E. R. dc Klwt. V. M. Wicgant and D. de Wied (Eds.) Progress in Brain Research, Vol. 72 0 1987 Elsevier Science Publishers B.V. (Biomedical Division)
Neuroendocrine states and behavioral and physiological stress responses B. Bohus, R. F. Benus, D: S. Fokkema, J. M. Koolhaas, C. Nyakas, G. A. van Oortmerssen, A. J. A. Prins, A. J. H. de Ruiter, A. J. W. Scheurink and A. B. Steffens Department of Animal Physiology. University of Groningen. Biological Center, P. 0 . Box 14. 9750 AA Haren, The Netherlands
In order to adapt to the altering social and physical environmental demands man and other animals require a chain of behavioral, neuroendocrine and autonomic physiological and metabolic responses to maintain bodily and mental homeostasis. The complexity of the organization of these processes has long been obvious and was recognized more or less from the time of Darwin (1871) on. From the beginning of this century a number of attempts have been made to conceptualize the organizational principles of adaptive bodily reactions. In his ‘emergency’ concept Cannon (1915) suggested that homeostatic functions in the adaptation to environmental challenge may be a result of links between brain, behavior and the endocrine system, particularly of the adrenomedullary system. In his stress theory Selye (see Selye, 1950) emphasized the adrenal cortex as a major organizer of non-specific adaptive responses to environmental demands of various types. Although these concepts had some ‘molecular’ character because of involving the idea of chemical messengers (hormones) in the organization of homeostatic processes, their main feature was the relation of the whole individual to organ systems. The recognition that psychological and social stimuli are among the most adverse ones that
activate the hormonal systems (see Mason, 1968) has initiated much research which led to the first discoveries of peptide and other hormone effects on brain and behavior (e.g. De Wied, 1969; Lisshk and EndrOczi, 1960). These early attempts that were aimed to find a chemical basis of adaptive behavior led to the discovery of several neuropeptides. Considerable information has been obtained concerning the probable mode of action of peptides and steroids at the synaptic/molecular level. A macroworld of organ systems has opened the way to a microworld of (sub)cellular machinery of brain, behavior and physiology. The macro- and the microworlds have used similar terms to express the plasticity of adaptive processes (e.g. modulation of ongoing behavior (Bohus, 1970) and modulation of synaptic transmission (Barchas et al., 1978; Krieger, 1983)). The question is whether knowledge of the microworld is sufficient to explain why the macroworld j s adapting or failing to adapt to environmental challenge or threat. Although a number of attempts have been made during the last 10 years to find a molecular cause of mental health and disease in particular, a gap remains between the molecular events at the cellular level and the behavior of the whole body in a certain environment. In the meantime the concept of stress has also
been introduced in psychological research directed to elucidating the relations between environment, personality and coping with demands. Among psychologists stress has always been considered as a causal factor in coping with failure and disease. An important aspect of the psychological stress concept is the recognition of the importance of interactions between the various factors (environment, personality, etc.) in inducing functional disturbances in man. The brain itself has remained a ‘black box’ for the psychologists. Attempts to open this black box in experimental animals have been made by Weiss (e.g. Weiss et al., 1976), Anisman (e.g. Anisman et al., 1979) and others by studying the influence of controllability and predictability of the environment on behavior, brain chemistry and pathology such as gastric ulceration, immune suppression, tumor growth, etc. (e.g. Sklar and Anisman, 1979; Weiss, 1968). Evidence of interactions between predictability and controllability of environmental events, pituitary-adrenal function and cardiovascular pathology in the rat has also been presented (Bassett and Cairncross, 1976; Bassett et al., 1978). Despite these attempts the problem still remains to link directly the macroand microworld. Stress, hormonal states and adaptation (in its broadest sense) need to be fitted into one concept. A novel, behavioral physiological stress concept that will be presented here originates from the classical view of Selye that stress is a response. This new concept is extended to environment, behavior and physiology, and it incorporates the novel neuroendocrine views including the neuropeptide concept. Stress is now viewed as ageneral biological and usually functional response to environmental and bodily demands. Whether a challenge or a threat - i.e. health or disease stress depends on interactions between (1) environment (controllability and/or predictability), individual characteristics (coping strategies) and the properties of stressors (frequency, duration), stress (response specificity and non-specificity) and the physiological systems (normal or patho-
logical state), and (2) the nervous system (brain and the autonomic nervous system), peripheral organ systems and the neuroendocrine system. The validity of the novel stress concept is illustrated by five major theses derived from experimental observations.
