Neuroendocrinology of Anxiety Disorders:
Post-traumatic Stress Disorder
W.S. de Loos
Endocrinology has strongly been linked to stress since Hans Selye formulated his concept of the 'general adaptation syndrome' (GAS) in his initial description of 'A syndrome produced by diverse nocuous agents' in Nature in 1936 (Selye, 1936a). He connected the initial response under the name 'alarm reaction' to the stage of resistance during continued exposure to the stressor and the subsequent stage of exhaustion ultimately followed by death. Shortly thereafter, he put the word 'stress' on stage as a concept of 'the nonspecific response of the body to any demand made upon it' . He drew the attention to the hypertrophic response of the adrenal glands, especially their cortical layers, and named the hormonal substances derived from them 'corticoids', such as 'cortisone' . Ever since, the glucocorticoids (cortisol/hydrocortisone and, in rodents, corticosterone) have figured as the stress hormones in optima forma and taken a role as the biological parameters or 'proof of the stress response. Selye did not deny the role of the adrenal medulla and its main product adrenaline/epinephrine (EP) but the scientific community became very much focused on Cortisol as the hallmark of the stress response.
Interestingly, Selye' s attention was primarily drawn by physical causes of stress such as injuries, cold, restraint, hunger and numerous chemical substances (atropine, morphine, formaldehyde, epinephrine) (Selye, 1936b). Already in this and a further publication, he outlined the role of the pituitary gland in exerting the effect on the adrenal (cortical) hypertrophy marking the road to our present-day interest in the hypothalamo-pituitary-adrenocortical (HPA) axis in psychoneuroendocrinology (Selye and Collip, 1936). He also made the link to the immune system in his observations on thymicolymphatic atrophy laying the base for modern psychoneuroimmunology.
Selye' s original focus at physical causes of the GAS is of great value as it draws our attention to the unconditional stimuli that provoke it. Twenty-five years earlier, Walter B. Cannon had already described the physical (= unconditional) and psychological (= conditional) stimuli for adrenomedullary activation (Cannon and de la Paz, 1911; Cannon and Hoskins, 1911). He extended his observations to a concept of the emergency response of the individual by changes tiiat are 'directly serviceable in making the organism more efficient in the struggle which fear or rage or pain may involve' (Cannon, 1914). His description of the 'Bodily Changes in Pain, Hunger, Fear and Rage' (Cannon, 1915) has become classical as the immediate response to the perception of threat mediated by epinephrine which is sensori strictu as much a hormone as Cortisol. He described these changes here as “The organic preparation for action … in fight or conflict—either one requiring perhaps the utmost struggle' . This emergency response has later been named the 'defence reaction' (Hess and Brügger, 1943) and has its organizational centre in the amygdala (LeDoux, 1998).
The defence reaction consists of both behavioural and physiological components. The behavioural components are species specific; the physiological ones are more general, such as: pupillodilation; pilo-erection; increase of muscle tone, ventilation, cardiac output, oxygen consumption and muscle blood flow; decrease of blood flow in the skin, intestine and kidneys; bladder and bowel emptying; and many others like neurohumoral, hormonal, immunological and haemostatic changes. Understanding of the ethology and comparative physiology of the defence reaction permits excellent understanding of the psychophysiology of alarm and anxiety in humans, both under normal and pathological conditions.
The other important survival response is the above-described GAS which is characterized by behavioural inhibition when active ways of surviving a challenge have been blocked off. It can be compared to the psychodynamic concept of unsolvable conflict or to Seligman' s behavioural model of learned helplessness (Abramson, Seligman and Teasdale, 1978), while Henry described it from a comparative physiological and etiological point of view as conservation-withdrawal expressing subordinate behaviour (Henry, 1992). The corresponding neuroanatomy has important organizing centres in the septum and hippocampus and has every right to be acronymized as the LHPA axis, for limbic-hypothalamo-pituitaryadrenocortical (Sapolsky, Zola-Morgan and Squire, 1991; López, Akil and Watson, 1999), including important physiological outflow through the vagal motor system. The effect of chronic mild stress on the HPA axis is organized in the hippocampus by modulation of hippocampal inhibition on die paraventricular nucleus (PVN) of the hypothalamus (Bratt et at., 2001).
The emergency, or alarm, or defence reaction and the general adaptation, or conservation-withdrawal, or inhibition syndrome have been renamed 'allostasis' (Charles Kahn, see Sterling and Eyer (1988). Allostatic responses are temporary encroachments on homeostasis, a term we owe to Walter B. Cannon.
Looking back on almost a century of stress hormone research (EP and Cortisol), we conclude that EP is a hormone mat increases energy expenditure acutely and mobilizes quickly avadable resources (glucose, free fatty acids). It generates a metabolic response that can only last for a rather short time and should be followed by recuperation under better circumstances. Cortisol,