Skip to main content
Log in

What can We Know from Pituitary–Adrenal Hormones About the Nature and Consequences of Exposure to Emotional Stressors?

  • Original Paper
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Exposure to stress induces profound physiological and behavioral changes in the organisms and some of these changes may be important regarding stress-induced pathologies and animal models of psychiatric diseases. Consequences of stress are dependent on the duration of exposure to stressors (acute, chronic), but also of certain characteristics such as intensity, controllability, and predictability. If some biological variables were able to reflect these characteristics, they could be used to predict negative consequences of stress. Among the myriad of physiological changes caused by stress, only a restricted number of variables appears to reflect the intensity of the situation, mainly plasma levels of ACTH and adrenaline. Peripheral hypothalamic–pituitary–adrenal (HPA) hormones (ACTH and corticosterone) are also able to reflect fear conditioning. In contrast, the activation of the HPA axis is not consistently related to anxiety as evaluated by classical tests such as the elevated plus-maze. Similarly, there is no consistent evidence about the sensitivity of the HPA axis to psychological variables such as controllability and predictability, despite the fact that: (a) lack of control over aversive stimuli can induce behavioral alterations not seen in animals which exert control, and (b) animals showed clear preference for predictable versus unpredictable stressful situations. New studies are needed to re-evaluate the relationship between the HPA axis and psychological stress characteristics using ACTH instead of corticosterone and taking advantages of our current knowledge about the regulation of this important stress system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF (2005) Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci 8(3):365–371

    Article  PubMed  CAS  Google Scholar 

  • Armario A, Lopez-Calderon A, Jolin T, Castellanos JM (1986) Sensitivity of anterior pituitary hormones to graded levels of psychological stress. Life Sci 39(5):471–475

    Article  PubMed  CAS  Google Scholar 

  • Badia P, Harsh J, Abbott B (1979) Choosing between predictable and unpredictable shock conditions: data and theory. Psychol Bull 86(5):1107–1131

    Article  Google Scholar 

  • Bassett JR, Cairncross KD, King MG (1973) Parameters of novelty, shock predictability and response contingency in corticosterone release in the rat. Physiol Behav 10(5):901–907

    Article  PubMed  CAS  Google Scholar 

  • Belda X, Fuentes S, Nadal R, Armario A (2008) A single exposure to immobilization causes long-lasting pituitary–adrenal and behavioral sensitization to mild stressors. Horm Behav 54(5):654–661

    Article  PubMed  CAS  Google Scholar 

  • Blanchard RJ, Yang M, Li CI, Gervacio A, Blanchard DC (2001) Cue and context conditioning of defensive behaviors to cat odor stimuli. Neurosci Biobehav Rev 25(7–8):587–595

    Article  PubMed  CAS  Google Scholar 

  • Breier A, Albus M, Pickar D, Zahn TP, Wolkowitz OM, Paul SM (1987) Controllable and uncontrollable stress in humans: alterations in mood and neuroendocrine and psychophysiological function. Am J Psychiatry 144(11):1419–1425

    PubMed  CAS  Google Scholar 

  • Campeau S, Falls WA, Cullinan WE, Helmreich DL, Davis M, Watson SJ (1997) Elicitation and reduction of fear: behavioural and neuroendocrine indices and brain induction of the immediate-early gene c-fos. Neuroscience 78(4):1087–1104

    Article  PubMed  CAS  Google Scholar 

  • Christianson JP, Benison AM, Jennings J, Sandsmark EK, Amat J, Kaufman RD, Baratta MV, Paul ED, Campeau S, Watkins LR, Barth DS, Maier SF (2008) The sensory insular cortex mediates the stress-buffering effects of safety signals but not behavioral control. J Neurosci 28(50):13703–13711

