Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior

Abstract

The potential contribution of chronic inflammation to the development of neuropsychiatric disorders such as major depression has received increasing attention. Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms. Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation. Further understanding of mechanisms by which cytokines alter behavior have revealed a host of pharmacologic targets that may be unique to the impact of inflammation on behavior and may be especially relevant to the treatment and prevention of depression in patients with evidence of increased inflammation. Such targets include the inflammatory signaling pathways cyclooxygenase, p38 mitogen-activated protein kinase, and nuclear factor-kB, as well as the metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down tryptophan into kynurenine. Other targets include the cytokines themselves in addition to chemokines, which attract inflammatory cells from the periphery to the brain. Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence. Taken together, identification of mechanisms by which cytokines influence behavior may reveal a panoply of personalized treatment options that target the unique contributions of the immune system to depression.

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

“…29 Therefore, the findings indicate that pharmacological normalization of stress-induced KYN pathway hyperactivity by IDO1 inhibition normalizes memory processing of aversive stimuli, and to a similar extent but via a different mechanism to that of escitalopram. With regard to mechanism-of-action on memory processes, both 3-HK and QUIN can induce oxidative stress and excitotoxicity in neurons, particularly when elevated chronically (Chiarugi et al, 2001;Haroon et al, 2012;Schwarcz et al, 2012). A limitation of the current study, given their important effects at several neurotransmitter-receptor types, was that QUIN and KYNA could not be measured in small brain-tissue samples.…”

“…One candidate stress-activated inflammation pathway, including for induction of hyperfearfulness, is the kynurenine pathway: increased TNF-, IL-6 and interferon- (IFN-) increase expression of indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO2), enzymes expressed by immune cells and other cell types in various tissues, that promote tryptophan (TRP) catabolism to kynurenine (KYN) in periphery and brain (Dai and Zhu, 2010;Gibney et al, 2014;Robinson et al, 2003;Vecsei et al, 2013;Werner-Felmayer et 6 al., 1989). KYN is further metabolized to, among others, 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA), catabolites that can contribute to oxidative stress, excitotoxicity, and neuroprotection (for review: (Chiarugi et al, 2001;Haroon et al, 2012;Schwarcz et al, 2012). There is growing evidence for kynureninepathway hyperfunction in stress-related disorders, particularly for MDD (Bay-Richter et al, 2015;Kim et al, 2012;Reus et al, 2015;Savitz et al, 2015;Steiner et al, 2011;Sublette et al, 2011) (for review: (Maes et al, 2011)).…”

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

“…One pathway via which increased central immune-inflammatory activity has been proposed to impact on brain function is 24 oxidative stress and neurotoxicity leading to inhibition of dopamine and serotonin function (Felger and Miller, 2012;Haroon et al, 2012;Miller et al, 2009). In this respect it is noteworthy that for AMYG, a number of the genes de-regulated by CSD express proteins that are either mediators or regulators of DA function: Drd2, Adora2a, Gpr88, Darpp-32, Rgs9, Slc29a4 and, as discussed above, Gng7 (as well as Prkcd in mPFC) ( Table 1).…”

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…Moreover, in the context of inflammation-induced oxidative stress, BH4 is very sensitive to being oxidized to the inactive compound dihydroxyanthopterin (Neurauter et al, 2008). Of relevance to dopamine as well as other monoamines, BH4 also serves as an essential cofactor for the ratelimiting enzymes that synthesize dopamine and serotonin including tyrosine hydroxylase and tryptophan hydroxylase, respectively (Neurauter et al, 2008;Felger and Miller, 2012;Haroon et al, 2012). BH4 is also a cofactor for phenylalanine hydroxylase that converts phenylalanine to tyrosine, the primary precursor for L-DOPA that is converted to dopamine.…”