Dear readers of ADxS.org, please forgive the disruption.

ADxS.org needs about $36850 in 2023. In 2022 we received donations from third parties of about $ 13870. Unfortunately, 99.8% of our readers do not donate. If everyone who reads this request makes a small contribution, our fundraising campaign for 2023 would be over after a few days. This donation request is displayed 18,000 times a week, but only 40 people donate. If you find ADxS.org useful, please take a minute and support ADxS.org with your donation. Thank you!

Since 01.06.2021 ADxS.org is supported by the non-profit ADxS e.V..

$9319 of $36850 - as of 2023-06-01
25%
Header Image
Neurophysiological mechanisms of action on behavior by immune responses.

Sitemap

Neurophysiological mechanisms of action on behavior by immune responses.

The stress hormones of the HPA axis (CRH, vasopressin, ACTH) mediate not only immune responses but also behavioral responses. These behavioral triggers of stress hormones explain some of the ADHD symptoms, but probably not all.

Pro-inflammatory and anti-inflammatory cytokines of the immune system activated by the various stress hormones also exhibit behavioral aspects.

A metastudy of 67 studies of about 4000 children and adolescents shows that inflammatory markers are elevated in quite a few neuropsychiatric disorders:1

  • Autism Spectrum Disorders (ASD)
  • Major depressive disorder (MDD)
  • Bipolar disorder (BD)
  • Post-traumatic stress disorder (PTSD)
  • Obsessive Compulsive Disorder (OCD)
  • Tourette’s Disorder (TD)
  • Attention deficit hyperactivity disorder (ADHD) and
  • Schizophrenia (SZ)

Further, correlations were found between atopic immune system conditions and ADHD.2

One hypothesis postulates that an increased reactivity of the immune system leads to a greater withdrawal behavior.3 This could be justified evolutionary-biologically by the fact that a higher reactivity of the immune system costs more resources. Since any activation of the immune defense requires effort, it would be conclusive if individuals with a lighter/faster activated immune defense are more likely to keep their distance from infection sites (other individuals) than those with a lower risk of (effort-intensive) immune system activation. It could be concluded that social phobia correlates with an easily activated immune system.

However, individuals with high extraversion were actually found to have a more highly activated immune system than individuals with high agreeableness. Another study found increased pro-inflammatory gene expression for extraversion, while it was decreased for conscientiousness.4

Immune system activation due to infections leads to social withdrawal.5 In people with high social withdrawal, one (very small, n = 14) study found increased immune activation of pro-inflammatory cytokines with concomitant decreased B lymphocyte function and IFN-α response in terms of gene expressions. Anti-inflammatory glucocorticoid response elements (GRE) were decreased and response elements for pro-inflammatory NF-κBRel transcription factors were increased.6

1. Neurophysiological mechanisms mediating behavioral effects of inflammatory responses

Basic neurophysiological mechanisms of mediation of behavioral effects by inflammatory responses are discussed:7

  • Glia activation8
  • Neuronal damage and neurodegeneration9
  • Increased oxidative stress10
  • Reduced BDNF levels11
  • Blood-brain barrier disorders12
  • Altered neurotransmitter metabolism13

2. Behavioral changes due to cytokine effects on neurotransmitters

Inflammation affects several brain neurotransmitter systems, including serotonin, dopamine, norepinephrine, and glutamate pathways, as well as the kynurenine pathway, which produces the neurotoxic metabolite quinolinic acid. Disruption of neurotransmitter systems correlates with inflammation-related changes that mediate motivation and motor function as well as fear, arousal, and alarm.1415

The innate immune system as well as pro-inflammatory cytokines directly affect dopamine in the basal ganglia, thereby influencing motivation (reduction) and motor function (slowing).1617 Inflammatory responses cause a preference for avoiding losses over achieving gains.18 Endotoxin decreases striatal activity to offered rewards.19

Dopamine transporters, prominently implicated in the pathogenesis of ADHD, are abundant on human T cells.20
In STAT6-deficient mice, DAT in the striatum are reduced, inducing hyperactivity (with STAT6 interacting closely with cytokines and growth factors).21