    Article  PubMed  CAS  Google Scholar 

  • Christianson JP, Jennings JH, Ragole T, Flyer JG, Benison AM, Barth DS, Watkins LR, Maier SF (2011) Safety signals mitigate the consequences of uncontrollable stress via a circuit involving the sensory insular cortex and bed nucleus of the stria terminalis. Biol Psychiatry 70(5):458–464

    Article  PubMed  Google Scholar 

  • Cordero MI, Merino JJ, Sandi C (1998) Correlational relationship between shock intensity and corticosterone secretion on the establishment and subsequent expression of contextual fear conditioning. Behav Neurosci 112(4):885–891

    Article  PubMed  CAS  Google Scholar 

  • Dal-Zotto S, Martí O, Armario A (2000) Influence of single or repeated experience of rats with forced swimming on behavioural and physiological responses to the stressor. Behav Brain Res 114(1–2):175–181

    Article  PubMed  CAS  Google Scholar 

  • Daviu N, Fuentes S, Nadal R, Armario A (2010) A single footshock causes long-lasting hypoactivity in unknown environments that is dependent on the development of contextual fear conditioning. Neurobiol Learn Mem 94(2):183–190

    Article  PubMed  Google Scholar 

  • De Souza EB, Van Loon GR (1982) Stress-induced inhibition of the plasma corticosterone response to a subsequent stress in rats: a nonadrenocorticotropin-mediated mechanism. Endocrinology 110(1):23–33

    Article  PubMed  Google Scholar 

  • Dess NK, Linwick D, Patterson J, Overmier JB, Levine S (1983) Immediate and proactive effects of controllability and predictability on plasma cortisol responses to shocks in dogs. Behav Neurosci 97(6):1005–1016

    Article  PubMed  CAS  Google Scholar 

  • Drugan RC, Eren S, Hazi A, Silva J, Christianson JP, Kent S (2005) Impact of water temperature and stressor controllability on swim stress-induced changes in body temperature, serum corticosterone, and immobility in rats. Pharmacol Biochem Behav 82(2):397–403

    Article  PubMed  CAS  Google Scholar 

  • Duncko R, Makatsori A, Fickova E, Selko D, Jezova D (2006) Altered coordination of the neuroendocrine response during psychosocial stress in subjects with high trait anxiety. Prog Neuropsychopharmacol Biol Psychiatry 30(6):1058–1066

    Article  PubMed  Google Scholar 

  • Fanselow M (1990) Factors governing one-trial contextual conditioning. Anim Learn Behav 18(3):264–270

    Article  Google Scholar 

  • Frank E, Salchner P, Aldag JM, Salome N, Singewald N, Landgraf R, Wigger A (2006) Genetic predisposition to anxiety-related behavior determines coping style, neuroendocrine responses, and neuronal activation during social defeat. Behav Neurosci 120(1):60–71

    Article  PubMed  Google Scholar 

  • Gagliano H, Fuentes S, Nadal R, Armario A (2008) Previous exposure to immobilisation and repeated exposure to a novel environment demonstrate a marked dissociation between behavioral and pituitary–adrenal responses. Behav Brain Res 187(2):239–245

    Article  PubMed  CAS  Google Scholar 

  • García A, Martí O, Vallès A, Dal-Zotto S, Armario A (2000) Recovery of the hypothalamic–pituitary–adrenal response to stress. Effect of stress intensity, stress duration and previous stress exposure. Neuroendocrinology 72(2):114–125

    Article  PubMed  Google Scholar 

  • Goldstein LE, Rasmusson AM, Bunney BS, Roth RH (1994) The NMDA glycine site antagonist (+)-HA-966 selectively regulates conditioned stress-induced metabolic activation of the mesoprefrontal cortical dopamine but not serotonin systems: a behavioral, neuroendocrine, and neurochemical study in the rat. J Neurosci 14(8):4937–4950

    PubMed  CAS  Google Scholar 

  • Hanson JD, Larson ME, Snowdon CT (1976) The effects of control over high intensity noise on plasma cortisol levels in rhesus monkeys. Behav Biol 16(3):333–340

