Psychopharmacology andGeneral Adaptation Syndrome

WALTER C. BRUSCHI, M.D.

"Hans Selye, in tackling a total, inclusive approach10 Ihe fi ..ld of sickness, began what Adolph Jonas hascontinu,-d in Irritation and Counter·irritation: namely,a quesl for Ihe responSl~ 10 injury as such or to novelimpact of any kind."

"Medical r<'!warchers like Hans Selye and AdolphJonas hold that all eXlensions of ourselves, in sicknessor in health, ar,' attempts 10 maintain equilibrium. Anyexlension of ourselves Ihey regard as 'autoamputation',and Ih..y find Ihal Ihe autoamputative power orslrall'gy i~ rewrled to by Ih.. hody wh..n Ihe perceplualpower cannot locale or avoid the cauSl' of irrilation."

"TI... same kind of lolal configuralional awaren..s~thaI r..veals why the m..dium is socially th.. messagehas occurn,d in Ihe most r..cent and radical medicaltheori,'s. In his Stress of Life, Hans Selye tells of thedismay of a r"SI"arch coll,'ague on hearing of Selye'sIheory."

'Wh,'n h.. saw me thus launched on yel anolherenraptur..d description of what I had obSl'rved in animalstrealed wilh this or thaI impure, toxic malerial, helooked at me with desp..ralely sad eyes and said inohvious d..spair: "But, Selye, try to realize what you aredoing before it is 100 late! You have now decided tospend your entire life studying Ih.. pharmacology ofDIRT.'

"As Sely,- deals with th., tolal environmental situa·tion in his 'stress' theory of disease, so the latest ap·proach to media sludy considers not only the 'cont..nt'but the m..dium and the cultural matrix within whichthe panicular medium operates."(McLuhan, Marshall; Understanding Medin, SignetBooks. New York, 1964.\

The title of this paper implies a connectionbetween psychopharmacology and the GeneralAdaptation Syndrome with its implicit phe­nomenon of non-specific resistance. For thepurposes of illustrating this relationship we havechosen one of the best known pharmacologicalagents, chlorpromazine. Selye often refers to it ashis link with psychiatry. Chlorpromazine caninhibit many of the acute connective tissuereactions experimentally produced in hisInstitute. Of these let us consider ischemic ne­crosis which regularly occurs in the fold of dorsalskin of the female Sprague-Dawley rat when it isclipped for nine hours with an umbilical clamp.After nine hours, when the clamp is removed, theintensity of necrosis is expressed as a percentageof the total clipped skin. In all controls the ne-

Dr. Bruschi is Associate Professor of Psychiatry,Louisiana State School of Medicine in Shrevepon andChief of Neuropsychiatry, Veterans AdministrationHospital, Shrevepon, La.

September.october, 1970

crotic tissue is rejected in two days and new skinappears in its place. This phenomenon, however,does not occur when chlorpromaizne is injectedinto the animal before clamping. After nine hoursthe anatomical region in question shows only mildtransient hyperhemia and edema. This inhibitionalso occurs when the animal is exposed tosystemic stress, At IMCE (Institut de Medicine etChirurgie Experimentales) systemic stress meansa massive attack upon the life of the animal, suchas by: 1) surgical trauma (section of the spinalcord by cautery between 012 and LI imme­diately before applying the damp); 2) restraint ofall movements by taping the limbs on a board forfifteen hours before clamping and for nine hoursafter application of the clamp; 3) starvation forseven days before clamp time so as to cause theanimal a loss of not more than five grams daily;4) forced muscular exercise and 5) exposure toplus nine degrees centigrade thirty minutesbefore damping. The effects of systemic or totalstress (as I prefer to call it) on the topical or localstress (Ischemic Necrosis) were striking: milkhyperemia and edema of a transient nature. Iremember vividly Selye holding one of these ratsin the palm of his hands and pointing to theunblemished dorsum: "Do you psychiatrists havea way of explaining this? Would you believe thatthis inhibition occurs even after removal of theadrenals?" My fresh, untrained and unbiasedmind groped for something to say. "The rat," Isaid, "was given two problems in adaptation atthe same time: a local-the clamping of the skin;and a totally involving one-the threat to its lifeby surgical trauma, cold, forced muscular exer­cise, etc. It apparently made a choice. Itpostponed or turned down the solution of thelocal problem, threatening it partially. for theother which was threatening its total existence."This flash of peripheral vision was received withominously polite chuckles and no comment.

