PSYCHONEUROIMMUNOLOGY: SEARCHING FOR THE MAIN DETERIORATING PSYCHOBEHAVIORAL FACTORGenetic, Social and general Psychology monographs, 1996, 122: 329-346. Vadim S. Rotenberg vadir@post.tau.ac.il Pinkhas Sirota Avner Elizur Sackler School of Medicine Tel Aviv University ABSTRACT Psychoneuroimmunology has become an independent science with a broad experimental basis However its theoretical basis is still very vague and ambiguous There are many contradictions in the experimental data that have not been integrated into a united conception and some accepted paradigms that remain doubtful The present critical review suggests a conceptual approach to the problem based on the proposition of two opposite types of behavior (search activity and renunciation of search) with attempts to integrate experimental results by avoiding contradiction The analysis of the literary data confirms that every behavior that includes search activity prevents psychoimmunological disorders whereas renunciation of search displays a general predisposition to such disorders Such an approach makes possible new solutions of paradoxes and broadens the possible interpretations of the alteration of immune functions in depression anxiety and stressful events. According to most publications, psychoneuroimmunology consists of two main branches (a) immunological functions in natural and experimental stressful conditions in humans as well as in animals, and (b) immunological functions in different psychopathological states, such as depression, anxiety, and so forth It is possible to consider depression and anxiety as internal distress, and from this point of view, both branches are interrelated STRESS AND IMMUNE FUNCTIONS The influence of stress on immunological functions is ambiguous and ambivalent It has been shown that stress may cause immunodepression (Irwin, 1991, Kiegolt-Glaser et al, 1987, Rosenbaum & Seligman, 1989) but may also exert an immunoenhancing effect on cell numbers and their functioning (Land-man et al, 1984, Laudenslager, Ryan, Drugan, Hyson, & Maier, 1983, Naliboff et al, 1991, Weiss, Sunder, & Cierpiac, 1990). The same stressor may have an immunoenhancing effect rather than an immunosuppressing one, depending on its duration (Herbert & Cohen, 1993, Monjean & Collector, 1977) or intensity (Korneva & Shkmek, 1988). According to some investigations (Bong Kohk, 1993), an objective stress (examination by itself) does not affect immune functions, but the subjective emotional reaction to some unusual events during examination has a positive correlation with natural-killers (NK) activity However, according to others (Herbert & Cohen, 1993), immunity (NK cell activity) is suppressed by objective stressful events even more than by the subjective estimation of stress intensity. A difference has been shown between acute laboratory stress and natural stress. Suppressor/cytoxic T cells increase following laboratory stress and decrease in short- and long-lasting natural stress (Herbert & Cohen, 1993), short-and long-term natural stressors are negatively related to NK cell functions, whereas laboratory stressors show a positive relationship to NK cell function It is possible to suppose that this difference is determined by the different behavioral outcome of stress. Laboratory stress has more of a chance to produce a mobilizing effect, whereas natural stress may often produce helplessness. Chronic stress may "depress" the immune processes, whereas acute stress may enhance them (Kiegolt-Glaser et al, 1988) However, chronic stress can also lead to the habituation of the immunological reactions and sometimes can even increase a body's resistance (see Seligman, 1991) The contradictive effect of stress on immune competence can partly explain a weak correlation between stress-producing life events and subsequent somatic disorders If stress can determine the suppression of immune function and sometimes its activation, the resulting outcome must be very subtle or indefinite (Solomon, 1987) The relationship between helplessness and neuroimmunological functions seems to be more definite. Inescapable shock, which is known to produce learned helplessness (Seligman, 1975), suppresses blood lymphocyte proliferation (Laudenslager et al, 1983, Marbach, Schleifer, & Keller, 1990). Rats who received the same amount of shock but could control it did not display a reduction of the proliferative responses to the mitogens (Laudenslager et al , 1983). The activity of NK cells was reduced during the inescapable stress but not during the escapable stress (Shavit et al, 1983). Animals in learned helplessness conditions show profound immunosuppression, whereas animals able to control their stress show immunoenhancement. Controllability and loss of control are attended by selective but highly dissociated patterns of neurosympathetic, adrenomedullary, and adrenocortical