Cytokine Targets in the Brain: Impact on Neurotransmitters and Neurocircuits

Abstract

Increasing attention has been paid to the role of inflammation in a host of illnesses including neuropsychiatric disorders such as depression and anxiety. Activation of the inflammatory response leads to release of inflammatory cytokines and mobilization of immune cells both of which have been shown to access the brain and alter behavior. The mechanisms of the effects of inflammation on the brain have become an area of intensive study. Data indicate that cytokines and their signaling pathways including p38 mitogen activated protein kinase have significant effects on the metabolism of multiple neurotransmitters such as serotonin, dopamine and glutamate through impact on their synthesis, release and reuptake. Cytokines also activate the kynurenine pathway which not only depletes tryptophan, the primary amino acid precursor of serotonin, but also generates neuroactive metabolites that can significantly influence the regulation of dopamine and glutamate. Through their effects on neurotransmitter systems, cytokines impact neurocircuits in the brain including the basal ganglia and anterior cingulate cortex, leading to significant changes in motor activity and motivation as well as anxiety, arousal and alarm. In the context of environmental challenge from the microbial world, these effects of inflammatory cytokines on the brain represent an orchestrated suite of behavioral and immune responses that subserve evolutionary priorities to shunt metabolic resources away from environmental exploration to fighting infection and wound healing, while also maintaining vigilance against attack, injury and further pathogen exposure. Chronic activation of this innate behavioral and immune response may lead to depression and anxiety disorders in vulnerable individuals.

Sick and Tired: Mood, Fatigue, and Inflammation in Cancer

“…Endogenous NMDA receptor agonists and antagonists, influenced by PICs, may play a role in the pathophysiology of depressive symptoms. PICs have also been shown to increase the release of glutamate from astrocytes, which may lead to increases in glutamate neurotransmission at extra-synaptic NMDA receptors [47], decreased expression of brain-derived neurotrophic factor (BDNF), and neuronal damage via glutamate excitotoxicity [48]. In summary, altered glutamate neurotransmission, either through increased neuroactive kynurenine metabolites or through increased release of glutamate, is a potential mechanism through which inflammation may affect behavior.…”

“…Elevations in PICs have been shown to decrease availability of BH4 by two potential mechanisms: • Inflammatory states set the stage for generation of reactive oxygen species and reactive nitrogen species. BH4 is particularly sensitive to oxidative stress, and is readily oxidized to an inactive state in which it can no longer function as a co-factor for the metabolism of the monoamines [47].…”

“…Increased expression and function of monoamine transporters: Inflammatory stimuli, through activation of signaling pathways such as p38 mitogen-activated protein kinase (MAPK), may increase both the expression and function of monoamine transporters; most work in this area has focused on serotonin transporters [55•]. This may in turn lead to decreased synaptic concentrations of monoamines [47].…”

“…Increased glutamate release: PICs have been shown to increase the release of glutamate from astrocytes, which may lead to increases in glutamate neurotransmission at extra-synaptic NMDA receptors [47], decreased expression of brain-derived neurotrophic factor (BDNF), and neuronal damage via glutamate excitotoxicity [48]. Effects on plasticity/ neurogenesis…”

“…In summary, studies of inflammatory stimuli in animals and humans begin to outline the interaction between inflammation, neurotransmitter systems, neurogenesis, and the neurocircuitry that may be involved in inflammationinduced behavioral change. For more comprehensive reviews of these potential neurobiological mechanisms of inflammation-induced behavioral symptoms, please see [11,20,47].…”