Chlorpromazine, an antiserotonin and an­tihistamine agent, can, like total stress, inhibit theeffects of topical stress. Selye, in a recent paper,commenting on the possibility of blockingpathogenic properties of drugs with their cor­responding antagonistic agents, writes: "Wefound, for example, that chlorpromazine, anantihistamine and an anti-5-RT compound,inhibits not only anaphylactoid edema, a nor-

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mally manifest effect of mast-cell products, butalso the Acute Conditioned Necrosis, DelayedTissue Clearance, Mastocalciphylaxis, andMastocalcergy which require a conditioner tobecome apparent." Later, in that same paper,after first doubting that chlorpromazine couldexercise a specific blocking action on ischemicnecrosis. he adds: "It might be argued thatliberation of histamine and/or 5-HT participatein the causation of ischemic necrosis; if so, pro­tection by the corresponding blocking agentswould be understandable. But how are we toexplain the effects of Stress? Meanwhile thequestion cannot be answered." By Stress, a~

mentioned earlier, Selye means the massive threatto the life of the animal carried out underexperimental conditions (trauma, cold. restraint,starvation, etc.). For the inhibition of ischemicnecrosis by total stress, as mentioned earlier, heoffers as a working hypothesis: the gradualrelease of the histolytic enzymes during thepretreatment period (exposure to total stress) andtheir inactivation and tissue-depletion before thefull impact of topical stress. Except for starvationand restraint, let us remember, total stress isapplied at the time of the clamping of the skin orimmediately aftetward. This hypothesis of gra­dual release and inactivation of histolytic en­zymes raises the following questions: \Vhere arethe enzymes deactivated? Are the enzymesdeactivated only in the dorsal region? Is theentire bodily store of enzymes depleted beforeonset of topical stress? In the case of con­temporaneous application of partial and totalstress, has the animal suffieient time to deactivateall available histolytic enzymes? Finally, whyshould the enzymes within the isolated flap ofskin be deactivated? Why not solve both pro­blems at the same time? I remember debating thiswhole issue with the Hungarian scientists whoperformed the actual experiments and with aTurkish neurophysiologist with whom I repeatedpart of those same experiments. The latter sug­gested that distilled water be introduced into thesac made by the clamp before total stress time.After nine hours the content of the sac wouldthen be reintroduced into the dermal sacs ofcontrols. This implied the hope of detecting theagent which inhibited this reaction and would,therefore, also inhibit it in rats within theclamped dorsal skin not exposed to total stress. Ileft IMCE without knowing the results of thisexperiment. What has truly impressed me in allthis, is the rigid empirical approach. They are

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interested in what they can see and touch, hopingto identify and maneuver the links in thisphenomenon's chain of causation. They are me­chanicists for whom deterministic causality hassolved many a problem related to the structureand dynamics of animal adaptation, withoutnonetheless, throwing any light on Selye'sgreatest contribution to science: A total con­6gurational approach to disease of any kind.

Marshall McLuhan, by contrast, an expert onmedia of communication, acknowledges some ofthis approach's monumental implications for man.He assigns Selye a place in the annals of time as aforenmner of the electronic age, the age of totalparticipation and involvement.

