PSYCHOLOGY Psychology & Neuroscience, 2010, 3, 1, 3 - 8 NEUROSCIENCE DOI: 10.3922/j.psns.2010.1.002 The hypothalamic-pituitary-adrenal axis in anxiety and panic Frederico Guilherme Graeff and Hélio Zangrossi Junior Universidade de São Paulo, Brazil Abstract This review article focuses on the differential activation of the hypothalamic-pituitary-adrenal (HPA) axis in generalized anxiety and panic. The results of experimental studies that assayed adrenocorticotropic hormone, cortisol and prolactin show that real-life panic attacks as well as those induced by selective panicogenic agents, such as lactate and carbon dioxide, do not activate the HPA axis. Accordingly, experiments carried out in two animal models of panic, namely electrical stimulation of the dorsal periaqueductal gray matter of the rat and the escape from the open arm of the elevated T maze, have shown that in neither case stress hormones are increased in the plasma. Also in humans, reported results have shown that neither cortisol nor prolactin levels were increased following simulated public speaking, an experimental task that has been related to panic, in either healthy volunteers or patients with panic disorder diagnosis. Therefore, although the panic attack causes a major sympathetic stimulation, it has little effect on the HPA axis. In contrast, anticipatory or generalized anxiety activates both the HPA and the sympatho-adrenal axes. Keywords: stress hormones, generalized anxiety, panic, simulated public speaking, periaqueductal gray matter, elevated T maze. Received 12 February 2010; received in revised form 12 April 2010; accepted 12 April 2010. Available on line 26 June 2010 Introduction introduce the word stressor, for the causative agent, … retaining stress for the resulting condition”. (Selye, The concept of stress is based on the observation that 1974, as cited in Pacák & Palkovits, 2001). different kinds of physical or psychological demands The most characteristic stress response is the on the organism elicit the same set of bodily changes, release of the adrenocorticotropic hormone (ACTH) the so called General Adaptation Syndrome (GAS) and corticoids (cortisol in humans and cortisone in the (Selye, 1936; Ursin & Olff, 1993). However, Hans rat) into the blood stream as a result of activation of the Selye (1974) himself acknowledged that the original hypothalamic-pituitary-adrenal (HPA) axis. In addition to name was not the best one: “…when I introduced the the HPA axis, acute stress also activates the sympathetic word stress …, my English was not yet good enough for division of the neurovegetative nervous system as part of me to distinguish between the words stress and strain. the fight/flight reaction, or emergency response, defined It was not until several years later that the British by Walter Cannon (1914). As a result, noradrenaline is Medical Journal called my attention … that according released from peripheral sympathetic nerve fibers in to Selye stress is its own cause. Actually I should have different tissues, and adrenaline (also some noradrenaline), called my phenomenon the strain reaction and that from the adrenal medulla into the blood stream. which causes it ‘stress’, which would parallel the use More recently, McEwen has introduced the of these terms in physics. However, … biological stress concept of allostasis, that is, maintaining stability in my sense of the word was so generally accepted through behavioral change, as a fundamental process in various languages that I could not have redefined through which animals actively adjust to predictable it. Hence, I was forced to create a neologism and or unpredictable stressors; allostatic load refers to the cumulative cost of allostasis to the organism, with Frederico Guilherme Graeff, Departamento de Neurociências allostatic overload being a state in which pathology can e Ciências Comportamentais, Faculdade de Medicina de Ribeirão occur (McEwen & Wingfield, 2003). Preto, Universidade de São Paulo, Brazil. Hélio Zangrossi Junior, Stressors may be physical, such as tissue damage Departamento de Farmacologia, Faculdade de Medicina de or extreme changes in temperature, but may also be Ribeirão Preto, Universidade de São Paulo, Brazil. Correspondence psychological. As to the latter, reported results have regarding this article should be directed to: Frederico G. Graeff, Departamento de Neurociências e Ciências Comportamentais, consistently shown that the HPA axis and sympathetic Faculdade de Medicina de Ribeirão Preto, USP, Hospital das nervous system are activated by novelty or cues that Clínicas, 3o andar, Avenida dos Bandeirantes 3900, Ribeirão Preto, signal the delivery of punishment or the withholding SP, Brazil, 14048-900. Phone: + 55-16-3602-2607. Fax: +55-16- of an expected