Psychotherapy and Neuroscience

Neurohormone Stress Challenges

According to the animal research acute immobilization stress produces significant increases in CRH mRNA expression in the hypothalamic paraventricular nucleus parvocellular neurons (PVNpc) and plasma ACTH and corticosterone levels (Makino et al., 1995) when compared to basal conditions (Ma et al., 1997a). Newly formed transcripts for both CRH and AVP mRNA in the PVN are expressed in the cytoplasm several hours after stress onset (Ma et al., 1997). A single immobilization session is capable of inducing prolonged expression of median PVNpc CRH and AVP mRNA levels that persist (without additional transcription and peptide release) for as long as one and four days respectively (Aubry et al., 1999). Repeated immobilization stress produces elevations in plasma corticosterone and even greater AVP mRNA expression when compared to CRH mRNA levels (Makino et al., 1995). Laboratory animals who have been repeatedly and chronically immobilized for as many as sixteen days produce concurrent significant increases in AVP mRNA and insignificant changes or decreases in PVNpc CRH mRNA levels and labeling when compared with basal states (Bartanusz et al., 1993; Ma et al., 1997b). These findings are fairly consistent across strains (Gomez et al., 1996). The slowing of CRH secretion suggests that AVP may take over as the major stimulator of ACTH as well as the HPA axis in response to repeated and chronic stress (Harbuz, 2002). Removal of the adrenal gland, adrenalectomy, induces immediate CRH mRNA gene transcription that is followed by decreases in the rate of CRH mRNA degradation (Ma et al., 2001) and decreases in pituitary CRH mRNA levels (Rabadan-Diehl et al., 1997). The former is suggestive of corticosterone/glucocorticoid’s role in regulating CRH mRNA by inhibiting its transcription and decreasing its nuclear mRNA stability. CRH receptor 1 knock out (CRHR1 KO) rats are unable to mount HPA activity in response to ACTH challenge, suggesting that this receptor specifically plays a significant role in the eventual release of corticosterone (Muller et al., 2001). Reductions in CRH and/or ACTH secretion on post-training day 28 in previously stressed rats in response to repeated immobilization stress may be suggestive of desensitization of HPA responsivity (Valles et al., 2003). Psychological stress produces neurohormonal alterations in stress-induced neurohormonal response.

These neurohormonal alterations can also be simulated by injection of respective neurohormones. Single injection of corticosterone immediately reduces pituitary CRH receptor mRNA, increases plasma corticosterone that persists for as long as six days (Ochedalski et al., 1998), and significantly decreases pituitary GR binding 30-90 minutes after injection (Cole et al., 2000). Single injection of ovine CRH (οCRH) decreases circulating CRH receptor expression (Ochedalski et al., 1998) by stimulating corticosterone release, which is comparable to typical stress response levels (Cole et al., 2000). Laboratory animals, 7 and 21 days after having experienced two sessions of chronic social defeat, respond to CRH injection with significant increases in ACTH levels immediately after injection (Buwalda et al., 1999).

Repeated daily restraint for 10 minutes over 3 days diminishes ACTH response. Corticosterone pretreatment similarly reduces adrenocorticotropin (ACTH) levels even further (Gadek-Michalska & Bugajski, 2003) reflecting this secretagogue’s vulnerability to steroid-influenced inhibition with furthering stimulation of HPA negative feedback inhibition (Dallman et al., 1987). Two weeks of chronic immobilization stress produces ACTH increases that are strain specific, i.e. Brown-Norway (BN), Spontaneous Hypertensive (SHR), Fisher (FIS), and Wistar-Kyoto(WKY) rats. Corticosterone increases have also been noted in Lewis, SHR, and WKY strains (Gomez et al., 1996). Reexposure to a previous acute stressor tends to reduce ACTH reactivity in adrenalectomized (ADX) or intact animals in the presence or absence of exogenous corticosterone respectively (Marti et al., 1999). But when a new stressor is introduced ACTH levels exceed levels achieved with the initial or preceding stressor (Johnson et al., 2002).

In summary CRH (intensified by subsequent vasopressin (AVP)) secretion in the medial PVN and median eminence induces CRH secretion of ACTH in the anterior pituitary. CRH-induced ACTH then sets off the cascade for adrenocortical steroid secretion (GCs). According to section 1.41 of this web site circulating GCs in vitro stimulate the expression of GR and MR transcription factors, which result in their nuclear transactivation and binding with steroid responsive DNA sequences. According to section 1.43 of this web site steroid transcription provides anti-inflammatory negative feedback by allowing transcription and expression of anti-inflammatory markers, like IL-10. Steroid transcription according to section 1.43 also interferes in proinflammatory transcription factor’s NF-κB expression (by allowing expression of inhibitory IκB) which contains NF-κB to the cell’s cytoplasm.

There are many ways neuroscientists and neuroendocrinologists can monitor neurohormone responses in certain patient populations. One way is to monitor human subject’s plasma neurohormone response to psychological stressors during an experimental paradigm or exposing a subject to script driven imagery or sensory cues and reminders of a previously stressful, traumatic event to which one has since adapted. Another way is to measure the course of a patient’s neurohormone response evidenced in secreted body fluids, i.e. resting cerebral spinal fluid, saliva, and urine over a sustained period of time. A third way is to monitor and document a patient’s response to neurohormonal injection and challenge relating to the stress-related neurohormonal cascade. As noted above the addition of or reduction of any component of the HPA neurohormonal cascade can alter its nature. Additionally these alterations are able to simulate the nature of the stress-induced neurohormonal cascade.

Different psychiatric and autoimmune populations present alterations in the nature of their neurohormonal cascade. This is typically monitored by methods noted above. For example post-traumatic stress disorder (PTSD) or certain inflammatory diseases (such as chronic fatigue syndrome and fibromyalgia) are associated with a hyposecretion of cortisol called hypocortisolemia (Yehuda et al., 1991; Heim et al., 2000; Raison & Miller, 2003). As noted earlier animal research demonstrates rather vividly that acute stress stimulates the secretion of stress-related neurohormones for HPA negative feedback inhibition; however, chronic stress induces alterations in CRH and ACTH secretion, likely at the level of the pituitary, regulating the nature of adrenocortical secretion (Tsigos & Chrousos, 2002). A state of hypersecretion of cortisol, hypercortisolemia, (McAllister-Williams et al., 1998; Pariante & Miller, 2001; Groenink et al., 2002) is characteristic of the neurohormone state that underlies major depression and obsessive-compulsive disorder as well as physical conditions, such as type 2 diabetes mellitus and central obesity (Tsigos & Chrousos, 2002). Changes associated with chronic stress may have the capacity to later induce changes in cortisol secretion.

Like animal models healthy individuals and patients in different diagnostic categories demonstrate particular neurohormonal and neuroimmune composites that are symptom-linked and predictable in their cascade. These concepts will be expanded on in subsequent sections.


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