output (De Boer, De Beun, Slangen, & van der Gugten, 1990). In older people, control over their life events protects health and decreases mortality (Rodin, 1986). However, the beneficial effect of the control over the stressor remains unknown from the point of view of physiology. Thus, when participants only believe that they have such control, stress responses are lessened, irrespective of whether they really can control the situation (Thompson, 1981). It has been shown (Mason, Giller, Kosten, & Harkness, 1988, Mason, Giller, Kosten, & Yehuda, 1990) that the crucial factor determining activation of the sympathoadrenal system without activation of the hypothalamopituitary adrenal axis (stress without distress) was the extent of perceived control Whether this perception is erroneous and the sense of control is a delusion is irrelevant, however, it means that the objective control per se is not responsible for the positive stress outcome, and the absence of the control is not responsible for the negative stress outcome, which may explain the lack of controllability effect in some investigations. The pragmatic result of the activity is also not crucial for the immunological response Brosschot et al (1992) presented their healthy participants difficult mental tasks (puzzles) that they were unable to solve In many other investigations, these unresolvable tasks have been used to produce learned helplessness, but in this investigation, participants demonstrated a significant increase in the number of NK cells after stress, which returned to baseline levels after 15 mm of rest A similar effect occurred on T suppressor/cytoxic cells. However, according to the report at the end of the experiment, participants did not display a helpless/hopelessness paradigm. Quite the opposite. They reported an increase of effort, concentration, and interest, combined with tension and irritation Is it possible that only actual effort, even unsuccessful effort, can determine the positive stress outcome' That seems to be a reasonable conclusion, because it has been shown that tasks involving efforts without distress primarily activate the norepinephrine (NE) system (Lovallo, Pincomb, Brackett, & Wilson, 1990). Effort, readiness for challenge, attempts to control the situation, and strength in the face of life's difficulties increase the immunological functions (Kobasa, 1979). Cattell (1992) emphasized the very important theoretical and practical differences between effort stress (which reflects the psychophysiological mobilization with the purpose to overcome obstacles) and anxiety, which in this context is synonymous with distress. It is possible to speculate that when participants believe that they have control over the stressor, they are more capable of performing efforts in an attempt to change the situation, and that is why the belief in control determines the positive stress outcome However, it remains unclear what it means to exert effort in psychophysiological terms and how effort influences somatic health and the immunological system. At the same time, the concept of effort stress versus anxiety is similar to the concept of adaptive versus maladaptive emotional tension (Rotenberg & Bouc-sein, 1993). The discrimination of adaptive and maladaptive emotional tension is based on the search activity concept (Rotenberg, 1984, 1992, 1993; Rotenberg & Arshavsky, 1979a, 1979b), which could explain what a psychophysiological state is beyond the effort stress that makes it beneficial. Search activity is defined as activity oriented to change a situation (or at least to change the participant's attitude toward it) in the absence of the precise prediction of the final outcome of such an activity, by taking into consideration intermediate outcomes at all stages of the activity. Search activity can be regarded as a psychobiological state that is common for active self-stimulation in non-human animals, creative behavior in humans, and exploratory and active defense (avoidance and fight/flight) behavior in both species. Renunciation of search is the opposite psychobiological state and encompasses neurotic anxiety and depression in humans and freezing in animals, as well as panic and stereotypical behavior in both species. Freezing is different from the defensive motionless behavior (passive avoidance, startle reaction); freezing is nonflexible behavior and is not accompanied by hippocampal theta-rhythm. Well-organized hippocampal theta-rhythm is one of the best indicators of search activity in animals: All forms of behavior that are accompanied by hippocampal theta-rhythm (orienting,-learning, searching for food, escape, startle) include search activity. Conversely, theta-rhythm is absent during freezing as well as during stereotyped consummatory behavior with a definite predictability of outcome (e.g., during the performance of an unconditioned