Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

Abstract

Motivational and motor deficits are common in patients with depression and other psychiatric disorders, and are related to symptoms of anhedonia and motor retardation. These deficits in motivation and motor function are associated with alterations in corticostriatal neurocircuitry, which may reflect abnormalities in mesolimbic and mesostriatal dopamine (DA). One pathophysiologic pathway that may drive changes in DAergic corticostriatal circuitry is inflammation. Biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins are reliably elevated in a significant proportion of psychiatric patients. A variety of inflammatory stimuli have been found to preferentially target basal ganglia function to lead to impaired motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal neural responses to reward anticipation, decreased DA and DA metabolites in cerebrospinal fluid, and decreased availability, and release of striatal DA, all of which correlated with symptoms of reduced motivation and/or motor retardation. Importantly, inflammation-associated symptoms are often difficult to treat, and evidence suggests that inflammation may decrease DA synthesis and availability, thus circumventing the efficacy of standard pharmacotherapies. This review will highlight the impact of administration of inflammatory stimuli on the brain in relation to motivation and motor function. Recent data demonstrating similar relationships between increased inflammation and altered DAergic corticostriatal circuitry and behavior in patients with major depressive disorder will also be presented. Finally, we will discuss the mechanisms by which inflammation affects DA neurotransmission and relevance to novel therapeutic strategies to treat reduced motivation and motor symptoms in patients with high inflammation.

Figure 1

Inflammation-induced decreases in dopamine (DA) may affect corticostriatal reward and motor circuitry to drive symptoms of anhedonia and psychomotor retardation. Peripheral innate immune activation and the release of inflammatory cytokines, and acute-phase reactants (eg, C-reactive protein (CRP)) in patients with major depressive disorder (MDD) have been associated with decreased functional connectivity between the ventral and dorsal striatum and reward and motor-related cortical regions, ventromedial prefrontal cortex (vmPFC) and pre-supplementary motor area (SMA; Felger et al, 2016). Inflammation-related changes in corticostriatal connectivity correlated with symptoms of anhedonia and psychomotor retardation, and may involve deficits in DA-relevant, goal-directed behaviors such as such effort expenditure, reinforcement learning, and motor control. A wealth of knowledge from studies in humans and animals administered inflammatory stimuli or cytokines indicates that these effects on corticostriatal circuits may be related to inflammation-induced decreases in DA availability and release. CRP, C-reactive protein; DS, dorsal striatum; IFN, interferon; IL, interleukin; SMA, supplementary motor area; SN, substantia nigra; TNF, tumor necrosis factor; vmPFC, ventromedial prefrontal cortex; VS, ventral striatum; VTA, ventral tengmental area.

Figure 2

Potential mechanisms of inflammation effects on dopamine (DA) synthesis, release, and receptor signaling. Evidence indicates that inflammation and release of cytokines from the periphery, or those produced locally by activated microglia or infiltrating macrophages, can produce nitric oxide, as well as quinolinic acid through indoleamine 2,3-dioxygenase (IDO) and kynurenine pathways, both of which contribute to oxidative stress, and reactive oxygen species (ROS) generation. Increased ROS and inflammation-induced nitric oxide contribute to oxidation of tetrahydrobiopterin (BH4), a cofactor required for the conversion of phenylalanine to tyrosine and tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which are necessary for the synthesis of DA. Furthermore, some evidence exists that inflammatory cytokines may decrease the expression or function of the vesicular monoamine transporter 2 (VMAT2) and/or increase expression or function of the dopamine transporter (DAT). Dysregulation of DAT and vesicular packaging mechanisms can increase cytosolic DA, leading to auto-oxidation and generation of ROS and neurotoxic quinones. In addition, inflammation-induced increased release and decreased reuptake of glutamate by glial cells, combined with quinolinic acid activation of N-Methyl-D-aspartic acid receptors, may lead to glutamate excitotoxicity that further contributes to oxidative stress and decreased DA availability. Finally, inflammatory cytokines may also decrease DA signaling by reducing DA D2 receptors. Figure adapted from Felger and Miller, 2012. 3-HAO, 3-hydroxyanthranilic acid oxygenase; AMPAR, 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid receptor; D1, dopamine 1 receptor 1; D2, dopamine 2 receptor; DDC, dopamine decarboxylase; KMO, kynurenine 3-monooxygenase; NMDAR, N-methyl-D-aspartic acid receptor; NO, nitric oxide; NOS, nitric oxide synthase; PAH, phenylalanine hydroxylase; ROS, reactive oxygen species; TH, tyrosine hydroxylase.