Individual characteristics of behavior and of physiological and endocrine states Attention, both from a physiological and a pathological point of view, has long been focussed on individual differences in response to environmental change and on the correlation between the various measures of behavioral, physiological and endocrine responses (e.g. Bohus et al., 1963; Henry, 1976; Lisshk and EndrOczi, 1960). The importance of individual characteristics of behavior in relation to social interactions and the development of cardiovascular pathology was emphasized by Koolhaas et al. (1983). Fokkema and Koolhaas (1985) have shown that there is a positive correlation between the amount of aggressive behavior of TMD-S3 rats displayed in their own territory or in a neutral area against a more dominant rat. Territorially offensive rats were also defensive against a dominant rat or they escaped rapidly. Another population of the S3 rats was ambivalent in its own territory against the intruder and showed freezing while meeting with a dominant in a neutral area. This finding has raised the question whether such individual differentation is restricted to social interactions or is a general characteristic of individual rats in social and non-social situations. Table 1 summarizes the evidence that suggests that two general behavioral strategies - active and passive -can be recognized in rats and mice (Koolhaas et al., 1986). Active animals seem to have a high demand to control the environment, they perform large numbers of routines and if the environment becomes familiar they behave rather independently from actual environmental stimuli. Passive animals show a low or no demand for control and they depend strongly on actual environmental signals.
TABLE 1 Individual characteristics in behavioral strategy Active
Defensive or Escape
Aggression against a dominant
Active avoidance (shuttle box)
Slow acquisition of freezing
Spatial orientation: changing intermaze configuration
Changing extramaze locations
Data from Fokkema and Koolhaas (1983, Koolhaas et al.
(1986) and Benus et al. (in press).
The behavioral characteristics are highly correlated with physiological and endocrine reactivity in various environments. Fokkema and Koolhaas (1985) have reported a positive correlation between offensive behavior towards an intruder and mean blood pressure increase in the home territory of the experimental rat. Positive correlations between behavior, plasma norepinephrine, epinephrine and corticosterone reactivity and ratios, and blood pressure reactivity exist as well (Fokkema, 1985). A correlation between exploratory behavior in a novel environment and cardiac response to an emotional stressor of fear of pain in an inhibitory avoidance situation was also found in individual Wistar rats (Nyakas et al., in prep.). The overall cardiac response to this emotional stressor as determined from the electrocardiogram (ECG) of the free-moving rats monitored by radiotelemetry (for details see Bohus, 1974; 1985) was a heart rate slowing relative to the heart rate of rats that had not received an aversive stimulus in the inhibitory avoidance situation. The individual
variation around the bradycardiac mean is substantial. There was a negative correlation between exploratory activity and cardiac response to the emotional stressor. Young adult male rats (3 and 5 mth old) that explored more showed less bradycardia as emotional stress reaction. The animals exploring less showed more bradycardia. Although exploratory activity was diminished and heart response was less bradycardiac, there was a negative correlation between the behavioral and physiological measures in aged (21 month old) and senescent (33 month old) individual male rats (Nyakas et al., 1986). TABLE 2 Behavioral strategy, physiology and neuroendrocrinology Active
Blood pressure reactivity
Data from Fokkema (1985) and Koolhaas et al. (1986).
Table 2 summarizes evidence supporting the general view that behaviorally active animals are more sympathetically and passive ones are more parasympathetically dominated. In addition, the neuroendocrine system responds differently to the same stimuli in active and passive animals. Taken together, individual characteristics in behavioral strategy (active or passive) manifest
themselves across diverse social and non-social situations. These behavioral characteristics are accompanied by differential reactivities of physiological and neuroendocrine responses in male rats.