reaction). It is crucial that search activity and renunciation of search display an opposite influence on body resistance in normal and especially in stressful conditions: Search activity increases body resistance, whereas renunciation of search decreases it (Rotenberg & Alexeyev, 1981; Rotenberg & Arshavsky, 1979b; Rotenberg & Korosteleva, 1990). Both active self-stimulation and active defense behavior reduced the manifestation of somatic disorders. Passive self-stimulation of the lateral hypothalamus (when a rat simply lay on the pedal, thus closing the circuit and sending rare pulse bursts to the brain) did not influence the course of the artificially induced disorders. Freezing speeds the progress of somatic disorders, rendering its course more difficult. This was confirmed on different artificial pathological models (artificial epilepsy, neuroleptic dyskinesia, aconitine arrhythmia, blood hypertension, ischemic heart disease, etc.). Let us present an example of the development of anaphylactoid edema of the animal's muzzle after intraperitoneal injection of 1.5 ml of the white of a hen's egg (Rotenberg & Arshavsky, 1979b). The manifestation of the edema was measured by the change in the shadow's width on a contact print. In control, the edema equaled 3.25 0.16 mm. Against the background of self-stimulation, it was weakly expressed (1.04 0.12 mm) or did not develop at all. Forcible stimulation of the lateral parts of the ventromedian hypothalamus, which leads to the reaction of freezing, made the latent period of the edema emergence almost twice as short, and its clarity of expression equaled that observed in the control animals (3.36 0.12 mm). Meanwhile, the stimulation of the medial part of the ventromedian hypothalamus, which provokes active-defense reaction of the fight-flight type, reduced the degree of edema (2.2 0.1 mm). The injections of librium (6 mg per kg) resulted in a drop in the animal's muscular tension and its motor activity and in a change in the character of self-stimulation (which became passive). In this case, the development of edema was not blocked (3.27 0.21 mm). At the same time, pathology was also not blocked by panic behavior, which was accompanied by exaggerated body movements; therefore, it is clear that body movements by themselves were not responsible for such a blockade. In hypophyseactomized rats, the introduction of protein led to the development of edema equal to the control condition (4.1 0.16 mm), whereas self-stimulation caused the decrease of edema (1.71 0.23 mm). This means that the hypophysadrenal system was not crucial for body resistance and stress outcome. This conclusion has been confirmed by data (Keller, Weiss, Schleifer, Miller, & Stein, 1980). That is, stress-induced alterations of immunity in adrenal-ectomized rats, presumably through the direct influence on the autonomic (sympathetic) nervous system were shown to be important for the short-term immunological change (Kiegolt-Glaser, Cacioppo, Malarkey, & Glaser, 1992). It was also shown (Herbert & Cohen, 1993) that the activation of the sympathetic nervous system was associated with alterations in human immune function before the hypothalamus-pituitary-adrenal axis had enough time to respond with an increase in cortisol. However, the increased activity of the sympathetic nervous system (high levels of epinephrine and norepinephrine excretion, high blood pressure, and heart rate; Davidson & Baum, 1986) did not determine the activation of immune function because such sympathetic exaggeration may accompany maladaptive anxiety (renunciation of search; Rotenberg & Boucsein, 1993). Thus, behavior attitudes determine the stress outcome; that is, the presence or absence of search activity in behavior is the crucial factor in psychoneu-roimmunology. We are going to show further how these behavioral attitudes are related to the balance between noradrenaline and cortisol-that is, what is the biochemical basis of body resistance. Our conclusion about the crucial role of behavior has many clinical outcomes. For example, the protective influence of hypochondria-sis on the somatic health of psychosomatic patients (Rotenberg & Schattenstein, 1990) can be explained as the result of active hypochondriac behavior (active search for help). According to the search activity concept, the process of search is more important than its pragmatic outcome. Herein lies the basic difference between the conception of search activity and the conception of coping behavior. Coping must be successful to be meaningful. Another difference is the inclusion m search behavior of a wider scope of phenomena than is usually understood by coping behavior, in particular, spontaneous creative activity and orienting-exploratory behavior, which are not related to stress. The above-mentioned approach is in agreement with the concept of the immune-prone