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Glutamate

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Glutamate

Glutamate is an excitatory neurotransmitter.
Glutamate neurons are mainly located as interneurons in the cerebral cortex. Glutamate provides 70 % of the brain’s excitatory impulses and, together with its inhibitory counterpart GABA, regulates the activity of almost all brain regions.1

Glutamine is a metabolite (degradation substance) of glutamate.

1. Glutamate receptors

  • NMDA (N-methyl-D-aspartate) receptors (ionotropic)
    • Consists of four to five subunits that are expressed at different times2
      • Grin1
      • Grin2a
      • Grin2b
      • Grin2c
      • Grin2d
    • Antagonists
      • Amantadine3
      • Ketamine3
    • Agonists
      • Glycine
  • AMPA receptors (ionotropic)
    • Agonists
      • Are said to have an antidepressant effect3
    • Fast glutamatergic transmission is mainly mediated by AMPA receptors4
  • Kainate receptors (ion-selective), less relevant
  • Quisqualate receptors (mGluR1-8) (metabotropic), less relevant
    • MGluRs modulate the response to ionotropic glutamate receptors and that of other transmitters, including dopamine, serotonin and GABA4

NMDA and AMPA receptors are blocked by Mg++ under resting conditions.1

Agonists:

  • Glycine
    Glycine
  • D-Serine
  • Pregnenolone sulfate
  • DHEA sulphate
    • Different: DHEA and DHEAS are glutamate NMDA and glutamate AMPA antagonists5

2. Effect on glutamate

The effect of glutamate on NMDA receptors is mediated by

  • Noradrenaline and
  • Vasopressin

increased. Noradrenaline and vasopressin have a synergistic effect on glutamate.67 As noradrenaline and vasopressin are both increased by stress, stress increases glutamate.

3. Effect of glutamate (on the HPA axis)

Glutamate influences the secretion of the hormones HGH and ACTH from the pituitary gland.1

Stress increases the release of dopamine in the mPFC, lateral PFC (lPFC) and nucleus accumbens (but not in the perirhinal or cingulate cortex, lateral basolateral amygdala, anterior ventromedial striatum or posterior dorsolateral striatum) and serotonin in the mPFC. A glutamate-NMDA-glycine receptor antagonist reduces the release of dopamine during stress in the mPFC and lPFC, while the stress-induced increases in dopamine in the nucleus accumbens, serotonin in the mPFC and cortisol remain undiminished. Thus, glutamate mediates the stress-induced increase in dopamine in the PFC.8

4. Regulatory range of glutamate

Glutamate is required for

  • Processing of sensory perceptions
  • Execution of movement
  • Higher brain functions
    • Learning
    • Memory
  • Appetite regulation
    • Appetite enhancing
    • Anti-saturating
  • Opposite of fear
    • Low glutamate levels and high GABA levels in the ACC correlate with a high harm-avoidance value9

Excessive glutamate levels have a neurotoxic effect by destroying the glutamate receptors and nerve cells. In this way, glutamate is involved in neurodegenerative diseases such as1

  • Epilepsy
  • Paralysis after a stroke
  • Parkinson’s disease
  • Alzheimer’s disease

5. Glutamate for various disorders

5.1. Depression and glutamate

Glutamate antagonists have an antidepressant effect

  • Amantadine10
  • Lamotrigine10
  • Ketamine10
  • Riluzole10 (Rilutek)
  • Memantine

as well as the partial glutamate antagonist

  • D-cycloserine (antibiotic, 500 mg/day)10

In our understanding, a distinction must be made between melancholic (endogenous) depression and atypical depression. Since melancholic depression (such as ADHD-I) is typically characterized by an excessive cortisol response to acute stress, while atypical depression (such as ADHD-HI) often shows a flattened cortisol stress response, we hypothesize that there could be corresponding type-specific GABA/glutamate imbalances at the same time. Melancholic depression and ADHD-I could, according to our hypothesis, correlate with a GABA deficiency and glutamate excess, while atypical depression and ADHD-HI could be characterized by a GABA excess and glutamate deficiency.

5.2. Schizophrenia and glutamate

One study discusses the treatment of schizophrenia with

  • D-cycloserine (antibiotic, 500 mg/day)10
  • Glycine
  • D-Serine

5.3. Glutamate for ADHD

5.3.1. Glutamate-glutamine to creatinine ratio

5.3.1.1. Reduced glutamate-glutamine to creatinine ratio in ADHD in the cingulum

One study found a reduced glutamate-glutamine to creatinine ratio in ADHD in the cingulum.11

5.3.1.2. Increased glutamate-glutamine to creatinine ratio in ADHD-HI compared to ADHD-I

Two studies found a higher glutamate/glutamine to creatinine ratio in ADHD-HI than in ADHD-I.1213
Mice with deactivated creatinine transporter in dopaminergic nerve cells showed hyperactivity.14

5.3.2. Glutamate-glutamine to myo-inositol ratio

Children with ADHD-HI showed a significantly increased ratio of glutamate+glutamine to myo-inositol-containing compounds in the anterior cingulate cortex.15

5.3.3. Imbalance of the glutamate/GABA balance

Further reports indicate an imbalance of the glutamate/GABA balance in ADHD.16
Children with ADHD were found to have increased glutamate levels and unchanged GABA levels in the brain. In contrast, adults showed a normalized glutamate level and a reduced GABA level.17

Fundamentally, research suffers from the fact that too many studies do not record separate scores for ADHD-I and ADHD-HI subtypes.