Dopamine has the unusual property of increasing upregulation by 500% of

  • TNFα within 24 hours, via the D3 receptor
  • IL-10 within 72 hours, via the D2 receptor
  • TNFα within 24 and IL-10 within 72 hours via the D1 / D5 receptors

trigger.22

  • IFN-γ and
  • IL-4

were not altered by dopamine via T cells.22

Inflammation and disease stress working memory by reducing the ability of short-term memory to process environmental stimuli. This effect is likely responsible for the changes in cognition caused by inflammation.5 In ADHD, working memory is significantly impaired.

3. Inflammatory processes and dopamine

Much of the presentation of the linkage between the inflammatory elements of the immune system and dopamine is based on the work of Felger.23

Inflammatory processes have a direct influence on the dopaminergic system.

3.1. Pro-inflammatory cytokines cause

  • Decreased ventral striatum responses to hedonic reward stimuli (anhedonia)2324
  • Decreased dopamine levels in the striatum23
  • Decreased levels of dopamine and dopamine metabolites in cerebrospinal fluid23
  • By CRP, IL-6, IL-1beta and IL-1 RA decreased functional connectivity of striatal reward systems.232517 Reduced connectivity between brain areas is thought to be a (co)cause of ADHD and is ameliorated by stimulants. See more at ⇒ ** Effect on connectivity between brain regions in the articleMethylphenidate (MPH) in ADHD.

3.1.1. Behavioral symptoms due to pro-inflammatory cytokines

The effects of pro-inflammatory cytokines correlate with (depressive) behavioral symptoms

  • Anhedonia2324
  • Fatigue23
  • Psychomotor slowdown2324

3.1.2. Cytokine effects on the dopamine system

Cytokines act on the dopamine system through various mechanisms.

3.1.2.1. Reduction of tetrahydrobiopterin (BH4) inhibits dopamine synthesis

BH4 is therefore essential for the synthesis of serotonin, norepinephrine and dopamine.

Dopamine is synthesized from phenylanaline (by means of the enzyme phenylanaline hydroxlase) to tyrosine, which is synthesized (by means of the enzyme tyrosine hydroxlase) to L-dopa and from that to dopamine.
Tetrahydrobiopterin (BH4) is involved (as an enzyme cofactor of tyrosine hydroxlase) in the synthesis of tyrosine from phenylanaline and (as an enzyme cofactor of phenylanaline hydroxlase) in the synthesis of L-dopa from tyrosine. Dopamine is in turn a precursor of norepinephrine.
Thus, a deficiency of BH4 impairs the synthesis of dopamine (and norepinephrine).
Vitamin B12 supports the generation of tetrahydrobiopterin (BH4).

Inflammation and cytokines, e.g. IFN-alpha, can reduce the availability of BH4.2627 This impairs the synthesis of dopamine and serotonin.

Inflammation increases inducible NOS (iNOS) activity, which binds BH4 (serving as a cofactor for nitric oxide synthases (NOS)). This causes formation of ROS (oxygen radicals) instead of NO.28 BH4 thus regulates the formation of superoxides.29 ROS cause oxidative stress, which in turn contributes to the oxidative reduction of BH4 itself. BH4 oxidizes very easily.28
These mechanisms decrease BH4 availability, which limits dopamine synthesis.28

Peripherally injected IFN-α decreases BH4 levels in amygdala and raphe nuclei in rats by increasing NO synthesis. When NO synthesis is inhibited, IFN-α loses its inhibitory effect on BH4 and dopamine levels in the brain.30

Cardiotrophin-1 (CT-1) reduced BF4 levels in neurons by 90%, as did ciliary neurotrophic factor (CNTF), whereas IL-6 or TNF-alpha did not significantly alter BF4.31

In ADHD, dopamine synthesis (e.g., using BH4) does not appear to be impaired, as administration of L-dopa shows no effect on ADHD symptomatology.