Genetic experience and the behavioral and physiological characteristics The question of the origin of the differences between individuals to react (and adapt) differently towards the same stimuli in social and non-social environments arises from the findings just described. Genetic and ontogenetic and recent experience are likely candidates. Genetic selection for behavioral characteristics such as active avoidance behavior (Brush et al., 1985; Driscoll and BSLttig, 1982), emotionality (Maudslay reactive and non-reactive rats; see Blizard, 1981) and aggressive attack behavior (short and long attack latency mice; van Oortmerssen et al., 1985) has been successful. In addition, selection for such (patho)physiological properties as high blood pressure with high sympathetic reactivity (see De Jong, 1984) has also been successful. Furthermore, abundant evidence is available suggesting perinatal influences on adult stress-related behavior, physiological and neuroendocrine responses (e.g. Ader, 1970; Bohus and Cottrell, 1985; Levine, 1970). Learning about the environment definitely represents one of the highest forms of adaptation. There is still insufficient information about individual characteristics, ontogenic or adult experience. Recent observations in this and other laboratories suggest that selection for a certain behavior is in effect selection for general behavioral characteristics (active or passive strategy) in diverse environments and for physiological reactivity that corresponds to these behavioral properties. This is illustrated in Table 3; Roman High Avoidance (RHA) rats that show a rapid acquisition of an active avoidance response (Driscoll and Battig, 1982) are highly offensive in social dyadic interactions in comparison to Roman Low Avoidance
TABLE 3 Behavioral strategy and physiology: genetic aspects Roman High and Low Avoidance Rats ~
Active Avoidance (selection)
Data from Driscoll and BBttig (1982). Koolhaas et al. (1986) and Bohus and Schoemaker (in prep.).
(RLA) animals. The RLA rats have difficulties in acquiring a shuttle-box response and show less or no offensive social activity (Koolhaas et al., in prep.). The cardiac response of RHA and RLA rats to an emotional stressor has also been investigated as a measure of physiological reactivity using an inhibitory avoidance situation (Bohus and Schoemaker, in prep.). In RLA rats the cardiac stress response was a very marked bradycardia and the conditioned behavioral response was immobility.The bradycardia was probably caused by marked vagal activation. In the RHA rats the heart rate was no more tachycardiac than in the non-stressed controls but the parasympathetic (vagal) influence was practically absent. The RHA animals failed to show the immobility response in the situation. Accordingly, a passive behavioral strategy of the RLA rats (low avoidance, low offensiveness and marked immobility) was accompanied by a parasympathetic reactivity to emotional stress. However, the observations on the cardiac response cannot answer the question whether RHA rats’ heart rate simply reflected a metabolically relevant coupling to somatomotor activity (Obrist, 1981) because of uninterrupted exploration. Alternatively, it is also possible that less attention was devoted to the actual stimulus situation. Orientation/attention
behavior of Wistar rats is accompanied by marked slowing of the heart rate (Hagan and Bohus, 1983; 1984). Recent findings suggest that RHA rats do alter their behavior in response to a stimulus change during an orientation/attention test from horizontal exploration to directed orientational movements and grooming and that the variability in cardiac rhythm decreases without a change of mean heart rate. The decrease in variability is due to diminished vagal activity as indicated by detailed analysis of the ECG recordings. The RLA rats display immobility with small head movements and the heart response is bradycardia. (Bohus and Balkan, in prep.). Accordingly, RHA rats fail to exert vagal control on the heart and also fail to inhibit their behavior following a stressor. Some observations from our laboratory suggest that selection for a certain physiological characteristic (e.g. hypertension and related high sympatheticreactivity) also carries over to general behavioral characteristics in diverse environments. This is suggested by comparing the behavior of spontaneously hypertensive male rats (SHR) to that of their normotensive Wistar-Kyoto (WKy) controls. SHR rats display more offensive activity than do WKy animals (Koolhaas et al., unpubl.). In addition, higher exploratory activity in an open field (Knardahl and Sagnolden, 1979), and in a residential maze (Knardahl and Chindaduangratu, 1984) has been reported in young adult SHR rats in contrast to WKy controls. SHRs also show more rapid acquisition of an active avoidance shuttle-box response (Knardahl and Sagvolden, 1981). The SHRs behavioral profile thus corresponds to the characteristics of ‘active’ rats although the criterion for selection was a physiological measure, i.e. high blood pressure.
