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
• 2. Effect on glutamate
• 3. Effect of glutamate (on the HPA axis)
• 4. Regulatory range of glutamate
• 5. Glutamate for various disorders
  • 5.1. Depression and glutamate
  • 5.2. Schizophrenia and glutamate
  • 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
      • 5.3.1.2. Increased glutamate-glutamine to creatinine ratio in ADHD-HI compared to ADHD-I
    • 5.3.2. Glutamate-glutamine to myo-inositol ratio
    • 5.3.3. Imbalance of the glutamate/GABA balance
    • 5.3.4. Elevated anandamide levels alter glutamate transmission in the striatum
    • 5.3.5. Glutamate and glutamine levels in basal ganglia in ADHD
    • 5.3.6. Glutamate levels in the right PFC in ADHD
    • 5.3.7. Increased glutamate levels in the anterior cingulate cortex
    • 5.3.8. Reduced cyclin-dependent kinase 5 (CDK5) blood levels
    • 5.3.9. Elevated MAP2, GKAP and PSD95 blood levels

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 decreased 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 suggest 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¶

Elevated AEA levels (= anandamide = N-arachidonoylethanolamine) have been found in people with ADHD due to a biochemical defect in the degradation 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 never-medicated and medicated adult people with ADHD. In untreated persons with ADHD, 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 frontal-striatal.²²

5.3.6. Glutamate levels in the right PFC in ADHD¶

One study reports decreased 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 individuals. Another study reported increased glutamate levels in children with ADHD in the dorsolateral PFC.²²

A meta-analysis of = 33 studies with 874 people with ADHD found that the right mPFC of children with ADHD had higher concentrations of a composite of glutamate and glutamine (Effect size (SMD): 0.53)²³

5.3.7. Increased glutamate levels in the anterior cingulate cortex¶

One study reports decreased 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 individuals. Another study reported increased glutamate levels in children with ADHD in the dorsolateral PFC.²²

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

Children with ADHD were found to have statistically significantly lower CDK5 blood levels²⁴

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.²⁴