5.3.4. Elevated anandamide levels alter glutamate transmission in the striatum

Increased AEA levels (= anandamide = N-arachidonoylethanolamine) have been found in ADHD sufferers due to a biochemical defect in the breakdown of AEA. This selectively alters the synaptic glutamate transmission in the striatum, but not the GABA transmission in the striatum.
This could cause an imbalance between exitatory and inhibitory neurotransmission in the striatum. In ADHD, the increase in AEA concentrations appears to be caused by an inhibition of FAAH. FAAH is an enzyme that is essential for the degradation of AEA. Interestingly, this change was replicated in the mouse striatum after stimulation of the dopamine D2 receptors, but not the D1 receptors.1819

5.3.5. Glutamate and glutamine levels in basal ganglia in ADHD

A study found reduced glutamate and glutamine levels in the basal ganglia in both unmedicated and medicated adults with ADHD. In untreated sufferers, glutamate/glutamine deficiency in the basal ganglia correlated with ADHD symptom severity. No changes in glutamate or glutamine were found in the parietal cortex. 20

In children with ADHD, one study found no change in glutamate in the left striatum in ADHD21, another study found increased glutamate levels in the frontal striatum.22

5.3.6. Glutamate levels in the right PFC in ADHD

One study reports reduced glutamate levels in the right PFC in a subgroup of children with ADHD.21 The study further reported a decoupling of executive functions from glutamate changes in these children compared to non-affected children. Another study reported increased glutamate levels in the dorsolateral PFC in children with ADHD.22

5.3.7. Increased glutamate levels in the anterior cingulate cortex

One study reports reduced glutamate levels in the right PFC in a subgroup of children with ADHD.21 The study further reported a decoupling of executive functions from glutamate changes in these children compared to non-affected children. Another study reported increased glutamate levels in the dorsolateral PFC in children with ADHD.22

5.3.8. Reduced cyclin-dependent kinase 5 (CDK5) blood levels

Children with ADHD were found to have statistically significantly lower CDK5 blood levels23

5.3.9. Elevated MAP2, GKAP and PSD95 blood levels

One study found siginificantly elevated MAP2, GKAP and PSD95 blood levels in children with ADHD.23


  1. Bieger (2011): Neurostressguide, Seite 18

  2. Graw (2015): Genetik, Seite 689

  3. Müller, Strobach (2005): Depressionen: Krankheitsbild und Therapie; Seite 53

  4. De Blasi, Conn, Pin, Nicoletti (2001): Molecular determinants of metabotropic glutamate receptor signaling, Trends in Pharmacological Sciences, Volume 22, Issue 3, 2001, Pages 114-120, ISSN 0165-6147, https://doi.org/10.1016/S0165-6147(00)01635-7.

  5. Kimonides, Khatibi, Svendsen, Sofroniew, Herbert (1998): Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc Natl Acad Sci U S A. 1998 Feb 17; 95(4): 1852–1857. doi: 10.1073/pnas.95.4.1852. PMCID: PMC19202. PMID: 9465106. Neurobiology

  6. Teicher, Andersen, Polcari, Anderson, Navalta (2002): Developmental neurobiology of childhood stress and trauma. Psychiatr Clin North Am. 2002 Jun;25(2):397-426, vii-viii. doi: 10.1016/s0193-953x(01)00003-x. PMID: 12136507. REVIEW

  7. Joëls, Urban (1984): Arginine-vasopressin enhances the responses of lateral septal neurons in the rat to excitatory amino acids and fimbria-fornix stimuli. Brain Res. 1984 Oct 8;311(2):201-9. doi: 10.1016/0006-8993(84)90084-2. PMID: 6149788.

  8. Goldstein, Rasmusson, Bunney, Roth (1994): The NMDA glycine site antagonist (+)-HA-966 selectively regulates conditioned stress-induced metabolic activation of the mesoprefrontal cortical dopamine but not serotonin systems: a behavioral, neuroendocrine, and neurochemical study in the rat. Journal of Neuroscience 1 August 1994, 14 (8) 4937-4950; DOI: https://doi.org/10.1523/JNEUROSCI.14-08-04937.1994

  9. Kim, Kim, Cho, Song, Bae, Hong, Yoon, Lyoo, Kim (2009): Associations between anterior cingulate cortex glutamate and gamma-aminobutyric acid concentrations and the harm avoidance temperament. Neurosci Lett. 2009 Oct 23;464(2):103-7. doi: 10.1016/j.neulet.2009.07.087.

  10. Sanacora, Rothman, Mason, Krystal (2003): Clinical studies implementing glutamate neurotransmission in mood disorders. Ann N Y Acad Sci. 2003 Nov;1003:292-308. REVIEW

  11. Perlov, Philipsen, Hesslinger, Buechert, Ahrendts, Feige, Bubl, Hennig, Ebert, Tebartz van Elst (2007): Reduced cingulate glutamate/glutamine-to-creatine ratios in adult patients with attention deficit/hyperactivity disorder — a magnet resonance spectroscopy study. J Psychiatr Res. 2007 Dec;41(11):934-41.

