergic functioning can be augmented by as much as five times without incurring the death of laboratory animals), the cholinergic system resists manipulation (1,2), readily resulting in morbidity and mortality in the research animal. Thus far, only one cholinolytic agent, acetylcholinesterase, has been identified. It seems unlikely that a compound which is so essential and which is so carefully regulated would have only one antagonist, even though it is recognized that almost all acetylcholine is rapidly metabolized by acetylcholinesterase as soon as it comes off the cholinergic receptor. The improbability that there exists only one regulator is enhanced by the observation that the cholinergic system can be blocked by an excess of acetyl choline (as occurs in the presence of an acetylcholinesterase inhibitor), and that the depolarizing block which results from such an excess can be released only by a competitive cholinergic antagonist which displaces acetylcholine from the receptor thus enabling catabolism by acetylcholinesterase. A competitive cholinergic antagonist, such as atropine, results in only a partial block of the cholinergic system (since the antagonist and the acetylcholine compete for the cholinergic receptor). There are at least three physiologic states, during which a competitive cholinergic antagonist could have survival value: stress, sleep, and pregnancy. 801
It is widely accepted, that adrenaline is the biochemical mediator of the "fight or flight" reaction. The efficiency of this reaction could however be enhanced if at the same time as the adrenergic system is stimulated, the cholinergic system were inhibited. Indeed, many of the components of the "fight or flight" reaction are more compatible with a cholinergic inhibition. Dilated pupils, dry mouth, rapid heart beat, sudden muscle weakness are in fact much more easily induced by an atropinic agent than by an adrenergic one (3,4). Furthermore, the release of a competitive cholinergic agent, which would rapidly inhibit the vagus, could help to prevent a vagal syncopal attack which might otherwise accompany such stressful situations. It has long been recognized that acetylcholine stimulates uterine activity (5). During pregnancy, the release of an agent which would keep both uterus and fetus relaxed would certainly enhance the survival of the fetus. The production by the placenta of a competitive cholinergic antagonist would be a safe and effective way of maintaining pregnancy, especially if the competitive cholinergic antagonist in its turn was rapidly metabolized. Deep sleep, in many ways resembles a depolarizing cholinergic block. The biochemical mechanism of inducing deep sleep is not presently known. Nevertheless, the circadian endocrine secretions which are known to accompany sleep are compatible with intermittent increases in cholinergic activity during the sleep cycle. An Hypothesis: Let us assume that there exists a competitive cholinergic antagonist in vivo. Any hypothesis which proposes such an agent should also state when it would be produced, what its function would be, and when it would be metabolized. A Biochemical Model of Sleep: A competitive cholinergic antagonist should be released by cholinergic neurons whenever a depolarizing block of the cholinergic system is imminent. Let us suppose that sleep begins with the release of a "sleep factor" (many are presently being postulated in the literature) which both stimulates cholinergic neurons to release a steady and sustained increase in acetylcholine and partially inhibits the activity of acetylcholinesterase. As the increase in cholinergic activity is thus maintained, the subject descends into deeper and deeper stages of sleep until stage 4 is reached and the subject is practically comatose (6). In the midst of stage 4 a change occurs in the subject (7), as muscle activity slowly reappears and sleep lightens and the subject ascends to stage 3, stage 2, etc. This ascent from stage 4 sleep could be mediated by the release of a competitive cholinergic antagonist which slowly displaces acetylcholine from the cholinergic receptor thus releasing the "depolarizing block". REM sleep would then represent the final stage during which the cholinergic system is active although partially blocked. Certainly the primary process thinking and hallucinatory activity which is so typical of the dream process (8) is reminicent of the primary process thought and hallucinatory activity
802
As the competitive cholinergic which is seen in an atropinic delirim(3,4). antagonist is itself displaced from the cholinergic receptor by acetylcholine the subject would either descend once more into deep sleep (if the sleep factor is still present) or ascend into wakefulness. It is postulated that the cholinergic competitive antagonist is metabolized very rapidly as it is displaced from the cholinergic receptor. Any constant disruption of REM sleep, could however result in the disruption of this cycle and a state of conscious delirium (due to the maintenance of the cholinergic block as a result of interrupting the metabolism of the competitive cholinergic antagonist), Figure 1 summarizes this model of sleep.
a
--NC)
u
SF-
tACH-
8 G
Depolarizing Block (Stage 4)
I_
Stage 3,2 --)
Figure 1: Proposed sleep cycle. Abbreviations: SF: sleep factor; ACH: acetylcholine; CA: competitive ztagonist; CAase: enzyme which metabolizes competitive antagonist. The Stress Reaction: At least two other functions of a competitive cholinergic antagonist could be postulated. The first would be release during periods of acute stress. This would necessitate postulating that adrenaline can stimulate cholinergic neurons to release the competitive cholinergic antagonist. It would enhance survival value during a stress reaction by preventing vagal syncope, by enhancing alertness, and by enhancing the rapid adrenergic stimulation of the heart (9). Pregnancy: A final function which is postulated for a competitive cholinergic antagonist would be during pregnancy. If the placenta was able to synthesize and release such an agent it would both inhibit uterine contraction and maintain the fetus in a state of motor laxity and semi-stupor. It would be necessary to postulate that the fetus has little or no ability to metabolize the putative competitive cholinergic antagonist. This in fact would be compatible with the theory of a partial cholinergic inhibition during REM sleep which has been proposed above since the newborn not only has over 70% REM sleep, but also demonstrates other more certain signs of cholinergic inhibition such as dilated pupils, no perspiration, and poor temperature regulation. It could be postulated that the enzymes which catalyze the metabolism of the putative competitive cholinergic compound have very low activity at birth and slowly increase in activity as the baby matures.