behavior pattern (Solomon, 1993). Biological (in-born) predisposition to the development of the immunological disorders may be blocked or exaggerated by different types of behavior. Our approach is also in agreement with data (Laudenslager et al, 1988) that showed that in both control and stressful conditions, rats who were immunized during the dark (active) part of their cycle produced more antibodies to a novel antigen than did rats immunized in the light phase. These data are usually explained by the daily rhythm of adrenal secretion, but this daily rhythm may be related to the behavior. The search activity concept can also explain why adult mice who had been stressed by immobilization during the first 2 weeks of life (an effective way to produce learned helplessness in the future) showed greater suppression of antibody response following exposure to a similar stress than controls did (Raymond, Reyess, Tokuda, & Jones, 1986). Although the hypothalamus-hypophys-adrenal axis is not crucial for the immunological reaction, this system seems to be very important in the biofeedback between brain and immune system. Immunization induces change in firing rates of hypothalamic neurons (Besedovsky, Sorkin, Felix, & Haas, 1977, Korneva & Shkmek, 1988). Rats injected via jugular catheters with lnterleukm-1 (1L-1) showed increased levels of adreno-corticotropic hormone (ACTH) and corticos-terone in the blood (Tapolsky, Rivier, Yamamoto, Plotsky, & Vale, 1987). The IL directly stimulates the synthesis and secretion of corticotropin, releasing hormone and vasopressin at the level of hypothalamus, the consequent activation of the pituitary-adrenal axis reduces the intensity of the immune response (Reichin,1993). The immune system may serve a sensory function, alerting the brain that the body is being stimulated by a particular foreign organism (Blalock, 1984). However, to alert the brain means also to influence the behavior that is regulated by the brain. The hypothalamus, especially sensitive to all alterations in the inner milieu, is at the same time a key structure in the brain system that manages search behavior and renunciation of search (Rotenberg & Arshavsky, 1979b). These two opposite types of behavior are accompanied by different reactions of the pituitary-adrenal system. Thus, it is possible to suggest that the biofeedback between brain and immune system includes behavior as an important modulator. However, this speculation has to be confirmed in experimental investigations. If search activity during stress is more important than the pragmatic outcome of stress for the immune functions, it is possible to explain all the contradictions we have noted. Participants are able to continue search activity if they believe that they can control the situation. It has been shown that low self-esteem (caused by the inability to control a situation and by previous negative experience) and negative expectations regarding the outcome of efforts are factors that determine the renunciation of search (Rotenberg & Korosteleva, 1990). The concept of search activity is able to explain seemingly paradoxical data of surgery stress. Preoperative relaxation training, instead of reducing adrenaline and cortisol responses to surgery, had a tendency to increase such responses, although state anxiety was really reduced (Manyande et al, 1992). Preoperative relaxation training also increased stressfulness at surgery and impaired recovery (increased the negative nitrogen balance and impaired immune functions). However, it is possible that the preoperative state anxiety (reduced by relaxation) reflects the emotional mobilization in an attempt to overcome stress (a cognitive preparation for surgery, see Jams, 1988). Thus, it is adaptive anxiety that includes search activity. This proposition corresponds with data (Salmon, Pearce, & Smith, 1992) that the preoperative state and trait anxiety correlated with lower postoperative circulating levels of adrenaline and cortisol (a combination of these hormones usually characterizes distress) and protects participants against the stressfulness of surgery (Salmon & Kaufman, 1990). On the other hand, relaxation intervention was associated with an increase in NK cell activity in geriatric residents of independent living facilities (Kiegolt- Glaser et al, 1985) In this situation, relaxation as well as a feeling of social support can reduce the maladaptive anxiety that is not object related and reflects the renunciation of search (Rotenberg & Boucsem, 1993). IMMUNE FUNCTIONS, HORMONAL ACTIVITY, AND DEPRESSION. The present approach can also explain the controversial data regarding the immune functions in depression Depressed participants exhibited a significant reduction in NK effector cells and NK cell activity (Evans et al, 1992). This was especially true for depressed males, who elicited greater