Lecture 4

What are the most common neurotransmitters in the brain?

Glutamate is present in approximately 80% of synapses (most common)

GABA in approximately 20% of synapses

acetylcholine in approximately 5% of synapses

dopamine, serotonin, and noradrenaline each in approximately 1% or less, although they are still very important for brain function.

How is glutamate synthesised?

Glutamate is taken up and recycled into astrocytes, where it is broken down into glutamine. Glutamine then leaves the astrocyte and enters the presynaptic neuron via transporters, where it is converted back into glutamate by the enzyme glutaminase.

What is the role of glutamate?

Glutamate is the main excitatory neurotransmitter in the brain, with glutamatergic neurons present in many brain regions. It also plays a role in neurological diseases including epilepsy, depression, schizophrenia, Alzheimer's disease, and ALS, which is thought to be due to glutamate excitotoxicity.

What types of glutamate receptors are there?

Glutamate receptors include ion channels and G-protein coupled receptors (GPCRs).

What are the ionotropic glutamate receptors and how do they work?

Ionotropic glutamate receptors are excitatory receptors whose activation causes depolarisation of the postsynaptic cell, leading to an influx of Na+ and/or Ca2+. They include AMPA receptors (Na+ channel), NMDA receptors (Na+ and Ca2+ channel), and kainate receptors (Na+ channel). Most drugs that interact with glutamate receptors target glutamate ion channels.

What are the metabotropic glutamate receptors (mGluRs)?

There are eight metabotropic glutamate receptors divided into three functional groups: Group 1 (Gq-coupled: mGlu1 and mGlu5), Group 2 (Gi-coupled: mGlu2 and mGlu3), and Group 3 (Gi-coupled: mGlu4, mGlu6, mGlu7, and mGlu8).

What are the functions and therapeutic potential of AMPA receptors?

AMPA receptors are the most common receptors in the CNS and are ionotropic glutamate receptors found on both postsynaptic and presynaptic neurons. They are involved in learning and memory. AMPA positive allosteric modulators (ampakines) are being investigated as cognitive-enhancing (nootropic) drugs and for treating neurological disorders by stimulating AMPA receptor activation to promote LTP and memory, while potentially reducing the side effects of AMPA agonists.

What are the functions of kainate receptors?

Kainate receptors are found on both postsynaptic and presynaptic neurons. On postsynaptic neurons they mediate excitatory neurotransmission by depolarising the neuron when activated, contributing to learning and memory. On presynaptic GABAergic neurons they produce a net inhibitory effect by increasing the release of inhibitory neurotransmitter. High levels of activation are involved in seizures, and kainic acid from seaweed can cause seizures and is used in epilepsy research.

Why is kainic acid significant?

Kainic acid, produced by red algae, is approximately 30 times more toxic than glutamate. High levels of glutamate receptor activation can overstimulate the brain and disrupt normal neuronal communication.

How do NMDA receptors contribute to synaptic plasticity and LTP?

NMDA receptors play a critical role in synaptic plasticity and long-term potentiation (LTP). Both glutamate and glycine must bind to the receptor, and the postsynaptic membrane must be sufficiently depolarised to expel the Mg2+ ion blocking the channel pore. This allows Ca2+ and Na+ to enter the cell. The influx of Ca2+ promotes the synthesis of additional AMPA receptors, making the postsynaptic neuron more sensitive to glutamate so that less glutamate is required to excite the neuron, forming the molecular basis of LTP.

What are the effects of NMDA receptor antagonists?

NMDA receptor antagonists can cause amnesia and are commonly used as anaesthetic drugs.

What are the actions and clinical uses of ketamine?

Ketamine is a non-competitive NMDA receptor antagonist. At high doses it causes anaesthesia and amnesia by temporarily blocking LTP. At moderate doses it acts as an antidepressant and is FDA approved for treatment-resistant depression.

What are the actions and clinical uses of memantine?

Memantine is a non-competitive NMDA receptor antagonist used to treat moderate to severe Alzheimer's disease. It is thought to reduce excitotoxicity that may damage neurons. It produces modest but significant improvements in cognition, treats symptoms without slowing disease progression, has an effect size of 0.27 for improving cognition, and has a low abuse potential due to its exceptionally long half-life of 60–80 hours.

What is nitrous oxide (NO) and how does it act on NMDA receptors?

Nitrous oxide (NO) is a non-competitive NMDA receptor antagonist that sits in the channel where Mg2+ would normally sit, preventing the NMDA receptor from opening

• causes sedation but not general anaesthesia

• can produce mild amnesia

• also a weak AMPA antagonist.

What is the excitotoxicity theory of glutamate?

The excitotoxicity theory states that excessive glutamate signalling overactivates glutamate receptors, causing excessive Ca2+ influx that triggers neuronal damage and cell death. Glutamate can produce lesions when injected into any brain region, and neurons in tissue culture die within a few hours of exposure to high glutamate concentrations.

What is domoic acid and what are its effects?

Domoic acid is a toxic amino acid produced by red algae that has high specificity for AMPA and kainate glutamate ion channels. It bioaccumulates in certain shellfish and has been associated with mental confusion and short-term memory loss.

How does excitotoxicity contribute to disease?

• excitotoxicity is believed to be a factor in amyotrophic lateral sclerosis (ALS) and Lou Gehrig’s disease

• can occur in epilepsy if convulsions are ongoing

• excitotoxicity can occur in ischemic stroke: partial oxygen deprivation leads to massive depolarisation of neurons as ion pumps lack ATP to maintain membrane potential → depolarisation results in high levels of glutamate release

What is clinical efficacy?

Clinical efficacy is the extent to which a drug produces the desired therapeutic effect under ideal, controlled conditions such as clinical trials.

What are measures of clinical efficacy?

Measures of clinical efficacy include years of life added, remission, odds ratio, rate ratio, standardised mean difference (SMD), and Hedges' g.

What is the standardised mean difference (SMD)?

The standardised mean difference (SMD) is a measure of effect size that expresses the difference between the treatment and control group means in units of standard deviation, allowing comparisons across studies that use different measurement scales.

What is an odds ratio (OR)?

An odds ratio (OR) is a measure of association that compares the odds of an outcome occurring in the treatment group with the odds of it occurring in the control group. An OR greater than 1 indicates higher odds, an OR less than 1 indicates lower odds, and an OR equal to 1 indicates no difference between groups.

What is a nootropic drug?

A nootropic drug is a cognition-enhancing drug.

What is piracetam and what evidence supports its use?

Piracetam is an AMPA positive allosteric modulator (PAM) investigated as a nootropic drug. A meta-analysis reported an effect size of 0.75 for memory enhancement, but the improvement was not statistically significant compared with placebo