ReviewCytokine effects on the basal ganglia and dopamine function: The subcortical source of inflammatory malaise
Graphical abstract
Highlights
► Cytokines released during inflammation target the basal ganglia and dopamine. ► Cytokines can disrupt dopamine function by effects on synthesis, packaging, release, and reuptake. ► Cytokine effects on basal ganglia dopamine may cause anhedonia, fatigue, and psychomotor slowing. ► Cytokines may contribute to behavioral disorders associated with chronic inflammation.
Introduction
There has been increasing recognition that inflammatory cytokines play an important role in neuronal integrity and can exert profound effects on neurocircuitry and neurotransmitter systems in the brain, ultimately affecting behavior (Haroon et al., 2012, Miller et al., 2009, Yirmiya and Goshen, 2011). Accordingly, there has been mounting interest regarding the role of cytokines in behavioral alterations and the development and progression of neuropsychiatric disorders. Under physiologic conditions, cytokines such as TNF-alpha and IL-1 have been shown to be involved in a number of essential brain processes such as synaptic remodeling, neurogenesis and long-term potentiation (Yirmiya and Goshen, 2011). However, in excess, inflammatory cytokines can act in the brain to affect monoamine neurotransmitter systems and behavior, and recent evidence indicates that dopamine function in the basal ganglia may be a primary target in this regard (Capuron et al., 2007, Capuron et al., 2012, Haroon et al., 2012, Liu and Hong, 2003, Theodore et al., 2006, Thorne et al., 2008). The basal ganglia are key subcortical structures that regulate motivation and motor activity, and dopamine plays a essential modulatory role in basal ganglia function (Grace, 2002). The effect of inflammatory cytokines on basal ganglia dopamine may be especially relevant to depression and fatigue as well as psychomotor disturbances and the development of neurodegenerative disorders. This review will highlight the current literature demonstrating the impact of peripheral inflammatory cytokines and local neuroinflammation on the basal ganglia and dopamine function and explore the potential mechanisms involved. In addition, cytokine interactions with other neurotransmitter systems as they relate to basal ganglia dopamine function will be described along with the implications of these findings for neuropsychiatric disease.
There is a vast literature in humans and laboratory animals describing the profound effects of inflammation and the release of inflammatory cytokines on the brain and behavior. In humans, inflammatory cytokines have been implicated in the development of behavioral disturbances including depression and fatigue in both medically ill and medically healthy individuals. For example, numerous studies have reported elevated cytokines and other inflammatory markers in depressed but otherwise healthy individuals (Dowlati et al., 2010, Maes, 1999, Maes et al., 1991, Maes et al., 1992, Sluzewska, 1999), and patients exposed to increased inflammation during chronic illness experience considerably higher rates of depression and fatigue than the general population (Yirmiya, 2000, Yirmiya et al., 1999, Yirmiya et al., 2000). Evidence that inflammatory cytokines can cause behavioral alterations exists in numerous reports of the neuropsychiatric symptoms induced by chronic administration of the inflammatory cytokine, interferon (IFN)-alpha, used to treat certain cancers and viral infections. Indeed, IFN-alpha produces an array of behavioral disturbances, many of which are consistent with decreases in basal ganglia dopamine function including anhedonia, fatigue and psychomotor slowing (Bersano et al., 2008, Capuron et al., 2002a, Capuron et al., 2009, Majer et al., 2008, Sunami et al., 2000). Of note, selective serotonin reuptake inhibitors (SSRIs) have been shown to alleviate IFN-alpha-induced anxiety and some depressive symptoms. However, IFN-alpha-induced fatigue and psychomotor retardation are less responsive to SSRI therapy (Capuron et al., 2002a, Morrow et al., 2003, Raison et al., 2005). These data are consistent with findings in patients with advanced cancer undergoing chemotherapy, who also exhibit increased inflammation in association with fatigue that is not responsive to SSRIs (Ahles et al., 2002, Bower et al., 2002, Miller et al., 2008). In addition, fatigue is one of the primary residual symptoms in SSRI-treated medically healthy depressed patients, who, as noted above, have been shown to exhibit evidence of increased inflammation. Taken together, these findings suggest that neurotransmitter systems other than serotonin, such as dopamine, may be involved in these SSRI-resistant, inflammation-related symptoms. Nevertheless, classical stimulant medications that increase dopamine release and/or block dopamine reuptake have demonstrated limited efficacy in the treatment of fatigue in cancer patients and patients with other medical disorders associated with inflammation (Butler et al., 2007, Mar Fan et al., 2008, Moraska et al., 2010). Therefore, a better understanding of the mechanisms by which inflammation and inflammatory cytokines affect dopamine function will inform strategies to improve the treatment of neuropsychiatric disturbances such as fatigue in medically ill as well as medically healthy individuals.
