L1 Clinical Pharmacology Neurotransmitters

Overview

This lecture covers how neurons communicate at the synapse and how that process is targeted therapeutically. It moves from the basic definition and criteria for a neurotransmitter, through the two core excitatory/inhibitory systems (glutamate/AMPA/NMDA and GABA), into how excitatory signalling underlies long-term potentiation (LTP) and learning, then surveys the classes of drugs that manipulate neurotransmission (agonists, antagonists, reuptake inhibitors, releasing agents, enzyme inhibitors, positive allosteric modulators, ion channel blockers) with worked examples (ketamine, SSRIs/SNRIs/NDRIs, amphetamines, MAO inhibitors, propofol, lidocaine). The second half shifts to receptor biology proper: how G protein-coupled receptors (GPCRs) are built and activated compared with ligand-gated ion channels, the three main Gα subtypes (Gs, Gi, Gq) and their downstream signalling, and worked GPCR examples (dopamine D1/D2, muscarinic M3, opioid receptors) linking receptor type to a clinical or physiological effect.

Synaptic transmission: the basics

• A synapse is the space between a presynaptic and postsynaptic neuron across which neurotransmitters act.
• Synaptic neurotransmission proceeds in order:
  1. Depolarisation of the presynaptic neuron — influx of Na+
  2. Influx of Ca2+ via voltage-dependent Ca2+ channels
  3. Vesicle mobilisation, fusion, and release
  4. Receptor activation
  5. Removal of neurotransmitter from the cleft — by transporter uptake or enzyme metabolism
• A chemical only qualifies as a neurotransmitter if all three criteria hold:
  1. It is present in the presynaptic terminal.
  2. It is released from that terminal as a result of presynaptic depolarisation.
  3. Experimental application of the chemical to the postsynaptic neuron evokes the same effect as presynaptic release.

Most common neurotransmitters in the brain, with their prevalence as given on the slides:

• Glutamate — present in 90% of excitatory synapses
• GABA — present in 30% of inhibitory synapses
• Acetylcholine — present in 5% of neurons
• Dopamine, serotonin, noradrenaline — less prevalent but very important for brain function

The brain is described as an electrochemical system: neurotransmitter binding and receptor activation cause depolarisation or hyperpolarisation, generating the electrical signals that many clinical tests (e.g. EEG) measure. An epileptic EEG shows more frequent, higher-amplitude spike-and-wave discharges than a normal EEG’s background activity. Neuropharmacological interventions work by mimicking, inhibiting, or releasing neurotransmitters.

Physiological example — fight or flight: noradrenaline, dopamine, and adrenaline are released during the fight-or-flight response, increasing heart rate, blood pressure, and lung capacity. Adrenaline binds Beta-1 G-protein-coupled receptors in the heart and blood vessels; noradrenaline binds alpha-2 receptors in the brain to enhance cognition.

Excitatory neurotransmission (glutamate)

Glutamate activates AMPA and NMDA receptors, found on both postsynaptic and presynaptic neurons.

• AMPA receptor: a ligand-gated ion channel. Glutamate binding lets Na+ flow into the postsynaptic neuron directly, making the membrane potential more positive and driving depolarisation. It is the faster of the two receptors.
• NMDA receptor: slower to activate. At rest, a Mg2+ ion sits lodged in the channel pore, held there by attraction to the negative intracellular environment, and blocks ion flow. Once the membrane depolarises (e.g. via AMPA activation), Mg2+ is no longer electrostatically held in the channel and leaves, allowing Na+ and Ca2+ to enter.

Net effect: sodium influx makes the membrane potential more positive, the neuron depolarises, and the postsynaptic neuron in turn releases neurotransmitter from its own terminal.

Functionally, excitatory transmission:

• Transmits sensory information (visual, auditory, etc.) — sensory neurons (eye/ear/olfactory) release excitatory neurotransmitters, perceived as sensation.
• Plays a key role in synaptic plasticity via long-term potentiation (see below); AMPA and NMDA receptor activation both drive LTP.

Inhibitory neurotransmission (GABA)

GABA is the main inhibitory neurotransmitter in the brain. It is synthesised from glutamic acid by the enzyme glutamic acid decarboxylase (GAD).

• GABA_A receptor: a Cl⁻ ion channel. Direct opening causes Cl⁻ influx, hyperpolarising the cell and preventing depolarisation. Activates in milliseconds.
• GABA_B receptor: a Gi-coupled GPCR. Also inhibits the action potential, but activates over roughly 100 ms — slower but the mechanism differs from GABA_A’s direct channel gating.

	GABA_A	GABA_B
Receptor type	Cl⁻ ion channel	Gi-coupled GPCR
Activation time	Milliseconds	~100 milliseconds
Effect	Inhibition of action potential	Inhibition of action potential

Very high levels of GABA can cause coma and death.

Important

AMPA (Na+ influx, excitatory) vs GABA_A (Cl⁻ influx, inhibitory) is the core push-pull of fast synaptic signalling: AMPA activation makes the membrane more positive and drives an action potential; GABA_A activation makes it more negative and inhibits one.