3.1.2.2. Increase in tyrosine hydroxylase

An increase in tyrosine hydroxylase by IL-1-beta indicates increased dopamine turnover in the hypothalamus. The change correlated with increased ACTH levels with unchanged prolactin levels.32

3.1.2.3. Reduced expression or action of VMAT2 promotes oxidative stress

The vesicular monoamine transporter (VMAT, VMAT2) is involved in the incorporation of dopamine into vesicles. Sex differences exist in neuronal VMAT2 activity that explain the differential response to methamphetamine. Packaging of dopamine in dopaminergic neurons by VMAT2 is required to prevent damage from oxidized dopamine during oxidative stress or after metamphetamine feeding. Mice with as little as 5% to 10% VMAT2 showed rapid damage to such neurons.33

3.1.2.4. Increased expression or effect of DAT
3.1.2.4.1. Increased expression or effect of DAT by VMAT and MAPK

Dopamine transporters move dopamine from the vesicles of the sending synapse (presynapse) into the synaptic cleft. At the same time, they have the task of reabsorbing dopamine that has been taken up by the receiving synapse (postsynapse) and subsequently returned to the synaptic cleft so that it can be stored in the vesicles for reuse. If the DAT are too active or too many (which is often the case in ADHD), the DAT will already reabsorb the dopamine freshly added to the synaptic cleft by the sending synapse before it could transmit the signal at the postsynapse. This leads to signal transmission disturbances.

Dysregulation of DAT and VMAT can increase dopamine in cellular fluid, which can trigger auto-oxidation, the generation of ROS (reactive oxygen species = oxygen radicals) and the generation of neurotoxic quinones (English: quinones). Higher ROS levels can lead to oxidative stress.

Protein kinase C (PKC) decreases dopamine reuptake and DAT number.34 Mitogen-activated protein kinase (MAPK) pathways appear to activate the dopamine transporter (DAT) in contrast. Striatal cells with particularly active MAPK showed increased dopamine reuptake, whereas with inhibited MAPK they correlated with decreased DA reuptake in a dose- and time-dependent manner.34

3.1.2.4.2. Increased DAT in HIV encephalitis

Affected individuals with neuropsychiatric disorders due to HIV infection are thought to have increased expression of DAT as a consequence of resultant neuroinflammation,35 whereas in HIV without encephalitis, unchanged DAT expression was found with decreased DAT activity. In addition, decreased levels of tyrosine hydroxylase and phosphorylated tyrosine hydroxylase were detected. Furthermore, the D2 receptor was decreased and the D3 receptor was increased in expression.36

IFN-α, given chronically, showed no change in DAT binding in monkeys.37

3.1.3. Reduced transmission of glutamate

IFN-γ (and, to a slightly lesser extent, IFN-α) activate indoleamine 2,3-dioxygenase (IDO) in peripheral immune cells or microglia. IDO converts tryptophan to kynurenine, this (by kynurenine aminotransferase) to kynurenic acid and quinolinic acid.15 Kynurenic acid acts as a glutamate receptor antagonist, which decreases glutamate neurotransmission. This in turn inhibits the release of dopamine in the striatum.
Excessive release of glutamate and quinolinic acid due to inflammation may increase oxidative stress and excitotoxicity.

This pathway is successfully treated by glutamate receptor antagonists such as ketamine.

For a more detailed account, see How IFN-α neurophysiologically triggers depression In the section Depression and dysphoria in ADHD in the section Diagnostics

4. Inflammatory processes and serotonin

4.1. Cytokine action on the serotonin system

IFN-γ, as well as, to a slightly lesser extent, IFN-α, decrease tryptophan, which is necessary for the synthesis of serotonin. Therefore, IFN may decrease serotonin levels.15

Stimulation of p38 mitogen-activated protein kinase (MAPK) can increase serotonin transporter expression and function, and thus serotonin reuptake, which can induce serotonin deficiency.3839 MAPK and its mediated serotonin transporter activation are activated by IL-1-β and TNF-α in a dose- and time-dependent manner and inhibited by IL-1-RA.38