    Article  PubMed  CAS  Google Scholar 

  • Haracz JL, Minor TR, Wilkins JN, Zimmermann EG (1988) Learned helplessness: an experimental model of the DST in rats. Biol Psychiatry 23(4):388–396

    Article  PubMed  CAS  Google Scholar 

  • Hauger RL, Millan MA, Lorang M, Harwood JP, Aguilera G (1988) Corticotropin-releasing factor receptors and pituitary adrenal responses during immobilization stress. Endocrinology 123(1):396–405

    Article  PubMed  CAS  Google Scholar 

  • Helmreich DL, Watkins LR, Deak T, Maier SF, Akil H, Watson SJ (1999) The effect of stressor controllability on stress-induced neuropeptide mRNA expression within the paraventricular nucleus of the hypothalamus. J Neuroendocrinol 11(2):121–128

    Article  PubMed  CAS  Google Scholar 

  • Helmreich DL, Parfitt DB, Walton JR, Richards LM (2008) Dexamethasone and stressor-magnitude regulation of stress-induced transcription of HPA axis secretagogues in the rat. Stress 11(4):302–311

    Article  PubMed  CAS  Google Scholar 

  • Hennessy MB, Levine S (1978) Sensitive pituitary-adrenal responsiveness to varying intensities of psychological stimulation. Physiol Behav 21(3):295–297

    Article  PubMed  CAS  Google Scholar 

  • Hennessy JW, King MG, McClure TA, Levine S (1977) Uncertainty, as defined by the contingency between environmental events, and the adrenocortical response of the rat to electric shock. J Comp Physiol Psychol 91(6):1447–1460

    Article  PubMed  CAS  Google Scholar 

  • Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE (2003) Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocrinol 24(3):151–180

    Article  PubMed  CAS  Google Scholar 

  • Isowa T, Ohira H, Murashima S (2006) Immune, endocrine and cardiovascular responses to controllable and uncontrollable acute stress. Biol Psychol 71(2):202–213

    Article  PubMed  Google Scholar 

  • Jezova D, Makatsori A, Duncko R, Moncek F, Jakubek M (2004) High trait anxiety in healthy subjects is associated with low neuroendocrine activity during psychosocial stress. Prog Neuropsychopharmacol Biol Psychiatry 28(8):1331–1336

    Article  PubMed  CAS  Google Scholar 

  • Johnson JD, O’Connor KA, Deak T, Spencer RL, Watkins LR, Maier SF (2002) Prior stressor exposure primes the HPA axis. Psychoneuroendocrinology 27(3):353–365

    Article  PubMed  CAS  Google Scholar 

  • Kant GJ, Mougey EH, Pennington LL, Meyerhoff JL (1983) Graded footshock stress elevates pituitary cyclic AMP and plasma beta-endorphin, beta-LPH corticosterone and prolactin. Life Sci 33(26):2657–2663

    Article  PubMed  CAS  Google Scholar 

  • Kant GJ, Bauman RA, Anderson SM, Mougey EH (1992) Effects of controllable vs. uncontrollable chronic stress on stress-responsive plasma hormones. Physiol Behav 51(6):1285–1288

    Article  PubMed  CAS  Google Scholar 

  • Keck ME, Welt T, Muller MB, Uhr M, Ohl F, Wigger A, Toschi N, Holsboer F, Landgraf R (2003) Reduction of hypothalamic vasopressinergic hyperdrive contributes to clinically relevant behavioral and neuroendocrine effects of chronic paroxetine treatment in a psychopathological rat model. Neuropsychopharmacology 28(2):235–243

    Article  PubMed  CAS  Google Scholar 

  • Keller-Wood ME, Shinsako J, Dallman MF (1983) Integral as well as proportional adrenal responses to ACTH. Am J Physiol 245(1):R53–R59