The above mentioned mechano-deterministicinvestigations on the inhibition of ischemic ne­crosis by chlorpromazine and total stress tread onthin ground because of the vague nature of someof the variables involved. If we assume that thisphenomenon is equally inhibited by systemicstressors A, B, C, D, E, then A, B, C, D, E areeither identical in themselves (which is not true)or they all have something in common:nocuousness which, under appropriate conditions,can either prevent or not prevent this acuteconnective tissue reaction. Nocuousness is aconcept conceived by the observer for an agentexercising a nocuous effect upon the animalundergoing experimentation. To say thatnocuousness can follow a neural pathway to thesite of clipping and cause the area to bediscarded by ischemic necrosis, or to inhibit it,may not be as naive as it sounds, if we can showhow nocuousness is translated into concrete ac­tion by the organism. But how are we to un­derstand the choice between two distinctnocuousnesses when they occur more or less atthe same time? How does the animal weigh thedifference? Selye theorizes, in substance, thattotal stress and chlorpromazine. somehow, stripthe animal of its inherent ability to cope with thepartial stress. All this apparently occurs withinthe context of blind, dispassionate mechano­deterministic causality. Eventually, in time, hemust presume, we shall know this phenomenon'sultimate physico-chemical definition by virtue ofLeibniz's Law of Sufficient Reason. But, why,then, designate this resistance non-specific? Isthis designation a temporary expedient, pendingdiscovery of precise causal relations between totalstress, chlorpromazine and topical stress? If so,we can look fotward to lumping into one amor­phous mass the entire universe of nocuous agents

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by virtue of Leibniz's Principle of identity. Selyewould have, indeed, spent a lifetime studyingthe pharmacology of "dirt".

Could we not view the problem from this per­spective: There is an environment to which wemust adapt. If not exposed, it is eitherfriendly or it is not. If it is friendly, we havesomehow previously met it and coped with it.Example: the intestinal bacterial flora of man. Ifit is not friendly, we either succumb to it orsurvive by coping or withdrawal. If the livingorganism were a closed system without anycapacity for novel action to meet novel situations,adaptation would eventually become impossible.The existence of a source of undifferentiatedenergy capable of transforming itself into specificforms of resistance is the only possible way ofstaying alive. Nonspecific adaptation, as far as Iam concerned, implies that and, maybe, onlythat. Selye asks: "What irritates tissues? Whatmakes them react and or not react under thesame conditions?" I ask: "Why do tissues react?Why the inhibition of or activation of theirreaction under the same conditions? Could not allthis be viewed within the general scheme of in­tended survival? Is it not equally valid to supposethat the organism purposefully puts into opera­tion against an intmder threatening its integritywhatever means are at its disposal: the bar­ricading of inflammation, trapping by calciumdeposition, autoamputation by necrosis, isolationby thrombus formation, and diluting by massiveedema?

We have now (purposefully) led ourselves intothe thick of Organismic Biology, where theconcepts of intended action, goal directedness aredecreed epistemological relevance. Selye ad­monished his young diSciples: "Try to look for themere outlines of big things with your fresh, un­trained and still unbiased minds. When you areolder you may no longer be able to see the forestfor the trees." Could we, by wild chance, beseeing the forest now in the purposeful nature ofnonspecific resistance. We are tempted to fit thisphenomenon into the broad conceptual edifice ofBertalanffy's General System Theory, whereliving matter is organismic; where it exists as asystem, an open system, all parts standingteleologically in mutual interaction. Livingsystems actualize themselves by rising from lessto more differentiated forms of evolution.Teleological determinism alone can adequatelyexplain this. It alone can show how undifferen­tiated energy of adaptation is available, upon

~pll·mber·October, 1970

demand, for transformation into specific forms ofadaptation. The selective metamorphosis ofprimitive undifferentiated stem cells within thehemopoietic organs into specific mature bloodcells when and where needed for defense, is aneloquent example in point. Selye has himselfexperimentally observed that specific and non­specific resistance can vary independently of eachother He observed that prolonged exposure to anocuous agent increases its resistance to it butdecreases resistance to other nocuous agents. It isas if the organism concentrated its efforts on thenocuous agent at hand by making adaptationenergy more and more specific for that agent. Itis as if it also made that same energy less and lessavilable for the other agents with which itbecomes less and less involved.