hypothalamic-pituitary-adrenal axis cortisol response, sympathetic-adrenal activity and systolic blood pressure responses during behavioral stress However, NK activity was unrelated to the severity of depression in this investigation. Irwin, Smith, and Gillm (1992) found that insomnia was associated with a reduction of NK activity independent of the severity of other depressive symptoms .Total sleep time, sleep efficiency, and duration of NREM sleep were positively correlated with NK activity. Age is another important variable that modulates the influence of depression on immune functions In the depressed participants, increasing age had a significant independent correlation with decreased numbers of total lymphocytes, cells, DR cells (sorts of lymphocytes) and reduced phytohemagglutinin (PHA, Andreoli et al, 1993). In the older patients, the proliferative response to PHA and the percent of CD4 (helper/mducer) cells was lower than in controls, whereas the reverse was true for the younger patients (Schleifer, Keller, Boud, Cohen, & Steven, 1989). It is worthwhile to take into consideration that in younger patients, depressive mood was often associated with hyperadaptive patterns of stress response, increased arousal, impulsivity, and instability (Andreoli et al, 1993). Thus, exactly these hyperadaptive patterns of stress response may be responsible for the positive outcome (an increase in NK cell number and activity). On the other hand, in healthy participants, similar immune effects have been found in the experimentally elicited "negative" and "positive" emotions (Knapp et al, 1992). This is in agreement with an assumption that the quality of emotion by itself is less important in the psychosomatic relationship than the type of behavior (Rotenberg, 1984). Thus, it is possible to suggest that if, in clinically depressed participants, the depressive mood is combined with corresponding behavioral attitudes (giving up, renunciation of search) its result on the immune system will be suppression, whereas the opposite will happen if the depressive mood is accompanied by the hyperadaptive patterns of behavior. It has been shown (Andreoli et al, 1992) that participants with major depression combined with panic disorders displayed greater numbers of cells and PHA mitogen responses than depressed patients without panic disorders did. Participants with a combination of major depression and panic disorders were characterized by a higher level of anxiety accompanied by increased noradrenergic activity. In patients with panic disorders without depression, immune functions were undisturbed. Of course, it is necessary to take into consideration that immunological as well as psychological and endocrinological investigations have been performed in these patients not during the panic attack itself but only between attacks. A state of panic, according to the clinical picture and to the above-mentioned assumption, represents renunciation of search. However, the overt behavior of these patients in a "quiet" period (between panic attacks) usually did not display signs of renunciation of search, and their emotional tension may have been an adaptive one. It is possible to suggest that the increased level of such emotional tension can prevent immunological disturbances. This suggestion corresponds with data that younger patients are more predisposed to panic attacks. Our suggestion also corresponds with data (Hellstrand, Hermodsson, & Strannegard, 1985) that increased noradrenergic activity can enhance the immunological function (NK cell activity), and indeed noradrenergic activity did increase in patients with panic attack. In the context of the present approach it is worthwhile stressing that noradrenaline excretion followed ratings of concentration and irritation during the process of the solution of complex sensomotor tasks, whereas adrenaline excretion followed ratings of unpleasantness and irritation (Frankenhaeuser, Nordheden, Myrsten, & Post, 1971). Noradrenaline excretion also increased in participants who had to perform a difficult sorting task (Carlson, Levi, & Oro, 1972). It was also shown that adaptive emotional tension that corresponds with active coping was accompanied by the predomination of the catecholamine (including noradrenaline) excretion, whereas maladaptive emotional tension, which reflects distress (and from our point of view, renunciation of search) was characterized by the increase of cortisol excretion either combined or not combined with catecholamine excretion (see Rotenberg & Boucsein, 1993). It has been shown that low resistance to emotional stress and the development of exhaustion and various complications are connected with individual CA metabolism peculiarities, particularly with the deficient CA synthesis (Anokhina, 1993) Paratrooper trainees showed sustained daily task-related catecholamine increases that