Physiological Manipulations

Direct administration of naturally occurring neuropeptides, hormones, and cytokines has been used in animal models to identify physiological factors that induce behavioral symptoms of depression in humans. For example, chronic stress levels of cortisol systemically administered to squirrel monkeys impair prefrontal-dependent cognitive control of impulsive behavior (Lyons et al. 2000). Cortisol administered to healthy humans induces prefrontal-dependent cognitive impairments that resemble those that are caused in humans by prefrontal lesions (Lupien et al. 1999; A. H. Young et al. 1999). Humans with psychotic major depression consistently present with endogenous hypercortisolism (Nelson and Davis 1997), and patients with psychotic major depression are impaired on standardized tests of prefrontal cognitive functions (Schatzberg et al. 2000). Based on these findings, drugs that block cortisol at the receptor level are now being tested as novel treatments for psychotic major depression (DeBattista and Belanoff 2006) and bipolar disorder (A. H. Young 2006).

In various animals, administration of CRF in the brain increases heart rate, arterial blood pressure, limbic brain glucose metabolism, and depressive- and anxiety-like behavior (Heinrichs and Koob 2004; Lowry and Moore 2006; Strome et al. 2002). Conversely, mice genetically engineered to be deficient in the CRF type 1 receptor (CRF-R1) demonstrate diminished depressive- and anxiety-like behavior in response to CRF administration (Muller et al. 2003). These findings from animal models support clinical studies of depression in humans (Nemeroff and Vale 2005) and suggest that drugs that dampen CRF signaling may be therapeutic for patients with depressive disorders. Receptors for CRF, and particularly CRF-R1, are therefore targets of interest in contemporary drug development (Chen 2006).

In rodents and monkeys, peripheral administration of proinflammatory cytokines (i.e., interleukin-1) mimics the effects of stress as a cause of so-called sickness behavior (Hennessy et al. 2001). Sickness behavior in animals is characterized by anhedonia, reduced activity, diminished social and sexual interests, increased sleep, and behaviors reminiscent of depression in humans. Administration of interferon, a potent inducer of proinflammatory mediators, triggers depression in a subset of humans receiving interferon treatment for cancer or hepatitis C (Asnis and De La Garza 2006). These findings suggest that drugs that block proinflammatory mediators may be novel antidepressants. Recent support for this possibility comes from a guinea pig model of stress-induced sickness behavior (Hennessy et al. 2007).

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