To assume that there are pre-existing specificdefenses for the indefinite number of unmetenvironmental conditions to be encountered in alifetime could be designated as Biological Ra­tionalism. To assume that our adaptations are theexclusive product of passive exposure, that weare, so to speak, a "tabula rasa" at birth isBiological Empiricism. This theory, precludes anyautonomous, responsible participation of the or­ganism in its growth. It could never explain whythe organism puts off coping with local threats forthe purpose of toal survival. Biological Transcen­dentalism (notice the analogy to Kant) would con­ciliate both views. This presupposes the existenceof (lpriori conditions (undifferentiated energy ofadaptation) that makes our adaptation to theenvironment pOSSible. Living matter, in thissense, is potentially and actively constitutive ofits own adaptation.

I see the living organism as ideally involved inadaptation when it is totally involved in theprocess; when all interested parts of the systemare aligned to a particular project of developmentat hand. This, of course, implies hierarchicalorganization, at the summit of which goal­directed action is initiated. The appraisal of anitem of experience is followed by a correspondingdesign of coping. The alignment to that designfrom lower to higher hierarchically set levels oforganization makes for harmonious coping withthe particular experience at hand. The inability toperform in this manner causes damming up ofadaptation energy and retreat to lower forms ofcoping. When rage is repressed, for instance, wesee this damming up in generalized musculartension, in the clenched fists, biting of the lips,

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often pounding upon one's own body and painfulgnawing within the stomach. On the other hand,in the perfectly executed blow of the pugilistupon his opponent, we see an example of thesmoothly creative alignment of the wholeorganism to an existing problem in adaptation.Now, if we consider total stress and its inhibitoryaction upon partial stress, I detect some creativealignment resulting in healthy integration intoour environment. Local breakdowns, such as is­chemi<: necrosis, within the context of teleologicaldeterminism, are failures in organismic par­ticipation by virtue of faulty alignment to the allencompassing project of adaptation.

The opposing polarity is absolute unconditionalretreat from the environment. Hibernation is anexample in point. Chlorpromazine can preventischemic necrosis, a local breakdown, by inducingunconditional withdrawal from the partial andtotal stress at the same time. 'Valter Cannon's"Fight or Right" now comes to my mind with notless relevance than when it inspired the youngAustrian Scientist who later authored the StressTheory of Disease.

Psychopharmacology has been able to induceboth polarities in adaptation: active involvementand unconditional withdrawal. Our psychotropi<:agents are therefore a temporary blessing tomankind. Until, of course, that distant future inwhich the wisdom of total creative involvementwith stress and strategic unconditional with-

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drawal from it will have become Man's only wayof life.

REFERENCES

I. Bertalanffy. L. von.: General System Theory. GeorgeBraziller, New York, 1968.

2. Bertalanfly, L. von.: Robots, Men and Minds. GeorgeBraziller. New York. 1967.

3. Boss, M.: Psychoanalysis and Daseinsanalysi5.(Transl. by L. B. Lefebre). Basic Books, Inc.• NewYork. 1963.

4. De Ruggiero. G., & Canfora. F.: Breve Stona denaFiloso/ia. Editori Laterza. Bari, 1962.

5. McLuhan, M.: Understanding Media. Signet Books.1964.

6. Selye, H.: A Syndrome Produced by Diverse NocuousAgents. Nature, London, 138, 32. 1936.

7. Selye. H.: In Vivo. Liversight Publishing Corp.,New York, 1967.

8. S..lye, H.: Non.specific R..sistance. Ergebnisse derAllgemeinen Pathologie und Pathologi5chen Ana·tomie, Springer·Verlag, Berlin, 1961.

9. St'lye, H.: Pluricausal Diseases. Experimental Medi·cine and Surgery, Brooklyn Medical Press, Inc.,Vol. XXIV, Nos. 2·3, 1966.

10. Selye. H.: The Significance of the Adrenal Glandsfor Adaptation. Arch. Int. I'harmacodyn, 55, 431.1937.

II. Sely... H.: The Stress 0/ Li/e. McGraw·Hill. NewYork. 1956.

12. Selye, H.: Somogyi. A. and Vegh. P. In/lamation.Topical Stress and the Concept 0/ PluricausalDiseases. Institut de Medicine et de Chirurgie Ex·perimentales, Universite de Montreal. 1967. Mon­treal, 1967. Montreal. Canada.

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