reward (frustration), thus generating 3602-2544. E-mail: [email protected] anticipatory anxiety. The neural circuits that mediate 4 Graeff and Zangrossi Junior the neuroendocrine responses to psychological stressors in response to actual danger that is at a certain distance include the cortical activation of the basolateral nucleus from the prey (distal threat). In this case, the animal of the amygdala, which in turn activates its central either evades the situation, whenever an escape route nucleus. The message is then conveyed to hypothalamic is available or becomes tensely immobilized (freezing), neurons by different pathways: a direct one, an indirect when there is no way out. Finally, panic corresponds to one, through the bed nucleus of the stria terminalis, and the vigorous flight reaction evoked by very close danger still another one, through brainstem serotonin (5-HT) (proximal threat), such as an approaching predator or by and catecholamine-containing neurons. Neurons of acute cutaneous pain. Complete immobility also occurs the hypothalamic paraventricular nucleus secrete in response to proximal danger, as well as defensive fight, the corticotropic releasing hormone (CRH) into the which occurs when flight is impossible. Nevertheless, portal circulation of the pituitary gland. In the anterior the latter strategy relates to rage, rather than to panic pituitary, CRH stimulates ACTH-secreting cells that (see also Gray & McNaughton, 2000, McNaughton & release ACTH into the blood stream. ACTH acts on the Corr, 2004). Concerning psychopathology, it has been adrenal cortex promoting cortisol release into the blood suggested that the same neurobiological processes that stream. In addition to ACTH, prolactin is consistently regulate anticipatory anxiety are involved in generalized released at the anterior pituitary in stressful conditions anxiety disorder (GAD); the ones that control fear, in (Van der Kar & Blair, 1999). phobic disorders, and those organizing proximal defense, To test the GAS hypothesis, Miklós Palkovits in panic disorder (PD) (Deakin & Graeff, 1991). and coworkers have used five different stressors: According to the DSM IV classification of immobilization, hemorrhage, cold exposure, pain, or psychiatric disorders (American Psychiatric Association, hypoglycemia. With the exception of immobilization 1994), PD is characterized by the occurrence of panic stress, these stressors also differed in their intensities. attacks, in which feelings of extreme fear and dread Their results showed marked heterogeneity of strike unexpectedly and repeatedly, accompanied by neuroendocrine responses to various stressors and that intense physiological symptoms. Over time, anticipatory each stressor has a neurochemical “signature.” By anxiety about having a further attack and avoidance of examining changes of Fos immunoreactivity in various places where having an attack is embarrassing develop. brain regions upon exposure to different stressors, The extreme form of avoidance is agoraphobia, in they also described stressor-specific pathways and which case the person is afraid of leaving home alone. circuits. As a result, they have defined stress as a state In contrast, the main symptom of GAD is exaggerated of threatened homeostasis (physical or perceived threat worry and tension over every day events and decisions, to homeostasis) that triggers stimulus-specific adaptive lasting for at least six months. In addition to the different compensatory responses. The adaptive response clinical manifestations, the pharmacological profile of reflects the activation of specific central circuits and these disorders also differs: GAD is rapidly ameliorated is genetically and constitutionally programmed and by anxiolytic drugs, PD by chronic administration of constantly modulated by environmental factors (Pacák antidepressants (Nutt, 2005). & Palkovits, 2001). This view may help to understand Emotions, either normal or abnormal, are manifested the seeming paradox on panic attacks and the HPA axis in both psychological (cognitive, affective, behavioral) that is discussed in the following section. and physiological (neurovegetative, neuroendocrine) domains. The question that is central to the present Defense-related emotions article is whether anxiety/GAD and panic/PD differ qualitatively or only quantitatively as to the activation Anxiety, fear and panic are emotions related to of the HPA axis. threat. The distinction between anxiety and fear has not always been clear, but the ethoexperimental approach Neuroendocrinology of panic and anxiety developed by Robert and Caroline Blanchard (Blanchard & Blanchard, 1988) has provided a sound criterion based A naturally occurring PA can be considered as a on the systematic study of animal