    PubMed  CAS  Google Scholar 

  • Koolhaas JM, Bartolomucci A, Buwalda B, de Boer SF, Flugge G, Korte SM, Meerlo P, Murison R, Olivier B, Palanza P, Richter-Levin G, Sgoifo A, Steimer T, Stiedl O, van Dijk G, Wohr M, Fuchs E (2011) Stress revisited: a critical evaluation of the stress concept. Neurosci Biobehav Rev 35(5):1291–1301

    Article  PubMed  CAS  Google Scholar 

  • Kovacs KJ, Sawchenko PE (1996) Sequence of stress-induced alterations in indices of synaptic and transcriptional activation in parvocellular neurosecretory neurons. J Neurosci 16(1):262–273

    PubMed  CAS  Google Scholar 

  • Kvetnansky R, Sabban EL, Palkovits M (2009) Catecholaminergic systems in stress: structural and molecular genetic approaches. Physiol Rev 89(2):535–606

    Article  PubMed  CAS  Google Scholar 

  • Landgraf R, Wigger A, Holsboer F, Neumann ID (1999) Hyper-reactive hypothalamo-pituitary-adrenocortical axis in rats bred for high anxiety-related behaviour. J Neuroendocrinol 11(6):405–407

    Article  PubMed  CAS  Google Scholar 

  • Liebsch G, Linthorst AC, Neumann ID, Reul JM, Holsboer F, Landgraf R (1998) Behavioral, physiological, and neuroendocrine stress responses and differential sensitivity to diazepam in two Wistar rat lines selectively bred for high- and low-anxiety-related behavior. Neuropsychopharmacology 19(5):381–396

    Article  PubMed  CAS  Google Scholar 

  • Maier SF, Watkins LR (2005) Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev 29(4–5):829–841

    Article  PubMed  CAS  Google Scholar 

  • Maier SF, Ryan SM, Barksdale CM, Kalin NH (1986) Stressor controllability and the pituitary–adrenal system. Behav Neurosci 100(5):669–674

    Article  PubMed  CAS  Google Scholar 

  • Márquez C, Belda X, Armario A (2002) Post-stress recovery of pituitary–adrenal hormones and glucose, but not the response during exposure to the stressor, is a marker of stress intensity in highly stressful situations. Brain Res 926(1–2):181–185

    Article  PubMed  Google Scholar 

  • Márquez C, Nadal R, Armario A (2006) Influence of reactivity to novelty and anxiety on hypothalamic–pituitary–adrenal and prolactin responses to two different novel environments in adult male rats. Behav Brain Res 168(1):13–22

    Article  PubMed  Google Scholar 

  • Martí O, Armario A (1998) Anterior pituitary response to stress: time-related changes and adaptation. Int J Dev Neurosci 16(3–4):241–260

    Article  PubMed  Google Scholar 

  • McGregor IS, Dielenberg RA (1999) Differential anxiolytic efficacy of a benzodiazepine on first versus second exposure to a predatory odor in rats. Psychopharmacology (Berl) 147(2):174–181

    Article  CAS  Google Scholar 

  • Mormede P, Dantzer R, Michaud B, Kelley KW, Le Moal M (1988) Influence of stressor predictability and behavioral control on lymphocyte reactivity, antibody responses and neuroendocrine activation in rats. Physiol Behav 43(5):577–583

    Article  PubMed  CAS  Google Scholar 

  • Muñoz-Abellán C, Daviu N, Rabasa C, Nadal R, Armario A (2009) Cat odor causes long-lasting contextual fear conditioning and increased pituitary–adrenal activation, without modifying anxiety. Horm Behav 56(4):465–471

    Article  PubMed  Google Scholar 

  • Natelson BH, Tapp WN, Adamus JE, Mittler JC, Levin BE (1981) Humoral indices of stress in rats. Physiol Behav 26(6):1049–1054