Long-term potentiation (LTP) and learning

• LTP allows neurons to fire with a lower stimulus threshold — i.e. a stronger, more easily activated connection.
• LTP occurs after a large release of glutamate activates AMPA receptors and depolarises the neuron; a single very strong stimulus (tetanus) produces a larger, more sustained excitatory postsynaptic potential (EPSP) to the same subsequent stimulus than before the tetanus.
• Molecular mechanism: calcium influx (via NMDA receptors, once Mg2+ block is relieved by depolarisation) activates calcium/calmodulin kinase II and other protein kinases, which promote insertion of additional AMPA receptors into the postsynaptic membrane from an internal pool. The cell becomes more sensitive to glutamate, so less glutamate is needed to excite it.
• LTP is input-specific: only the pathway that was actively stimulated has its synapse strengthened; an inactive pathway onto the same neuron is not strengthened.
• LTP is theorised to be the primary molecular basis of learning. Supporting evidence given: NMDA antagonists (which block LTP) can cause amnesia and are used clinically as anaesthetics.

Neurotransmitters in psychiatric disease

The slides link specific neurotransmitter abnormalities to specific disorders:

• Epilepsy: too much excitatory activity from glutamate.
• Anxiety: high levels of noradrenaline, leading to an elevated fight-or-flight response.
• Parkinson’s disease: dopamine-releasing neurons die; lack of dopamine production leads to difficulty moving.
• Depression: low levels of several neurotransmitters, resulting in depressed mood.
• Schizophrenia: too much production of dopamine, resulting in hallucinations.
• ADHD: low levels of dopamine, leading to decreased cognition.

Classes of neuropharmacological drugs

Six mechanisms by which drugs modulate neurotransmission, each matched on the slides to an example disorder where NT levels/activity are too low (except antagonists):

• Agonists — activate receptors when NT levels are low (e.g. Parkinson’s). All endogenous neurotransmitters are themselves agonists.
• Antagonists — prevent NTs from activating receptors (e.g. schizophrenia, where dopamine is in excess).
• Enzyme inhibitors — increase NT levels when too low, by blocking the enzyme that breaks the NT down (e.g. Parkinson’s).
• Reuptake inhibitors — increase NT levels when too low, by blocking removal from the synapse (e.g. depression).
• Releasing agents — increase NT levels when too low (e.g. ADHD).
• Positive allosteric modulators (PAMs) — increase receptor activation when NT levels are too low (e.g. anxiety).

Receptor superfamilies these drugs act on:

• Ligand-gated ion channels (ionotropic receptors): ion binds receptor directly → ion flow → hyperpolarisation or depolarisation → cellular effects. Timescale: milliseconds. Example: nicotinic ACh receptor.
• G protein-coupled receptors (metabotropic): ligand binds receptor coupled to a G protein and effector → change in excitability and/or second messengers (Ca2+ release, protein phosphorylation, other) → cellular effects. Timescale: seconds. Example: muscarinic ACh receptor.

Worked drug examples

Ketamine (NMDA antagonist):

• Very high doses: anaesthesia and amnesia, via temporarily blocking LTP.
• High doses (ketamine or PCP): psychotic symptoms, with deficits in working memory and learning.
• Moderate doses: effective antidepressant properties, through an unknown mechanism — current theory is disinhibition of GABAergic neurons, producing net excitation that increases LTP and BDNF production.
• Moderate–high doses: analgesia, through inhibition of pain signals.

Reuptake inhibitors: transporters normally clear NTs from the synapse back into the presynaptic neuron, preventing further receptor activation. Reuptake inhibitors bind transporters and stop this, boosting existing connections by slowing NT clearance and increasing receptor activation.

• SSRIs (selective serotonin reuptake inhibitors) — depression. Example: escitalopram.
• SNRIs (serotonin and norepinephrine reuptake inhibitors). Example: venlafaxine.
• NDRIs (norepinephrine and dopamine reuptake inhibitors) — ADHD. Example: methylphenidate (Ritalin).

Releasing agents: the most common are amphetamines. They bind reuptake transporters and vesicle storage proteins, causing neurotransmitter to build up in the cytoplasm; transporters then reverse direction, so neurotransmitter accumulates in the synapse and drives a high level of receptor activation.

Enzyme inhibitors: bind enzymes and stop them working, causing endogenous agonist to build up and increasing receptor activation.

• Monoamine oxidase (MAO) inhibitors — used to treat Parkinson’s disease and depression. MAO normally converts dopamine to 3,4-dihydroxyphenylacetaldehyde; inhibiting it lets dopamine accumulate.
• (Other enzyme-inhibitor drug classes noted for context, not neuropharmacological: protease inhibitors as antiviral drugs; inhibitors of cell-replication enzymes as anti-cancer drugs.)
• Some drugs inhibit liver enzymes as an unwanted side effect unrelated to their primary action — e.g. fluoxetine and bupropion inhibit CYP3A4.

Positive allosteric modulators (PAMs): bind the receptor at a site separate from the agonist site. A PAM binding alone (without agonist present) has no efficacy; a PAM binding while agonist is also bound produces very high efficacy. PAMs have the advantage of boosting endogenous neurotransmission rather than replacing it. Examples: alcohol and benzodiazepines (e.g. diazepam).

