Chronic Stress

Chronic stress models in rodents prevent acclimatization by presenting a variety of stressors in an unpredictable sequence over several weeks. Rats exposed to immobilization, immersion in cold water, and other stressors fail to show the typical increase in open-field activity observed in rats not exposed to chronic stress (Katz et al. 1981). A variety of antidepressants restore normal open-field activity in rats exposed to chronic stress, whereas nonantidepressants do not reproduce this effect (Willner 1990). A modified version of the chronic stress model employs milder manipulations, such as exposure to flashing lights, intermittent white noise, and short-term deprivation of food or water. After several weeks of chronic mild stress, rats exhibit decreased consumption of a palatable sucrose solution (Willner 1997). This measure of anhedonia is restored to normal in rats who receive concurrent treatment with an antidepressant during exposure to stress (three different TCAs and two atypical antidepressants were effective in restoring normal consumption behavior). Evidence that antidepressants reverse the anhedonic effects of chronic stress by potentiating dopamine neurotransmission comes from studies in which the therapeutic response to TCAs was reversed by administration of dopamine receptor antagonists (Willner 1997). These findings concur with numerous studies linking dopamine neurotransmission with stress (Pani et al. 2000), reward processing (Martin-Soelch et al. 2001), and the neural mechanisms of action for antidepressants (Willner et al. 2005).

In the original chronic stress model, it was reported that sustained elevations in glucocorticoid levels were restored to normal by antidepressants (Katz and Sibel 1982; Katz et al. 1981). These findings are of interest because patients with major depression often present with increased levels of the glucocorticoid stress hormone cortisol (see Chapter 45, "Neurobiology of Mood Disorders"). In rodents, however, chronically elevated glucocorticoid levels are difficult to maintain (Rivier and Vale 1987; E. A. Young and Akil 1985), and rodent models often rely on manipulations that differ from the stressors that induce or exacerbate depression in humans. An intriguing exception is the visible burrow model, which enables small groups of rats to produce natural stress-engendering social interactions well suited for behavioral, neural, and hormonal investigations of stress pathophysiology (Blanchard et al. 1995).

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