were not associated with distress (Baade, Ellertsen, Hohnson, & Ursin, 1978), whereas Type A persons with a family history of cardiovascular diseases had higher cortisol levels than did Type As without such history (Ursm & Knardahl, 1985). During efforts without distress (such efforts include search activity), catecholamines increased, but cortisol responses were below the base rate in humans (Frankenhaeuser, Lundberg, & Forsman, 1980), whereas in efforts with distress, both adrenaline and cortisol were elevated (Lundberg & Frankenhaeuser, 1980). Cortisol elevation in stressful situations was not maintained by the high activity level per se but by the lack of appropriate responses (Dienstbier, 1989). Cortisol elevation, together with catacholamine depletion, predominated during unavoidable stress when it caused learned helplessness (renunciation of search). However, even the ineffective but active response of fighting among rats subjected to inescapable shock inhibited catecholamine depletion (Anisman & La Pierre, 1982). Thus, in a previous publication (Rotenberg & Boucsein, 1993) we suggested that it is possible to use the noradrenaline/cortisol ratio for the discrimination between two types of emotional tension those accompanied by search activity and those that reflect renunciation of search This conclusion is in agreement with data showing that depression is usually associated with high cortisol base rates (Sacher et al, 1973), as well as with data showing that corticosteroids can suppress blood lymphocyte proliferation and TH and NK cell activity (Cupps & Fauci, 1982). The relationship between plasma cortisol and and lymphocyte numbers appears to be an inverse one (Kronfol, House, & Silva, 1986), whereas the relationship between noradrenaline and immune cells is positive. Thus, it is possible to suggest that the noradrenaline/cortisol ratio reflects behavioral attitudes. The increase of this ratio characterizes search activity, whereas its decrease corresponds to renunciation of search. Neither the excretion of noradrenaline nor the excretion of cortisol taken separately was able to characterize the psycho-behavioral state of the participant. Catecholamines may be excreted when the situation by itself involves uncertainty and is indefinite (Frankenhaeuser, 1984). However, such a situation can determine renunciation of search with the corresponding increase of cortisol excretion, or it can stimulate search activity not accompanied by cortisol excretion. On the other hand, the de crease of this ratio determines the suppression of the immune activity. In addition, depression is often associated with the increase of cortisol excretion and with suppression of immune functions. However, in some conditions (i e , in combination with panic attacks), when depression is associated with the relative increase of noradrenaline excretion and corresponding behavior attitudes, immune functions can be relatively intact It has been shown (Seligman, 1991) that pessimism as an explanatory style that predisposes participants to give up in a challenging situation can lower immune activity, unmediated by depression. This confirms our suggestion that behavioristic attitudes are even more important than the clinical symptoms of depression, and it can presumably explain some controversy in depression/immunity relationships. These relationships are complicated, and it is necessary to also take into consideration the severity, recurrence, and chronicity of illness, the possible role of opioid peptides, and so forth. We are not going to discuss all these aspects in the present article. Our aim here is only to discuss whether the difference in immune reactions of depressed patients could be understood according to their different behavioral attitudes. Obviously, it is an oversimplification to discuss the function of the immune system as a single function. There are dissociations between different immune subsystems. The number of NK cells does not correlate with their functional activity, and so forth. However, with the present level of knowledge, it is difficult to specify the particular immune correlates of behavior. Search activity and renunciation of search, as well as stress exposure (Laudenslager et al, 1988) may alter the integrated outcome of the immune response to the deteriorative factor. STRESSFUL LIFE EVENTS, PSYCHOLOGICAL VARIABLES, AND IMMUNITY The present approach can also explain complicated relationships between stressful life events, psychological variables, and immunological functions. So-called hassles, everyday sources of stress such as time pressure, work problems, and so forth, and trait anxiety have a positive synergetic effect on psychiatric symptomatology, on immunological reactivity, and on minor physical ailments. Hassles had a more severe impact on the highly trait-anxious participants than on their