Specificity or non-specificity of stress, organizational principles and localization in the brain The original stress hypothesis of Selye (see Selye, 1950) emphasized the non-specificity of the re-
sponse. Subsequent studies have recognized specific elements in the response patterns due to the involvement of a behavioral response in the stress and the level within the central nervous system at which the stress responses are integrated (Mason, 1971). Subsequent work on stress, adaptation and disease further emphasized the specificity of neuroendocrine response and disease processes (see Henry and Stephens-Larson, 1985). In our view the individual characteristics of behavioral strategies and the accompanying physiological and neuroendocrine response patterns and a number of other observations to be described below justify the following thesis. Activation (or inhibition) of behavioral, physiological and endocrine systems represents the non-specific component of the stress response. Its specific character is the result of interactions between the environment (controllability/predictability), the coping strategy (i.e. passive vs. active), the properties of the stressor and the system (cardiovascular, metabolic, etc.). Together these factors determine the magnitude, the temporal pattern, and the response ratio which then represent the specific component of the stress reponse. One example is the relative bradycardiac heart response to an emotional stressor, fear or pain, in young adult Wistar rats as described for the inhibitory avoidance situation. This response has a generalized (expectancy) component, i.e. bradycardiac response even in the experimental room where the inhibitory avoidance apparatus is placed. The bradycardiac response also occurs in the environment where aversive experience had been received 24 h earlier. The bradycardia diminishes with the time during exposure to the emotional stressor. It is independent of somatic activity because immobility persists during the whole stress period (Bohus, 1985; Hagan and Bohus, 1983). One may conclude that the characteristic of the response in this situation is of parasympathetic nature. However, mean blood pressure is increased substantially even in the expectancy phase and the increase persists during the
entire stress period (Van der Meulen and Bohus, 1984).This implies that under such circumstances - passive coping strategy or conservation withdrawal (Engel, 1977) - both vagal and (neural and/or humoral) sympathetic activation occur in parallel. Baroreceptor reflex-induced bradycardia as the consequence of the blood pressure increase can be excluded (Bohus et al., 1976). While vagal overactivity is sometimes considered as a metabolically irrelevant response (see Obrist, 1981), it may also serve to temper the blood pressure changes induced by certain emotional stimuli. The immobile form of natural defensive behavior in cats is often accompanied by bradycardia and a decrease of cardiac output (Adams et al., 1968; 1971) and only a minimal blood pressure rise occurs (Mancia et al., 1971). There is increasing evidence suggesting that the sympathetic and parasympathetic systems function not only reciprocally but also non-reciprocally. The latter function is organized at the level of both the hypothalamus (Kollai and Koizumi, 1961) and the brain-stem (Langhorst et al., 1981). A different response pattern emerges when male Wistar rats are subjected to the work-load of swimming (Scheurink and Steffens, in prep.). Blood pressure (BP), heart rate (HR), plasma epinephrine (E) and norepinephrine (NE) and free fatty acid (FFA), glucose (GLC) levels increase differentially before, during and after repeated swimming. BP and HR, as measured on the starting platform of the pool, increase together with E even before the start of the 15-min swimming period. After a few minutes of swimming, all these measures show a considerable fall (BP is back to baseline, HR about 30% lower and E about 50% lower). At the same time the plasma NE, FFA and GLC levels begin to rise and the plasma insulin level decreases. The post-swimming period on the goal platform is characterized by a secondary increase in BP, HR and plasma E while NE, FFA, GLC levels decrease. This phase is mostly accompanied by wet-shaking and vigorous grooming behavior.
