The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

Abstract

Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

“…13 In fact, heightened glutamate receptor activity may play an important role in major depression. 15,16 To test the possibility that activation of IDO during inflammation is responsible for development of major depressive disorders, we determined whether inhibition of IDO indirectly (by a treatment that targets proinflammatory cytokines that induce IDO) or directly (by a treatment that blocks IDO activation) abrogates depressive-like behavior in the LPS model of acute immune stimulation. The semisynthetic tetracycline derivative, minocycline, was chosen for the first approach.…”

The Pro-inflammatory Cytokine TNF-α Regulates the Activity and Expression of the Serotonin Transporter (SERT) in Astrocytes

“…[12,13]). Elevated levels of pro-inflammatory cytokines IL-1b, TNF-a and IL-6 has been reported in patients suffering from neuropsychiatric disorders [12,[14][15][16]. In addition, immune activation in human disease as well as in animal models is often accompanied by a discrete set of psychiatric and behavioral alterations which bear many of the hallmarks of depressive illness [17,18].…”

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…IDO activity can be stimulated by a number of inflammatory cytokines and their signaling pathways including NF-κB. When activated, IDO converts tryptophan, the primary precursor of serotonin, into kynurenine, thus reducing serotonin synthesis and availability (Robinson et al, 2006;Muller and Schwarz, 2007). Given the importance of serotonin in T-cell activation, the reduction of serotonin availability by IDO is a major pathway by which IDO regulates the immune system and T-cell function (Mellor et al, 2003).…”