BH4 is also required for the activities of tryptophan hydroxylase, which is a rate-limiting enzyme in serotonin synthesis. BH4 is therefore essential for the synthesis of serotonin, norepinephrine and dopamine (see above).
BH4 deficiency is a relevant pathway for understanding depression. If elevated IFN-alpha is detected, treatment with 5-HT, a prodrug of serotonin, might be recommended to counteract the impairment of tryptophan generation. We know of cases of treatment-resistant depression in which 5-HTP produced immediate improvement, at least temporarily. Since 5-HTP is converted exclusively to serotonin, 5-HTP is helpful only with respect to mood problems, but not with respect to the primarily dopaminergic and noradrenergic ADHD symptoms.
One study suggests that tryptophan levels are reduced in adult ADHD sufferers and that the degree of reduction in the level of tryptophan and its metabolites (= breakdown products) correlates with the severity of ADHD symptoms.40 Another study tended to find increased tryptophan levels in children with ADHD.41
Vitamin B12 supports the generation of tetrahydrobiopterin (BH4).

Endotoxin activates serotonin transporters (which can induce a serotonin deficit) and decreases physical activity in mice in stress tests. The endotoxin-induced reduction in physical activity does not occur in mice with deactivated serotonin transporters and in mice whose IL-1 receptors were inhibited by an antagonist.42


  1. Mitchell, Goldstein (2014): Inflammation in children and adolescents with neuropsychiatric disorders: a systematic review. J Am Acad Child Adolesc Psychiatry. 2014 Mar;53(3):274-96. doi: 10.1016/j.jaac.2013.11.013.

  2. van der Schans, Cao, Bos, Rours, Hoekstra, Hak, de Vries (2019): The temporal order of fluctuations in atopic disease symptoms and attention-deficit/hyperactivity disorder symptoms: a time-series study in ADHD patients. Eur Child Adolesc Psychiatry. 2019 Apr 24. doi: 10.1007/s00787-019-01336-2

  3. Lopes (2017): Why are behavioral and immune traits linked? Horm Behav. 2017 Feb;88:52-59. doi: 10.1016/j.yhbeh.2016.09.008.

  4. Vedhara, Gill, Eldesouky, Campbell, Arevalo, Ma, Cole (2015): Personality and gene expression: Do individual differences exist in the leukocyte transcriptome?, Psychoneuroendocrinology, Volume 52, 2015, Pages 72-82, ISSN 0306-4530, https://doi.org/10.1016/j.psyneuen.2014.10.028. n = 121

  5. Dantzer, O’Connor, Freund, Johnson, Kelley (2008): From inflammation to sickness and depression: when the immune system subjugates the brain; Nature Reviews Neuroscience volume 9, pages 46–56, 2008

  6. Cole, Hawkley, Arevalo, Sung, Rose, Cacioppo (2007): Social regulation of gene expression in human leukocytes, Genome Biology 2007 8:R189. n = 14

  7. Leffa, Torres, Rohde (2018): A Review on the Role of Inflammation in Attention-Deficit/Hyperactivity Disorder. Neuroimmunomodulation. 2018;25(5-6):328-333. doi: 10.1159/000489635.

  8. Réus, Fries, Stertz, Badawy, Passos, Barichello, Kapczinski, Quevedo (2015): The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders, Neuroscience, Volume 300, 2015, Pages 141-154, ISSN 0306-4522, https://doi.org/10.1016/j.neuroscience.2015.05.018.

  9. Allan, Rothwell (2001): Cytokines and acute neurodegeneration. Nature Reviews Neuroscience 2, 734–744, 2001

  10. Hassan, Noreen, Castro-Gomes, Mohammadzai, Batista Teixeira da Rocha, Landeira-Fernandez (2016): Association of Oxidative Stress with Psychiatric Disorders. Current Pharmaceutical Design, Volume 22, Number 20, 2016, pp. 2960-2974 15

  11. Sen, Duman, Sanacora (2008): Serum Brain-Derived Neurotrophic Factor, Depression, and Antidepressant Medications: Meta-Analyses and Implications. Biological Psychiatry, Volume 64, Issue 6, 2008, Pages 527-532, ISSN 0006-3223, https://doi.org/10.1016/j.biopsych.2008.05.005.