This picture seems to fit into the ‘classical’ idea of sympathetic stress-discharge. However, the differential nature of patterns suggests that the response is differentially organized. The first phase of the response (BP, HR and plasma E elevation) may be the consequence of a certain prediction (expectancy) which then fades because of less need for the expected activation. The NE, FFA and GLC rise probably secures the necessary metabolic state. This complex pattern may be the consequence of differential activation of the various subdivisions of the sympathetic nervous system. Such a differential output may originate in the brain-stem (or a higher level) or is organized at the ganglion or nerve ending level. The peptides in these locations (see Lundberg and Hakfelt, 1983) may serve such an organizational function. The importance of environmental factors (predictability and/or controllability) in the appearance of certain physiological stress responses in a social situation has been demonstrated by Fokkema et al. (1986). Episodes of large amplitude blood pressure oscillation occur in the defeated rat during a territorial fight. The same phenomenon could be observed during the application of a psychosocial stimulus associated with this defeat provided that the rat had experienced victory before. The blood pressure oscillation coincides with the respiratory pattern described as pressure breathing. The intrathoracic pressure is strongly positive and prolonged expiration can be observed. This expiration is accompanied by a rise in blood pressure and a decrease in heart rate. This response outlasts the actual fight and never occurs in victorious rats. Together, these findings support the view that stress is not necessarily an overall activation (mass discharge) of the sympathetic nervous system, and sympathetic and parasympathetic activation may occur in parallel. The various components of the physiological response which are regulated by the autonomic nervous system directly or via adrenomedullary hormones may have different patterns. These differential patterns represent the specific character of the stress
reaction to environmental and internal demands (milieu exterieur and interieur). Organizational principles of stress and localization in the brain A neuroendocrine view is the keynote of the recent behavioral physiological stress concept. The interaction between the nervous system, the peripheral organ systems and the neuroendocrine system would determine whether the stress is a challenge or a threat. This view is based upon a re-analysis of the organizational principle of the stress response. Knowledge of the organization of the pituitary-adrenal system reaction led to the hypothesis that behavioial, neuroendocrine, autonomic and metabolic responses to environmental challenges are organized at four levels: in the limbic-midbrain system in conjunction with the cerebral cortex, in the hypothalamus, in the pituitary gland and at the level of the target organs (for details see Bohus, 1984a). Two salient features of this hypothesis are the following. First, besides the well known ‘stress hormones of the first generation’, i.e. adrenal corticosteroids and catecholamines, a ‘stress function’ has been assigned to a group of known hypothalamo-hypophyseal hormones (vasopressin, oxytocin, prolactin, ACTH/MSH-related peptides) and a group of recently discovered or recognized brain, pituitary and adrenal medullary peptides (endorphins, enkephalins, CRF, VIP, CCK). These peptides have been named as ‘stress hormones of the second generation’. Various stressors are potent, sometimes specific activators of their release. According to the second point of the hypothesis the brain is probably the most important target organ for stress hormones of the first and second generation. Although peripheral sites such as the cardiovascular, immune or neuromuscular or gastrointestinal systems may be important targets of the hormones to generate the specific patterns of adaptative responses the neuroendocrine state of the brain may be taken as the ultimate mechanism for organization of the response.
In this general, organizational view the limbicmidbrain system is considered as a unit. There are a number of reasons to suggest that certain aspects of the specific response patterns, and thus individual differences, are the result of functional imbalance between various limbic-midbrain structures/subsystems. Henry and Stephens (1977) were the first to propose that the amygdala controls the behavioral, physiological and neuroendocrine reactions that fit in the Cannonian fight-flight response pattern. The hippocampus and septum are involved in the organization of depression or conservation-withdrawal responses (Selyean distress reaction). The importance of the noradrenergic input to the limbic structures through the dorsal noradrenergic bundle system in determining the interaction with the environment has been emphasized (e.g. Aston-Jones et al., 1985). Individual differences may be related to noradrenergic-dopaminergic interactions in the nucleus accumbens (Cools et al., submitted) and inputs from the amygdala and hippocampus to the accumbens modify behaviors that are mediated through the mesolimbic dopaminergic system (e.g. Isaacson et al., 1983). The neuroendocrine state and behavior The fourth thesis suggests that the neuroendocrine state(s) - the result of an interaction between the availability of the hormones and the functional state of their receptors - is a major determinant of the behavioral and physiological stress reactions. Evidence suggests that the specific behavioral stress responses, i.e. learning, retention and extinction, depend on neuroendocrine states as induced by neuropeptides (see, e.g. Bohus, 1981; Bohus and De Wied, 1980; De Wied and Jolles, 1982). This type of evidence was obtained by using either a classical endocrine approach - removal of the pituitary and subsequent replacement with one of the peptides - or administering the peptide or its antagonist to intact animals. The definition of response specificity lies in the assumption that learning, retention
