Inflammation Models of Depression in Rodents: Relevance to Psychotropic Drug Discovery

Abstract

Inflammation and depression are closely inter-related; inflammation induces symptoms of depression and, conversely, depressed mood and stress favor an inflammatory phenotype. The mechanisms that mediate the ability of inflammation to induce symptoms of depression are intensively studied at the preclinical level. This review discusses how it has been possible to build animal models of inflammation-induced depression based on clinical data and to explore critical mechanisms downstream of inflammation. Namely, we focus on the ability of inflammation to increase the activity of the tryptophan-degrading enzyme, indoleamine 2,3 dioxygenase, which leads to the production of kynurenine and downstream neuroactive metabolites. By acting on glutamatergic neurotransmission, these neuroactive metabolites play a key role in the development of depression-like behaviors. An important outcome of the preclinical research on inflammation-induced depression is the identification of potential novel targets for antidepressant treatments, which include targeting the kynurenine system and production of downstream metabolites, altering transport of kynurenine into the brain, and modulating glutamatergic transmission.

Stressed and Inflamed, Can GSK3 Be Blamed?

“…Increases in many cytokines, particularly IL-6 and TNFα, have been found in the serum of patients with depression. Inflammation in patients with depression is associated with resistance to treatment with classical antidepressant drugs, and there is some evidence that anti-inflammatory drugs can improve antidepressant actions [23,24]. Administration of LPS, the agonist of TLR4, induces symptoms of depression in humans [25], and administration of interferon to bolster immunity induces depression in many patients [26].…”

“…Most investigators feel that aberrant activation of inflammation, in combination with genetic and environmental factors, contributes to susceptibility and onset of mood disorders, rather than inflammation arising as a consequence of mood disorder episodes [23], and this is supported by evidence from studies in animals. In rodents, administration of inflammatory cytokines or LPS causes depression-like behaviors that are attenuated by antidepressants [24]. In rodents, aberrant innate (microglia) and adaptive (Th17 cells) immune system responses have been associated with depression-like behaviors [20,27,28].…”

An examination of changes in maternal neuroimmune function during pregnancy and the postpartum period

“…It is also known that immune dysregulation is often linked to the onset of certain mental health disorders, including depression and anxiety (Raison and Miller, 2017; Remus and Dantzer, 2016). The peripartum period is a critical time-point in a woman’s life that is associated with an increased risk of certain mental health disorders, most notably peripartum anxiety and depression, which have also been concurrently linked with altered cytokine production in the periphery (Osborne and Monk, 2013).…”

Antidepressant effects of combination of brexpiprazole and fluoxetine on depression-like behavior and dendritic changes in mice after inflammation

“…A meta-analysis shows higher blood levels of pro-inflammatory cytokines in drug-free depressed patients, compared with healthy controls (Dowlati et al 2010). Peripheral administration of the bacterial endotoxin lipopolysaccharide (LPS) induces depression-like behavior in rodents after the induction of inflammation (Dantzer et al 2008; O’Connor et al 2009; Remus and Dantzer 2016; Zhang et al 2016). LPS-induced depression-like behavior can be blocked by pretreatment with antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (Dong et al 2016; Ma et al 2014; Ohgi et al 2013; Yao et al 2015).…”