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, with its inhibitory counterpart GABA, regulates the activity of almost all brain regions.¹

Glutamine is a metabolite (breakdown agent) of glutamate.

• 1. Glutamate receptors
• 2. Effect on glutamate
• 3. Effect of glutamate (on the HPA axis)
• 4. Glutamate regulatory area
• 5. Glutamate in various disorders
  • 5.1. Depression and glutamate
  • 5.2. Schizophrenia and glutamate
  • 5.3. Glutamate in ADHD
    • 5.3.1. Glutamate-Glutamine to Creatinine Ratio
      • 5.3.1.1. Decreased glutamate-glutamine to creatinine ratio in ADHD in the cingulate
      • 5.3.1.2. Increased glutamate-glutamine to creatinine ratio in ADHD-HI versus 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

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 supposed to have an antidepressant effect³
  • Fast glutamatergic transmission is mediated mainly 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 sulfate
  • Different: DHEA and DHEAS are glutamate NMDA and glutamate AMPA antagonists⁵

2. Effect on glutamate¶

The action of glutamate at NMDA receptors is mediated by

• Norepinephrine and
• Vasopressin

increased. Norepinephrine and vasopressin act synergistically on glutamate.⁶⁷ Since norepinephrine and vasopressin and 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 decreased the release of dopamine during stress in the mPFC and lPFC, whereas stress-induced increases in dopamine in the nucleus accumbens, serotonin in the mPFC, and cortisol remained unabated. Accordingly, glutamate mediates the stress-induced increase in dopamine in the PFC.⁸

4. Glutamate regulatory area¶

Glutamate is required for

• Processing of sensory perceptions
• Movement execution
• Higher brain functions
  • Learning
  • Memory
• Appetite regulation
  • Appetite enhancing
  • Anti-saturation
• Opposite of fear
  • Low glutamate levels and high GABA levels in the ACC correlate with a high harm-avoidance score⁹

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

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

5. Glutamate in 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 (like ADHD-I) is typically characterized by an exaggerated cortisol response to acute stress, whereas atypical depression (like ADHD-HI) often shows a flattened cortisol stress response, according to our hypothesis, corresponding type-specific GABA/glutamate imbalances could exist at the same time. Melancholic depression and ADHD-I could, according to our hypothesis, correlate with GABA deficiency and glutamate excess, whereas atypical depression and ADHD-HI could be characterized by GABA excess and glutamate deficiency.

5.2. Schizophrenia and glutamate¶

One study discusses the treatment of schizophreniawith

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

5.3. Glutamate in ADHD¶

5.3.1. Glutamate-Glutamine to Creatinine Ratio¶

5.3.1.1. Decreased glutamate-glutamine to creatinine ratio in ADHD in the cingulate¶

One study found a decreased glutamate-glutamine to creatinine ratio in ADHD in the cingulate.¹¹

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

Two studies found a higher glutamate/glutamine to creatinine ratio in ADHD-HI than in ADHD-I.¹²¹³
Mice with deactivated creatinine receptor in dopaminergic neurons 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¶

Other reports suggest an imbalance of 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 normalized glutamate levels and decreased GABA levels.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¶

In ADHD patients, elevated AEA levels (= anandamide = N-arachidonoylethanolamine) have been found due to a biochemical defect in the degradation of AEA. This selectively alters synaptic glutamate transmission in the striatum, but not 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 inhibition of FAAH. FAAH is an enzyme that is instrumental in the degradation of AEA. Interestingly, this change was replicated in the mouse striatum after stimulation of dopamine D2 receptors but not D1 receptors.¹⁸¹⁹

5.3.5. Glutamate and glutamine levels in basal ganglia in ADHD¶

In both never-medicated and medicated adult ADHD sufferers, one study found decreased glutamate and glutamine levels in the basal ganglia. In untreated affected individuals, 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 an uncoupling of executive functions from glutamate changes in these children compared with unaffected individuals. 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 decreased glutamate levels in the right PFC in a subgroup of children with ADHD.²¹ The study further reported an uncoupling of executive functions from glutamate changes in these children compared with unaffected individuals. Another study reported increased glutamate levels in the dorsolateral PFC in children with ADHD.²²