and extinction of one particular behavioral response mean adaptation to a given environment. Even minor changes in the environment require new strategies, i.e. the establishment of a new specific behavioral stress response. (For details see Bohus, 1984a.) Non-specific behavioral responses to stressors,i.e. behaviors that usually do not contribute to a learning process in a specific environment (displacement behavior, exploration, analgesia, reflex immobility, etc.), are also affected by neuroendocrine factors. Endogenous opioids, most probably pendorphin, are often involved in the modulation of exploration, grooming, analgesia, etc. (e.g. Gispen and Isaacson, 1981; Katz and Gelbart, 1978; Watkins and Mayer, 1982). Prolactin also affects grooming behavior and facilitates analgesia (Drago et al., 1983). A number of observations suggest a role of adrenal medullary and cortical hormones in behavioral adaptation (see Bohus et d., 1982; McGaugh, 1983). There is now evidence indicating that the kind of controllability of a stressful situation determines whether medullary or cortical hormones are indispensable for the expression of behavior. The following experiments prompted this suggestion. One-trial learning step-through inhibitory avoidance training allows two kinds of tests of the retention of learned behavior. If avoidance behavior is tested the rat is able to actively control the situation. However, if the animal is placed directly into the compartment where the aversive experience was received one day earlier and escape is not easy, the rat displays immobility. This is considered to mean passive control. Behavioral performance both in the immobility and subsequent avoidance test was impaired shortly after adrenalectomy. Post-learning administration of corticosterone corrected the immobility but not the avoidance deficit. Adrenomedullectomy, i.e. removal of the source of circulating epinephrine, does not significantly affect immobility behavior but impairs avoidance behavior. The avoidance deficit of adrenalectomized or adrenomedullectomized rats was normal-
ized by epinephrine (Bohus and Del Cerro, in prep.; Borrell et al., 1983). These findings suggest that optimal hormonal states provided by the two adrenal hormone systems are essential, but two different mechanisms: medullary catecholamines serve active controllability and corticosterone is involved in passive controllability. These mechanisms are built in the same individual and the proper mechanisms are then selected according to the environmental requirements. Individual differentiation in the behavioral and neuroendocrine adaptation may mean preferred development and/or use of the one above the other mechanism. Such differentiation may fit into the hypothesis of Henry and Stephens (1977) who suggested that the amygdala-related fight-flight type of behavior (active strategy and control in our terminology)is accompanied by activation of the adrenal medulla while the hippocampus-septum-relateddepression (immobility, i.e. passive strategy and control) is reflected by high adrenal cortical activity. All these observations suggest that the neuroendocrine state modifies and/or contributes to the organization of specific and non-specific behavioral stress responses. The diverse stress hormones are differentially involved in the various phases and the various kinds of behavioral stress responses. Whether the amygdaloid and hippocampal mechanisms indeed serve two strategies remains to be shown by more direct experiments now in progress in our laboratory.
Neuroendocrine state, behavior and physiology Various neuropeptides have a profound influence on the form or the magnitude of the cardiac responses to emotional stressors in the inhibitory avoidance situation (see Table4 and Bohus, 1977; 1985). The effects of ACTH 4-10 and arginine vasopressin are the most interesting in this respect. ACTH 4-10 facilitates avoidance and causes tachycardia in young adult male rats. It was suggested that this peptide probably increases sympathetic effects on the heart as a con-
TABLE 4 Neuropeptides: effects on acute cardiac responses Inhibitory avoidance
Tonic response Form
Control ACTH 4-10 Vasopressin
Bradycardia Tachycardia Bradycardia
Phasic response Magnitude
Bradycardia Bradycardia Bradycardia
Control Naltrexone pendorphin a-endorphin Vasopressin Oxytocin
Bradycardia Bradycardia Bradycardia Bradycardia Bradycardia Bradycardia
Unchanged Enhanced Unchanged Enhanced Enhanced
Data from Bohus (1977, 1985), Hagan and Bohus (1983) and unpublished.