Section snippets
Access of peripheral cytokines and immune cells to the central nervous system
Activation of peripheral inflammation and the systemic release of inflammatory cytokines can exert profound effects on the brain and behavior as a result of communication between the periphery and brain. Of note, local tissue inflammation in the absence of a systemic immune response may activate discrete brain regions (Belevych et al., 2010), however, it is unlikely that such local immune responses and their effects on the brain lead to the more global changes in neurotransmitter metabolism and
Potential mechanisms of cytokine effects on dopamine synthesis, release, and reuptake
Cytokines can potentially affect multiple aspects of dopamine neurotransmission, leading to decreased synthesis, impaired packaging or release, and increased reuptake, all of which may interact to a greater or lesser extent to reduce dopamine function in the basal ganglia (see Fig. 2). The following section will discuss potential mechanisms by which cytokines may affect these aspects of dopamine function, ultimately resulting in reduced dopamine signaling in the basal ganglia.
Translational implications: potential therapeutic targets for treating cytokine effects on basal ganglia dopamine function
The data summarized herein demonstrate that inflammatory cytokines affect dopamine function and may contribute to the development of neuropsychiatric symptoms such as fatigue, anhedonia, psychomotor slowing, sleep disturbances, and depression in multiple patient populations with increased inflammation. Moreover, the prevalence of neuropsychiatric symptoms, and particularly fatigue, in patients exposed to chronic inflammation or inflammatory cytokines substantiate the need to understand the
Future directions
Although neuroimaging and biochemical data have provided evidence of functional effects of immune activation on the basal ganglia and dopamine function, future studies to further elucidate the mechanisms of these effects are warranted. These studies will ultimately be required to determine the most appropriate treatments to target basal ganglia dopamine-mediated symptoms. Provided that monkeys experience similar behavioral changes in response to IFN-alpha as humans (Felger et al., 2007), and
Summary
There is strong evidence that inflammatory cytokines specifically target the basal ganglia and dopamine function to contribute to neuropsychiatric symptoms including depression and fatigue in medically ill and depressed subjects. Much of this evidence stems from biochemical and behavioral studies in humans and animals administered cytokines, such as IFN-alpha, and from neuroimaging experiments that demonstrate altered basal ganglia and dopamine function in response to inflammatory cytokines or
Financial support
This work was supported in part by Grants from the National Institutes of Health to AHM (K05MH069124, R01HL073921, R01MH075102, T32MH020018, and U19MH069056) and JCF (F32MH093054) as well as the Emory Center for AIDS Research (P30AI050409). In addition, the study was supported by PHS Grant UL1RR025008 from the Clinical and Translational Science Award program and PHS Grant M01RR0039 from the General Clinical Research Center program, National Institutes of Health, National Center for Research
Financial disclosure
All authors declare that there are no conflicts of interest, and all financial disclosures are listed for each author: Andrew H. Miller has served as a consultant for Abbott Laboratories, AstraZeneca, Glaxo-SmithKline, Lundbeck Research USA, F. Hoffmann-La Roche, Johnson and Johnson, Schering Plough Research Institute, and Wyeth/Pfizer, and has received research support from Centocor, GlaxoSmithKline, and Schering-Plough Research Institute; Jennifer C. Felger has nothing to disclose.
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