Cytokine effects on the basal ganglia and dopamine function: The subcortical source of inflammatory malaise

Abstract

Data suggest that cytokines released during the inflammatory response target subcortical structures including the basal ganglia as well as dopamine function to acutely induce behavioral changes that support fighting infection and wound healing. However, chronic inflammation and exposure to inflammatory cytokines appears to lead to persisting alterations in the basal ganglia and dopamine function reflected by anhedonia, fatigue, and psychomotor slowing. Moreover, reduced neural responses to hedonic reward, decreased dopamine metabolites in the cerebrospinal fluid and increased presynaptic dopamine uptake and decreased turnover have been described. This multiplicity of changes in the basal ganglia and dopamine function suggest fundamental effects of inflammatory cytokines on dopamine synthesis, packaging, release and/or reuptake, which may sabotage and circumvent the efficacy of current treatment approaches. Thus, examination of the mechanisms by which cytokines alter the basal ganglia and dopamine function will yield novel insights into the treatment of cytokine-induced behavioral changes and inflammatory malaise.

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.