sequence of enhanced arousal (Bohus, 1985). Vasopressin, on the other hand intensifies the bradycardiac response by increasing the vagal influence on the cardiac rhythm generation. Facilitated attention and/or expectation may underlie the action of vasopressin (Bohus, 1985). Vasopressin also enhances the bradycardiac response to sudden changes in background noise (Hagan and Bohus, 1984). This finding also seems to support an attentional hypothesis. Neuropeptides, arginine vasopressin in particular, also affect the cardiac response of aged rats to emotional stressor. The bradycardiac response diminishes with age in male Wistar rats (Nyakas et al., 1986). Administration of the amphetamine reinstates the bradycardiac response. This is probably due to an increase in a catecholaminedependent arousal state in the brain that enhances parasympathetic outflow. Vasopressin interacts with catecholaminergic systems in the brain (see Kovacs et al., 1979; Tanaka et al., 1977). The effect of the ACTH 4-9 analog ORG 2766 was also investigated. Chronic administration of the peptide ameliorates some morphological,
biochemical and behavioral consequences of ageing (Landfield et al., 1978; Rigter et al., 1984). Arginine-vasopressin (10 pg/kg s.c.) subcutaneously reinstates the bradycardiac response in aged (14 months old) rats. The peptide may selectively normalize the arousal state in certain brain structures, which leads to a normalized parasympathetic outflow. It remains to be shown whether this effect is related to attentional and/or expectancy mechanisms. Org 2766 in a single dose of 5 pg/kg S.C. elicits tachycardia in the aged rats. In this way this peptide mimics the effect of ACTH 4-10 in young adult rats. Finally, it is worth mentioning that adrenal hormones play an important role in the behavioral hypertension seen in rats (Van der Meulen and Bohus, 1984). Whether the hypertensive response depends on the behavior remains to be investigated. Interestingly, Bakulin (cited by Sudakov, 198 1) found that long-term stimulation of the ventromedial hypothalamic nucleus in immobilized, non-anesthetized rabbits failed to produce arterial hypertension following adrenalectomy. Intravenous cortisol and epinephrine in-
jection reinstates the hypertensive response. Injection of these hormones into the midbrain reticular formation is also effective, indicating a central action. Thus, the neuroendocrine states as due to the first and/or the second generation of stress hormones promote the selection of the most appropriate behavioral and physiological stress responses in a given situation. The proper neuroendocrine state may be achieved by a differential release of stress hormones and/or an activated state of their receptors during certain phases of stress-related specific behavioral processes such as learning, retention and extinction.
Neuroendocrine states and (psychosomatic) disease According to the last thesis of this paper an imbalance between environmental demand, behavioral and physiological characteristics and neuroendocrine states is considered as a key factor in the pathology of diverse psychosomatic diseases. The complexity of a neuroendocrine state may ensure the maintenance of behavioral and physiological functions even under extreme stressful conditions. However, such complexity also includes the possibility that dysfunction of one or more components of the neuroendocrine system will lead to the disintegration of adaptive brain mechanisms. In these ways a neuroendocrine imbalance (hypo- or hyperactivity) - in interaction with environmental factors - may be involved in psychosomatic diseases. The role of neuroendocrine principles, particularly endorphins, as etiological factors in mental diseases has often been hypothesized (e.g. Bloom et al., 1976; De Wied, 1979; Jacquet- and Marks, 1976). The first formulation of the psychosomatic hypothesis (Bohus, 1980; 1984b)based mainly upon observations of cardiac responses to acute emotional stressors in the rat, which may be viewed as an animal model of stress-induced cardiac dysrhythmias and/or sudden cardiac death syndrome.