  12. Ferreira, Palmini, Bau, Grevet, Hoefel, Rohde, Anés, Ferreira, Belmonte-de-Abreu (2009): Differentiating attention-deficit/hyperactivity disorder inattentive and combined types: a (1)H-magnetic resonance spectroscopy study of fronto-striato-thalamic regions. J Neural Transm (Vienna). 2009 May;116(5):623-9. doi: 10.1007/s00702-009-0191-3. zitiert nach Bollmann, Ghisleni, Poil, Martin, Ball, Eich-Höchli, Edden, Klaver, Michels, Brandeis, O’Gorman (2015): Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder. Transl Psychiatry. 2015 Jun 23;5:e589. doi: 10.1038/tp.2015.79.: Zusatzgrafik

  13. Sun, Jin, Zang, Zeng, Liu, Li, Seidman, Faraone, Wang (2005): Differences between attention-deficit disorder with and without hyperactivity: a 1H-magnetic resonance spectroscopy study. Brain Dev. 2005 Aug;27(5):340-4.zitiert nach Bollmann, Ghisleni, Poil, Martin, Ball, Eich-Höchli, Edden, Klaver, Michels, Brandeis, O’Gorman (2015): Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder. Transl Psychiatry. 2015 Jun 23;5:e589. doi: 10.1038/tp.2015.79.: Zusatzgrafik

  14. Abdulla, Pahlevani, Lundgren, Pennington, Udobi, Seroogy, Skelton (2019): Deletion of the Creatine Transporter (Slc6a8) in Dopaminergic Neurons Leads to Hyperactivity in Mice. J Mol Neurosci. 2019 Sep 13. doi: 10.1007/s12031-019-01405-w.

  15. Moore, Biederman, Wozniak, Mick, Aleardi, Wardrop, Dougherty, Harpold, Hammerness, Randall, Renshaw (2007): Differences in brain chemistry in children and adolescents with attention deficit hyperactivity disorder with and without comorbid bipolar disorder: a proton magnetic resonance spectroscopy study. Am J Psychiatry. 2006 Feb;163(2):316-8. doi: 10.1176/appi.ajp.163.2.316. Erratum in: Am J Psychiatry. 2007 Jan;164(1):175. PMID: 16449488; PMCID: PMC4068129. n = 30

  16. Zheng J1, Chen (2018): [Research advances in pathogenesis of attention deficit hyperactivity disorder]. [Article in Chinese] Zhongguo Dang Dai Er Ke Za Zhi. 2018 Sep;20(9):775-780.

  17. Bollmann, Ghisleni, Poil, Martin, Ball, Eich-Höchli, Edden, Klaver, Michels, Brandeis, O’Gorman (2015): Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder. Transl Psychiatry. 2015 Jun 23;5:e589. doi: 10.1038/tp.2015.79.

  18. Centonze, Battistini, Maccarrone (2008): The Endocannabinoid System in Peripheral Lymphocytes as a Mirror of Neuroinflammatory Diseases. Current Pharmaceutical Design, 2008, 14, 2370-2382 1381-6128/08

  19. Centonze, Bari, Rossi, Prosperetti, Furlan, Fezza, De Chiara, Battistini, Bernardi, Bernardini, Martino, Maccarrone (2007): The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis. Brain, Volume 130, Issue 10, October 2007, Pages 2543–2553, https://doi.org/10.1093/brain/awm160

  20. Maltezos, Horder, Coghlan, Skirrow, O’Gorman, Lavender, Mendez, Mehta, Daly, Xenitidis, Paliokosta, Spain, Pitts, Asherson, Lythgoe, Barker, Murphy (2014): Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study. Transl Psychiatry. 2014 Mar 18;4:e373. doi: 10.1038/tp.2014.11.

  21. Hai, Duffy, Lemay, Swansburg, Climie, MacMaster (2020): Neurochemical Correlates of Executive Function in Children with Attention-Deficit/Hyperactivity Disorder. J Can Acad Child Adolesc Psychiatry. 2020 Mar;29(1):15-25. Epub 2020 Mar 1. PMID: 32194648; PMCID: PMC7065568. n = 36

  22. MacMaster, Carrey, Sparkes, Kusumakar (2003): Proton spectroscopy in medication-free pediatric attention-deficit/hyperactivity disorder. Biol Psychiatry. 2003 Jan 15;53(2):184-7. doi: 10.1016/s0006-3223(02)01401-4. PMID: 12547476. n = 18

  23. Ulu E, Demirci E, Sener EF, Özmen S, Gul MK, Tahtasakal R, Dal F (2024): Role of Glutamate Receptor-related Biomarkers in the Etiopathogenesis of ADHD. Clin Psychopharmacol Neurosci. 2024 Feb 29;22(1):79-86. doi: 10.9758/cpn.23.1056. PMID: 38247414; PMCID: PMC10811385.

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