803
A Related Disease State: It has been stated elsewhere that hypotonic schizophrenia,could well reflect an inhibited cholinergic system (10). Postulating a failure to metabolize the competitive cholinergic agent proposed above as one of the major causes of hypotonic schizophrenia is compatible with a great deal of observed data: - Bender suggested many years ago (11) that childhood schizophrenia was a dysmaturation process. The hypotonic childhood schizophrenic in fact resembles in many ways the newborn infant (who it has been postulated lacks the enzymatic capacity to break down the putative cholinergic antagonist). Like the newborn infant, the hypotonic schizophrenic child has difficulty controlling temperature, has a soft velvety skin, dilated pupils, lax joints, very soft muscle tone, is very pale, and has a higher incidence of blue eyes than is found in the normal population (many babies are born with blue eyes which subsequently turn brown) (12). - Although sleep studies have nctyet been done on the subgroup of hypotonic schizophrenics, there is evidence that chronic schizophrenics have significantly reduced stage 3 and stage 4 sleep (13). This would also be compatible with the hypothesis of sleep proposed above, which would predict that an excess of the cholinergic antagonist would prevent descent into deep sleep (a depolarizing block of the cholinergic system could not occur in the presence of such an antagonist). - Decompensation into schizophrenia in females commonly occurs postpartum. If there is a competitive cholinergic antagonist secreted by the placenta during the pregnancy it could well be that its persistence postpartum helps precipitate the psychotic episode. It would of course then be necessary to postulate that the hormones which are elevated during the pregnancy somehow mask the effects of this competitive cholinergic antagonist during the pregnancy (perhaps by stimulating its breakdown), but as the hormones rapidly drop postpartum the subject is no longer protected from the higher level of partial cholinergic inhibitionwhich has prevailed during the pregnancy. Many clinicians have observed that females are especially vulnerable to psychosis during low levels of estrogen and progesterone (such as postpartum, during menses, and post menopause). There is presently no satisfactory explanation for this phenomenon. - Finally, the well known schizophrenic susceptibility to stress could be a function of stress-induced increases of the putative cholinergic antagonist followed by inadequate metabolism of the antagonist. CONCLUSIONS It has been postulated that there exists in vivo a competitive cholinergic antagonist whose function it is: (a) protect the body against a depolarizing block of the cholinergic system during sleep; (b) to partially
804
inhibit the cholinergic system during stress reactions; and (c) to help maintain pregnancy. It has further been postulated that inadequate breakdown of this competitive cholinergic antagonist is one of the causes of hypotonic schizophrenia. REFERENCES 1.
Giarman NJ, Pepeu G. Drug Induced Changes in Brain Acetylcholine. Br. J. of Pharm. 19:226 (1962).
2.
Richter D, Crossland J. Variation in Acetylcholine Content of the Brain with Physiological States. Amer. J. of Phys. 159:247 (1949).
3.
Longo VG. Behavioural and Electroencephalographic Effects of Atropine and Related Compounds. Pharm. Rev. 18(2):965 (1966).
4.
Eger EK. Atropine, Scopalamine, and Related Compounds. Anesthesiology 23(3):365 (1962).
5.
Goodman LS, Gilman A. The Pharmacological Basis of Therapeutics 4th Ed. The MacMillan Co. N.Y., N.Y. (1970).
6.
Williams RL, Karacan I, Hursch CJ. EEG of Human Sleep: Clinical Applications. John Wiley and Sons, New York, N.Y. (1974).
7.
Hobson JA, Spagna T, Malenka R. Ethology of Sleep Studied with TimeLapse Photography: Postural Immobility and Sleep-Cycle Phase in Humans. Science 201:1251 (1978).
8.
Freud S. The Interpretation of Dreams. Standard Edition, Vol IV and V. Hogarth Press, London, England 1958.
9.
Evans DE, Gillis RA. Reflex Mechanisms Involved in Cardiac Arrhythmias Induced by Hypothalamic Stimulation. Amer. J. of Physiol. 234(2): H199 (1978).
10.
Cantor Ss Trevenen C, Postuma R, Dueck R, Fjeldsted B. Is Childhood Schizophrenia a Cholinergic Disease? Arch. of Gen. Psych. to be published 1980.
11.
Bender L. Childhood Schizophrenia: Clinical Study of 100 Schizophrenic Children. Amer. J. Orthopsychiat. 17:40 (1947).
12..
Cantor S, Inayatulla M, Villafana P. The Subgroup of Hypotonic Childhood Schizophrenics. In Preparation.
13.
Caldwell DF, Domino EF. EEG and Eye Movement Patterns During Sleep in Chronic Schizophrenic Patients. EEG and Clinical Neurophys. 22:414 (1967).
805