Recent observations on behavioral hypertension (Van der Meulen and Bohus, 1984) and on a kindling model of epilepsy (see Cottrell et al., 1983) provide additional support for a neuroendocrine psychosomatic hypothesis. As far as kindling-induced epilepsy is concerned, our studies show that ACTH- and y-MSH related peptides attenuate the electrical appearance of seizure activity (after-discharge) in the amygdala and the hippocampus and shorten the duration of behavioral depression which follows the fullblown tonic-clonic seizures. The effect of these peptides is probably related to their properties as opiate antagonists or partial antagonists. The opiate antagonists naloxone and naltrexone are very potent to reduce the consequences of kindling-induced epilepsy (Cottrell et al., 1984a). In addition, the neuropeptide VIP (Cottrell et al., 1984b) and adrenal steroids (Cottrell et al., 1984c) exert effects on after-discharge and behavioral depression following kindling. The antiepileptic activity of ACTH has long been known (e.g. Klein and Livingston, 1950). The role of stress in the outcome of epileptic disease has been suggested recently (Temkin and Davis, 1984). The proposed neuroendocrine model for psychosomatic disease consists of five elements. The first element is a brain state which is induced by the external or internal environment. This brain state (activation, non-specific arousal) activates (or inhibits) physiological and neuroendocrine systems and evokes certain nonspecific behavioral responses. The second element is the establishment of a certain (specific) ‘neuroendocrine state’. The neuroendocrine state is determined by the availability of stress hormones and the functional properties of their receptors both in the periphery and the brain. The third element is an ‘integrated brain state’ resulting from modulation of the original brain state by the neuroendocrine state. The integrated brain state also depends on genetic factors and recent experiences in the environment (controllability, predictability) and on experiences acquired in the past (e.g. ontogeny). The fourth element is the organization of an ‘inte-
grated’ physiological and neuroendocrine response and of more specific behavior. The fifth element is ‘health’ or the development and outcome of the psychosomatic disease. Since the integrated brain state is highly dependent on the neuroendocrine state, neuroendocrine dysbalance in the brain may be followed by behavioral and somatic imbalance and different forms and degrees of disease. If this neuroendocrine view of the mind-body interaction is correct the reinstallation of neuroendocrine imbalance by peptides and/or other hormones or by their antagonists may be curative in psychosomatic diseases. The ‘acute’ model as presented here may be applicable to semichronic and chronic situations as well. It has already been shown by Alexander (1974), Henry and Stephens (1977), and in this laboratory by Fokkema (1985) that long-term stress in social settings, as due to the individual‘s position may be followed by hypertension and represents a risk for other diseases for certain members of the colony. Long-term social stimulation leads to immune changes in subdominant (active) rats (Koolhaas et al., in prep.). In addition, cardiac responses to an acute emotional stressor are also affected by long-term colony experience (Bohus and Schoemaker, in prep.). In addition, long-term consequences of a repeated stressful experience such as social defeat have to be taken into account. Pressure breathing following defeat persists for some time following the cessation of social interaction (Fokkema et al., 1986). Repeated social defeat leads to a disturbance of the circadian rhythmicity of food intake lasting for weeks (Koolhaas, unpubl.). Finally, the blood pressure of spontaneously or DOCA/salt hypertensive rats falls markedly for a few days as a consequence of social defeat or forced swimming. The acute cardiac response to an emotional stressor suggests a baroreceptor reflex regulation of heart rate in these rats (Nyakas and Bohus, in prep.). Baroreceptor mechanisms are generally overriden by higher (e.g. limbic or hypothalamic) brain influences during behavior (see Stephenson, 1984). It remains to be
shown whether or not alterations in the neuroendocrine state affect these phenomena. A neuroendocrine hypothesis of mind-body relationships is somewhat different from former psychosomatic views. For example, Alexander (1950) postulated that particular emotional states are the ones which determine bodily responses. Such strong specificity was later denied (e.g. Lader, 1972). Ursin (1978) emphasized that activation, expectancy, predictability and coping are of interest for the development of psychosomatic diseases. Recently, Ursin and Murrison (1984) have argued that stress and activation are the same processes and questioned whether it is worth searching for specific activation patterns for specific conflicts or stress stimuli. Instead, they classify stress as phasic and tonic types of activation and describe hormonal and autonomic factors belonging to these types of activation. The relations between psychosocial stressors, behavioral, neuroendocrine response patterns, and specific organ pathology has been emphasized by Henry and associates (e.g. Henry and StephensLarson, 1985). The recent hypothesis also recognizes the significance of the interaction between environment, individual characteristics and temporal properties of the stressors. However, special importance is assigned to the way specific response patterns are organized. The neuroendocrine state of the brain is furthermore given a central position in determining the state of health or disease of mind and body.
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