less trait-anxious peers (Kohn & MacDonald, 1992). Fuchs and Hahn (1992) found that trait anxiety was a moderator of stress-illness relationships. In their investigation, a very stressful factor-unemployment- was used. However, results showed that this factor was not crucial by itself, because persons who were less anxious had similar low levels of illness, regardless of whether they were under unemployment stress or not. Only highly anxious persons who were unemployed had higher illness scores than those who were employed. But at the same time, trait anxiety per se was also not important for physical health. Highly anxious participants who were employed did not have a higher illness score. On the other hand, Shea, Clover, and Burton (1991) found that people with low scores in state and trait negative affect had poor immune responses. How is it possible to explain these data? According to Endler (1988), trait anxiety is a personal vulnerability factor that has the capacity to affect the relationships between life events and illness, because it increases both the likelihood and the extent of perceiving life events as stressful and threatening. From our point of view, this explanation is missing the factor of behavioral attitudes. Life events perceived as threatening normally mobilize all efforts to overcome these events. As mentioned above, decreased emotional tension caused by relaxation increased the postoperative distress and postoperative complications (Manyande et al, 1992). Thus, for good adaptation, the challenging life events must be perceived as threatening. However, there are some data that can explain the detrimental effect of trait anxiety when confronted with stressful events. In our investigation, performed on healthy and psychosomatic patients (Rotenberg & Korosteleva, 1990), we have shown that in a stressful situation (experimental learned helplessness), high trait anxiety predisposes participants to renounce search (give up), and this behavior has a detrimental effect on health. Thus, neither trait anxiety by itself nor the stressful events alone caused the decrease of body resistance, but only the change of behavior m the direction of renunciation of search. This change of behavior can be determined by a combination of trait anxiety and real stressful events. It is also possible that the high trait anxiety and daily hassles were related to each other by the means of positive feedback. Stable daily hassles can increase trait anxiety, whereas increased trait anxiety makes the participant oversensitive to everyday, unavoidable small events so that the latter become frustrators (hassles). This can explain how trait anxiety predisposes participants to a renunciation of search In this model, a real stressful life event, such as unemployment, works like a trigger. The behavioristic approach also helps to explain the relationships between cardiovascular reactivity and immune changes in stressful conditions (Kiegolt-Glaser et al, 1992). In our previous investigations (Rotenberg & Alexeyev, 1981, see also Rotenberg & Boucsein, 1993), we have shown that emotional stress (examination, the representation of insoluble tasks) can cause two different reactions of the cardiovascular system (a) a short lasting, sympathetically induced activation (heart rate and blood pressure increase), which is almost totally reduced immediately after the termination of stress, and (b) long-lasting activation that remains stable after the termination of stress and requires REM sleep for compensation and reduction. Because the enhanced REM sleep requirement characterizes renunciation of search (Rotenberg, 1984, 1993), it is possible to suggest that the first type of reaction corresponds to the adaptive mobilization, whereas the unreasonable, long-lasting sympathetic activation reflects the mal-adaptive emotional tension and can be responsible for the more persistent down regulation of the immune function. Thus, not the different duration of stress by itself (Kiegolt-Glaser et al, 1992), but different forms of behavior during stress, accompanied by the different duration of the sympathetic activation, determine the different outcomes of stress on immune systems. Consequently, the concept of search activity can help to explain many contradictions in the neuroimmunological literature and to integrate experimental data. This concept invests a real behavioral sense into the concept of physiological toughness (Dienstbier, 1989). The latter emphasizes all the physiological variables accompanied by enhanced or suppressed immune functions but did not present the causal explanation of these variables in relationship to behavior. However, without such an explanation, the term toughness is the only synonym of the term resistance We suggest that toughness is related to search activity. 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