A Drug That Increases Dopamine Can Reverse the Effects of Inflammation on the Brain in Depression – Neuroscience News

Summary: Levodopa, a drug commonly prescribed for the treatment of Parkinson’s disease that increases dopamine in the brain was found to reverse the effects of neuroinflammation on the reward system and improve symptoms associated with depression.

Source: Emory University

An Emory University study published in Molecular Psychiatry shows levodopa, a drug that increases dopamine in the brain, has potential to reverse the effects of inflammation on brain reward circuitry, ultimately improving symptoms of depression.

Numerous labs across the world have shown that inflammation causes reduced motivation and anhedonia, a core symptom of depression, by affecting the brain’s reward pathways.

Past research conducted by the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine has linked the effects of inflammation on the brain to decreased release of dopamine, a chemical neurotransmitter that regulates motivation and motor activity, in the ventral striatum.

In the study, researchers demonstrated that levodopa reversed the effects of inflammation on the brain’s functional connectivity in reward circuitry and anhedonia (inability to feel pleasure) in depressed individuals with higher C-reactive protein (CRP), a blood biomarker produced and released by the liver in response to inflammation.

Levels of inflammation can be easily measured by simple blood tests, like CRP, readily available in clinics and hospitals throughout the U.S.

The study included 40 depressed patients with a range of CRP levels from high to low who underwent functional brain scans on two visits after receiving in random order either placebo or levodopa, a drug often prescribed for disorders like Parkinson’s disease.

Levodopa improved functional connectivity in a classic ventral striatum to ventromedial prefrontal cortex reward circuit but only in patients with higher levels of CRP. This improvement in reward circuitry in depressed individuals with higher CRP also correlated with reduced symptoms of anhedonia after levodopa.

This shows a young man cryingLevels of inflammation can be easily measured by simple blood tests, like CRP, readily available in clinics and hospitals throughout the U.S. Image is in the public domain

“This research demonstrates the translational potential for use of inflammation-related deficits in functional connectivity and could have important implications for the future investigations of precision therapies for psychiatric patients with high inflammation,” says principal investigator and senior author Jennifer C. Felger, Ph.D., associate professor of psychiatry and behavioral sciences, Emory School of Medicine.

Felger says the study findings are critical for two reasons. First, they suggest depressed patients with high inflammation may specifically respond to drugs that increase dopamine.

Second, Felger says these findings also provide additional evidence that functional connectivity in reward circuitry may serve as a reliable brain biomarker for the effects of inflammation on the brain.

“Moreover, as the effect of levodopa was specific to depressed patients with higher inflammation, this functional connectivity may be used to assess the responsiveness of the brain to novel treatments that might be targeted to this subtype of depressed patients in future studies and clinical trials,” says Felger.


Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study

Increased inflammation in major depressive disorder (MDD) has been associated with low functional connectivity (FC) in corticostriatal reward circuits and symptoms of anhedonia, relationships which may involve the impact of inflammation on synthesis and release of dopamine.

To test this hypothesis while establishing a platform to examine target engagement of potential therapies in patients with increased inflammation, medically stable unmedicated adult MDD outpatients enrolled to have a range of inflammation (as indexed by plasma C-reactive protein [CRP] levels) were studied at two visits involving acute challenge with the dopamine precursor levodopa (L-DOPA; 250 mg) and placebo (double-blind, randomized order ~1-week apart).

The primary outcome of resting-state (rs)FC in a classic ventral striatum to ventromedial prefrontal cortex reward circuit was calculated using a targeted, a priori approach.

Data available both pre- and post-challenge (n = 31/40) established stability of rsFC across visits and determined CRP > 2 mg/L as a cut-point for patients exhibiting positive FC responses (post minus pre) to L-DOPA versus placebo (p < 0.01).

Higher post-L-DOPA FC in patients with CRP > 2 mg/L was confirmed in all patients (n = 40) where rsFC data were available post-challenge (B = 0.15, p = 0.006), and in those with task-based (tb)FC during reward anticipation (B = 0.15, p = 0.013).

While effort-based motivation outside the scanner positively correlated with rsFC independent of treatment or CRP, change in anhedonia scores negatively correlated with rsFC after L-DOPA only in patients with CRP > 2 mg/L (r = -0.56, p = 0.012).

FC in reward circuitry should be further validated in larger samples as a biomarker of target engagement for potential treatments including dopaminergic agents in MDD patients with increased inflammation.


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