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Adaptation to Stress 99

galanin. This supports the notion that resilience to stress is associated with

the regulation of noradrenergic activity within an optimal window.

Hypothalamic-Pituitary-Adrenal Axis Responses to Stress

In response to acute and chronic stresses, the hypothalamus secretes
corticotropin-releasing factor (CRF), which in turn stimulates the anterior
pituitary gland to synthesize and release adrenocorticotropin hormone
(ACTH). ACTH stimulates the synthesis and release of adrenal cortisol and
dehydroepiandrosterone (DHEA). In the short run, cortisol mobilizes and
replenishes energy stores, inhibits growth and reproductive systems, con-
tains the immune response, and affects behavior through actions on multiple

neurotransmitter systems and brain regions (Yehuda, 2002). However, ani-
mal studies have shown that if stress remains chronic, prolonged elevations
of glucocorticoid may cause damage to CA3 pyramidal neurons of the hip-
pocampus; changes include reductions in dendritic branching, a loss of den-
dritic spines, and a reduction in the growth of new granule cell neurons in
the dentate gyrus (Sapolsky, 2003). Damage to the hippocampus may impair
its normal capacity to inhibit the HPA axis, resulting in even greater gluco-
corticoid levels and possible additional damage to the hippocampus.
Corticotropin-releasing hormone (CRH) initiates the neuroendocrine
response to stress by stimulating the pituitary gland to release ACTH and the
locus coeruleus to release NE (Grammatopoulos & Chrousos, 2002). When
CRF is administered centrally, it causes increased heart rate, increased blood
pressure, decreased appetite, decreased sexual activity, increased arousal,
and a reduction in reward expectations (Owens & Nemeroff , 1991). Th ese
changes and symptoms are commonly seen in depression and anxiety. Th e
activation of CRH-1 receptors is associated with anxiety-like responses,
while the stimulation of CRH-2 receptors is associated with anxiolytic-like
responses (Bale et al., 2000, 2002). It has been proposed that regulation of

these two CRH receptor types influences psychological and physiologi-

cal responses to stress. The capacity to restrain or regulate the initial CRH
response to acute stress and the prolonged CRH response to chronic stress
may facilitate psychobiological resilience to stress-induced disorders such as
PTSD and depression.

DHEA helps to modulate the effects of cortisol. In the brain, DHEA’s
antiglucocorticoid and antiglutamatergic activity may confer neuroprotec-
tion (reviewed in Charney, 2004). The administration of DHEA has been

shown to exert antidepressant effects in patients diagnosed with major
depression (Wolkowitz et al., 1999). Various studies of DHEA eff ects sug-
gest that DHEA plays a role in neurobiological resilience to stress. Findings
include a negative correlation between plasma DHEA levels and depres-
sion (Goodyer, Herbert & Altham, 1998); a negative relationship between

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