Monoamine Systems

Since its neurons respond exquisitely to all attention-provoking and alarming external stimuli, the locus coeruleus is a primary gatekeeper of central nervous system (CNS) sympathetic nervous system responses to stress. However, this type of arousal occurs irrespective of whether the pervading stressful stimulus is of peripheral origin (such as with threatening physiological situations that require immune activation) or initiated centrally (as in the case of some perceptual or cognitive event). As a result, disturbances in locus coeruleus function have been implicated in a variety of psychiatric illnesses such as major depression. Specifically, it has been hypothesized that exposure to stressors can produce adaptations in locus coeruleus function that ultimately lead to depressivelike symptoms (Harro and Oreland, 2001). Along these same lines, adaptations in locus coeruleus function in response to stress would be expected to alter the individual's response to subsequent stressors (either hypo- or hyperrespon-sivity, depending on the nature of the stressor). Indeed, there is strong evidence to suggest that stress-induced alterations in locus coeruleus function and corresponding sympathetic output may play an etiological role in psychiatric illness, especially in the case of depression. Such a connection has long been suggested by the utility of monoamine modulating drugs to treat individuals suffering from this disorder. Clearly, the interaction of qualitatively different stressors and their corresponding effects on the ability of the locus coeruleus to integrate and coordinate sympathetic nervous system responses to subsequent challenge is a critical area of research in both basic and applied arenas today.

Indeed, one emerging animal model of depression relies on the interaction among multiple different stressors administered over 5 to 7 days to produce depressivelike symptoms. These models come in a variety of forms and are typically referred to as "chronic mild stress" paradigms (Willner, 1997). The real advantage of these models is that by employing different stressors on each day (foot shock on day 1 followed by social conflict on day 2, etc.), researchers can more appropriately model the cumulative nature of stress in human populations. Furthermore, using the sum consequence of exposure to multiple stressors helps eliminate experimental conclusions that might be a result of the contrived nature of some rodent stressor paradigms. (After all, what does a stressor such as foot shock in the rat really model in humans?) Nevertheless, evidence from chronic stress paradigms clearly demonstrate a role for sympathetic nervous system output and its governance by the locus coeruleus in psychiatric illness.

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