    Article  PubMed  CAS  Google Scholar 

  • O’Connor KA, Johnson JD, Hammack SE, Brooks LM, Spencer RL, Watkins LR, Maier SF (2003) Inescapable shock induces resistance to the effects of dexamethasone. Psychoneuroendocrinology 28(4):481–500

    Article  PubMed  Google Scholar 

  • Peters ML, Godaert GL, Ballieux RE, van Vliet M, Willemsen JJ, Sweep FC, Heijnen CJ (1998) Cardiovascular and endocrine responses to experimental stress: effects of mental effort and controllability. Psychoneuroendocrinology 23(1):1–17

    Article  PubMed  CAS  Google Scholar 

  • Porsolt RD, Deniel M, Jalfre M (1979) Forced swimming in rats: hypothermia, immobility and the effects of imipramine. Eur J Pharmacol 57(4):431–436

    Article  PubMed  CAS  Google Scholar 

  • Rivier C, Vale W (1987) Diminished responsiveness of the hypothalamic–pituitary–adrenal axis of the rat during exposure to prolonged stress: a pituitary-mediated mechanism. Endocrinology 121(4):1320–1328

    Article  PubMed  CAS  Google Scholar 

  • Seligman ME, Meyer B (1970) Chronic fear and ulcers in rats as a function of the unpredictability of safety. J Comp Physiol Psychol 73(2):202–207

    Article  PubMed  CAS  Google Scholar 

  • Tsuda A, Tanaka M (1985) Differential changes in noradrenaline turnover in specific regions of rat brain produced by controllable and uncontrollable shocks. Behav Neurosci 99(5):802–817

    Article  PubMed  CAS  Google Scholar 

  • Tsuda A, Ida Y, Satoh H, Tsujimaru S, Tanaka M (1989) Stressor predictability and rat brain noradrenaline metabolism. Pharmacol Biochem Behav 32(2):569–572

    Article  PubMed  CAS  Google Scholar 

  • Van de Kar LD, Piechowski RA, Rittenhouse PA, Gray TS (1991) Amygdaloid lesions: differential effect on conditioned stress and immobilization-induced increases in corticosterone and renin secretion. Neuroendocrinology 54(2):89–95

    Article  PubMed  Google Scholar 

  • Vigas M (1984) Problems of definition of stress stimulus and specificity of stress response. In: Usdin E, Kvetňanský R, Axelrod J (eds) Stress, the role of catecholamines and other neurotransmitters: proceedings of the third international symposium on catecholamines and other neurotransmitters in stress. Gordon and Breach Science Publishers, New York, pp 27–35

    Google Scholar 

  • Weiss JM (1968) Effects of coping responses on stress. J Comp Physiol Psychol 65(2):251–260

    Article  PubMed  CAS  Google Scholar 

  • Weiss JM (1970) Somatic effects of predictable and unpredictable shock. Psychosom Med 32(4):397–408

    PubMed  CAS  Google Scholar 

  • Weiss JM (1971a) Effects of coping behavior in different warning signal conditions on stress pathology in rats. J Comp Physiol Psychol 77(1):1–13

    Article  PubMed  CAS  Google Scholar 

  • Weiss JM (1971b) Effects of coping behavior with and without a feedback signal on stress pathology in rats. J Comp Physiol Psychol 77(1):22–30

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from Ministerio de Ciencia e Innovación (SAF2008-01175), Instituto de Salud Carlos III (RD06/0001/0015, Redes Temáticas de Investigación Cooperativa en Salud, Ministerio de Sanidad y Consumo), Plan Nacional sobre Drogas and Generalitat de Catalunya (SGR2009-16).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Antonio Armario.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Armario, A., Daviu, N., Muñoz-Abellán, C. et al. What can We Know from Pituitary–Adrenal Hormones About the Nature and Consequences of Exposure to Emotional Stressors?. Cell Mol Neurobiol 32, 749–758 (2012). https://doi.org/10.1007/s10571-012-9814-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-012-9814-6

Keywords

Navigation