  12. Pollak, Drndarski, Stone, David, McGuire, Abbott (2018): The blood–brain barrier in psychosis, The Lancet Psychiatry, Volume 5, Issue 1, 2018, Pages 79-92, ISSN 2215-0366, https://doi.org/10.1016/S2215-0366(17)30293-6.

  13. Kronfol, Remick (2000): Cytokines and the Brain: Implications for Clinical Psychiatry. American Journal of Psychiatry 2000 157:5, 683-694

  14. Miller, Raison (2016): The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature Rev Immunol 2016; 16: 22-34

  15. Dunn (2006): Effects of cytokines and infections on brain neurochemistry. Clin Neurosci Res. 2006 Aug;6(1-2):52-68.

  16. Felger (2018): Imaging the Role of Inflammation in Mood and Anxiety-related Disorders, Curr Neuropharmacol. 2018 Jun; 16(5): 533–558. doi: 10.2174/1570159X15666171123201142

  17. Felger, Miller (2012): Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front Neuroendocrinol. 2012 Aug;33(3):315-27. doi: 10.1016/j.yfrne.2012.09.003.

  18. Goldsmith, Haroon, Woolwine, Jung, Wommack, Harvey, Treadway, Felger, Miller (2016): Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder. Brain Behav Immun. 2016 Aug;56:281-8. doi: 10.1016/j.bbi.2016.03.025.

  19. Eisenberger, Berkman, Inagaki, Rameson, Mashal, Irwin (2010): Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry. 2010 Oct 15;68(8):748-54. doi: 10.1016/j.biopsych.2010.06.010.

  20. Pelsser, Buitelaar, Savelkoul (2009): ADHD as a (non) allergic hypersensitivity disorder: A hypothesis, Pediatric Allergy and Immunology, Volume 20, Issue 2, https://doi.org/10.1111/j.1399-3038.2008.00749.x

  21. Yukawa, Iso, Tanaka, Tsubota, Owada-Makabe, Bai, Takeda, Akira, Maeda (2005): Down-regulation of dopamine transporter and abnormal behavior in STAT6-deficient mice. International Journal of Molecular Medicine 15, no. 5 (2005): 819-825. https://doi.org/10.3892/ijmm.15.5.819

  22. Besser, Ganor, Levite (2005): Dopamine by itself activates either D2, D3 or D1/D5 dopaminergic receptors in normal human T-cells and triggers the selective secretion of either IL-10, TNFα or both, Journal of Neuroimmunology, Volume 169, Issues 1–2, 2005, Pages 161-171, ISSN 0165-5728, https://doi.org/10.1016/j.jneuroim.2005.07.013.

  23. Felger (2017): The Role of Dopamine in Inflammation-Associated Depression: Mechanisms and Therapeutic Implications. Curr Top Behav Neurosci. 2017;31:199-219. doi: 10.1007/7854_2016_13.

  24. Miller AH, Jones, Drake, Tian, Unger, Pagnoni (2014): Decreased Basal Ganglia Activation in Subjects with Chronic Fatigue Syndrome: Association with Symptoms of Fatigue. PLoS ONE 9(5): e98156. https://doi.org/10.1371/journal.pone.0098156

  25. Felger, Li, Haroon, Woolwine, Jung, Hu, Miller (2016): Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. Molecular Psychiatry volume 21, pages 1358–1365, 2016

  26. Neurauter, Schröcksnadel, Scholl-Bürgi, Sperner-Unterweger, Schubert, Ledochowski, Fuchs (2008): Chronic immune stimulation correlates with reduced phenylalanine turnover. Curr Drug Metab. 2008 Sep;9(7):622-7.

  27. Haroon, Raison, Miller (2012): Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 2012 Jan;37(1):137-62. doi: 10.1038/npp.2011.205.

  28. Cunnington, Channon (2010): Tetrahydrobiopterin: pleiotropic roles in cardiovascular pathophysiology Heart 2010;96:1872-1877.

