A critical review of human endotoxin administration as an experimental paradigm of depression

Abstract

The syndrome called depression may represent the common final pathway at which different aetiopathogenic processes converge. One such atiopathogenic process is innate immune system activation. Some depressed patients increased levels of inflammatory cytokines and other immunologic abnormalities. It is not known whether immune system activation contributes to the pathogenesis of depressive symptoms. Supporting this possibility is the observation that in both rodents and humans, exogenous immune stimuli such as endotoxin can produce symptoms that resemble depression. A new approach to depression research would be to use immune stimuli to elicit depressive symptoms in humans. Here we review each of the symptoms elicited in humans by endotoxin administration, and compare this model to two other immune depression paradigms: interferon-alpha treatment and typhoid vaccine administration, to assess to what degree endotoxin administration represents a valid model of immune depression. We also review corresponding behavioral changes in rodents and the potential molecular pathways through which immune system activation produces each symptom.

Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

“…Imipramine increase the levels of serotonin and/or norepinephrine by blocking reuptake of these neurotransmitters to presynaptic terminals, although an increase in monoamine levels occurs soon after drug administration, the effects of antidepressants emerge gradually over several weeks of continuous application, it is possible that in addition to an increase in monoamine levels, other more temporal neuronal events may be responsible for the action of imipramine (Yagasaki et al 2006). The immobility is a parameter evaluated in the forced swimming test and a reduction in sucrose preference in anhedonia test is interpreted as a depression-like behavior (Porsolt et al 1977;Katz et al 1981b;DellaGioia and Hannestad 2010;Réus et al 2011), suggesting an imbalance in the noradrenergic and serotoninergic neurotransmission. In fact, human and animal studies have showed low levels of dopamine and serotonin associated with high levels of BCAA (Wajner and Vargas 1999;Wajner et al 2000;Araújo et al 2001).…”

Animal models as tools to study the pathophysiology of depression

“…Studies have also reported that many of these changes, both behavioral and cellular, are reversed by several classes of antidepressants used in the clinic. 1 With both behavioral changes and changes in neurotransmitters and in the immune system occurring after OB, we can conclude that this may be a good animal model of depression, since it has both face and construct validity. Moreover, different classes of therapeutically effective antidepressants reverse the behavioral and molecular changes caused by OB, thus showing that this model presents predictive validity.…”

“…Nevertheless, a few studies have addressed this issue. 1 In rodents, the administration of endotoxin, a cell wall component of Gram-negative cells, led to behavioral changes similar to those seen in humans, such as anhedonia and sleep disorders, which are parameters of face validity. Neuroendocrine changes, which help determine construct validity, were also found.…”

“…Table 4 lists the major cytokines and their respective functions. 1 Animal models of depression involving the immune system have been the target of criticism, but the fact remains that there is still great difficulty in understanding the complexity of the communication between the immune system and the brain. Nevertheless, a few studies have addressed this issue.…”

“…These are presented in Table 1. 1 Animal models are important tools for investigating the etiology of depression, as well as progress in the development of effective therapeutic targets for its treatment. Although animal models greatly help our understanding of psychiatric disorders, they do have some limitations.…”