  29. Xia, Tsai, Berka, Zweier (1998): Superoxide Generation from Endothelial Nitric-oxide Synthase A Ca2+/CALMODULIN-DEPENDENT AND TETRAHYDROBIOPTERIN REGULATORY PROCESS.The Journal of Biological Chemistry 273, 25804-25808.1998, doi: 10.1074/jbc.273.40.25804

  30. Kitagami, Yamada, Miura, Hashimoto, Nabeshima, Ohta (2003): Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood–brain barrier, Brain Research, Volume 978, Issues 1–2, 2003, Pages 104-114, ISSN 0006-8993, https://doi.org/10.1016/S0006-8993(03)02776-8.

  31. Li, Knowlton, Woodward, Habecker (2003): Regulation of noradrenergic function by inflammatory cytokines and depolarization. Journal of Neurochemistry, 86: 774-783. doi:10.1046/j.1471-4159.2003.01890.x

  32. Abreu, Llorente, Hernández, González (1994): Interleukin-1 beta stimulates tyrosine hydroxylase activity in the median eminence. Neuroreport. 1994 Jun 27;5(11):1356-8.

  33. Wikipedia: VMAT

  34. Morón, Zakharova, Ferrer, Merrill, Hope, Lafer, Lin, Wang, Javitch, Galli, Shippenberg (2003): Mitogen-Activated Protein Kinase Regulates Dopamine Transporter Surface Expression and Dopamine Transport Capacity. Journal of Neuroscience 17 September 2003, 23 (24) 8480-8488; DOI: https://doi.org/10.1523/JNEUROSCI.23-24-08480.2003

  35. Gelman, Spencer, HolzerI, Soukup (2006): Abnormal Striatal Dopaminergic Synapses in National NeuroAIDS Tissue Consortium Subjects with HIV Encephalitis, Journal of Neuroimmune Pharmacology, December 2006, Volume 1, Issue 4, pp 410–420

  36. Ferris, Mactutus, Booze (2008): Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: current status of dopamine system vulnerability in NeuroAIDS. Neurosci Biobehav Rev 32(5):883–909

  37. Felger, Mun, Kimmel, Nye, Drake, Hernandez, Freeman, Rye, Goodman, Howell, Miller (2013): Chronic Interferon-α Decreases Dopamine 2 Receptor Binding and Striatal Dopamine Release in Association with Anhedonia-Like Behavior in Nonhuman Primates, Neuropsychopharmacology volume 38, pages 2179–2187, 2013, n = 8

  38. Zhu, Blakely, Hewlett (2006): The Proinflammatory Cytokines Interleukin-1beta and Tumor Necrosis Factor-Alpha Activate Serotonin Transporters. Neuropsychopharmacologyvolume 31, pages2121–2131, 2006

  39. Zhu, Carneiro, Dostmann, Hewlett, Blakely (2005): p38 MAPK Activation Elevates Serotonin Transport Activity via a Trafficking-independent, Protein Phosphatase 2A-dependent Process. The Journal of Biological Chemistry 280, 15649-15658. doi: 10.1074/jbc.M410858200

  40. Aarsland, Landaas, Hegvik, Ulvik, Halmøy, Ueland, Haavik (2015): Serum concentrations of kynurenines in adult patients with attention-deficit hyperactivity disorder (ADHD): a case-control study. Behav Brain Funct. 2015 Nov 5;11(1):36. doi: 10.1186/s12993-015-0080-x.

  41. Oades, Dauvermann, Schimmelmann, Schwarz, Myint (2010): Attention-deficit hyperactivity disorder (ADHD) and glial integrity: S100B, cytokines and kynurenine metabolism–effects of medication. Behav Brain Funct. 2010 May 28;6:29. doi: 10.1186/1744-9081-6-29.

  42. Zhu, Lindler, Owens, Daws, Blakely, Hewlett (2010): Interleukin-1 Receptor Activation by Systemic Lipopolysaccharide Induces Behavioral Despair Linked to MAPK Regulation of CNS Serotonin Transporters. Neuropsychopharmacology volume 35, pages 2510–2520, 2010