• Propofol is a PAM for the GABA_A receptor: it increases the frequency of GABA_A channel opening, increasing Cl⁻ influx, making the membrane potential more negative, and decreasing neurotransmission. Commonly used to induce anaesthesia.

Ion channel blockers: lidocaine blocks Na+ ion channels in axons, so sodium cannot enter, the membrane cannot become more positive, and depolarisation does not occur. Without depolarisation there is no neurotransmitter release and no pain signal transmission — the basis of its local anaesthetic effect.

Lecture 1 (part 1) summary, as given

• Glutamate and GABA form the basis of neural connectivity, increasing and decreasing neuron depolarisation respectively.
• Neuromodulators (dopamine, noradrenaline, serotonin) modulate neurotransmission to increase or decrease perception, thought, and emotion.
• Neuropharmacology drugs act therapeutically via: agonists, antagonists, releasing agents, reuptake inhibitors, positive allosteric modulators, and ion channel blockers.

Self-test

1. State the three criteria that define a chemical as a neurotransmitter.
2. List, in order, the five steps of synaptic neurotransmission from presynaptic depolarisation to neurotransmitter removal.
3. Describe how AMPA receptor activation leads to depolarisation of the postsynaptic neuron.
4. Explain the role of Mg2+ in NMDA receptor gating, and why NMDA receptors are slower to activate than AMPA receptors.
5. Distinguish GABA_A from GABA_B in terms of receptor type, activation speed, and mechanism.
6. Describe the molecular mechanism by which calcium influx through NMDA receptors produces long-term potentiation.
7. Why is LTP described as “input-specific,” and what evidence in the lecture links LTP to learning and memory?
8. List the six classes of drugs that modulate neurotransmission, with the type of receptor/transport event each acts on.
9. A patient is prescribed escitalopram for depression. Explain, in terms of transporters and synaptic NT levels, how this drug is expected to help.
10. Explain why ketamine can produce anaesthesia, psychotic symptoms, and antidepressant effects at different dose ranges, referencing its receptor target and the proposed disinhibition mechanism.
11. Integrative: a drug increases GABA_A channel opening frequency (like propofol) while another drug blocks NMDA receptors (like ketamine at high dose). Explain why both can produce anaesthesia despite acting on different neurotransmitter systems.

Answers

Reveal answers

1. The chemical must be present in the presynaptic terminal; it must be released from that terminal as a result of presynaptic depolarisation; and experimental application of the chemical to the postsynaptic neuron must evoke the same effect as presynaptic release.
2. (1) Depolarisation of the presynaptic neuron via Na+ influx; (2) influx of Ca2+ via voltage-dependent Ca2+ channels; (3) vesicle mobilisation, fusion, and release; (4) receptor activation; (5) removal of neurotransmitter from the cleft by transporter uptake or enzyme metabolism.
3. Glutamate binds AMPA, a ligand-gated ion channel, which directly opens to let Na+ flow into the postsynaptic neuron, making the membrane potential more positive and driving depolarisation.
4. At rest, Mg2+ sits lodged in the NMDA channel pore, held there by attraction to the negative intracellular environment, blocking ion flow. Depolarisation (e.g. from AMPA activation) removes the electrostatic attraction holding Mg2+ in place, so it leaves the channel and allows Na+ and Ca2+ to enter — this extra dependence on prior depolarisation makes NMDA slower to activate than AMPA, which opens directly on ligand binding.
5. GABA_A is a Cl⁻ ion channel that opens directly on GABA binding, activating within milliseconds and causing fast inhibition via Cl⁻ influx/hyperpolarisation. GABA_B is a Gi-coupled GPCR, activating over ~100 milliseconds; it also inhibits the action potential but via a slower, indirect G-protein pathway rather than direct channel gating.
6. Calcium entering through NMDA receptors activates calcium/calmodulin kinase II and other protein kinases, which promote insertion of additional AMPA receptors into the postsynaptic membrane from an internal pool. This makes the cell more sensitive to glutamate, so less glutamate is needed to reach threshold — a stronger, potentiated connection.
7. LTP is input-specific because only the synapse on the pathway that was actively stimulated is strengthened; an inactive pathway onto the same neuron is not. The lecture links LTP to learning/memory because NMDA antagonists, which block LTP, cause amnesia — and are used clinically as anaesthetics — supporting LTP as the molecular basis of learning.
8. Agonists (activate receptors), antagonists (block receptor activation by NTs), enzyme inhibitors (block NT breakdown, raising NT levels), reuptake inhibitors (block transporter removal of NT from the synapse), releasing agents (cause NT to be released/accumulate in the synapse), and positive allosteric modulators (increase receptor activity when NT is bound, via a separate binding site).
9. Escitalopram is an SSRI: it inhibits the serotonin transporter, slowing removal of serotonin from the synapse. This increases serotonin levels at the synapse and increases receptor activation, boosting existing serotonergic connections.
10. Ketamine is an NMDA antagonist. At very high doses it blocks LTP and produces anaesthesia/amnesia. At high doses (like PCP) it produces psychotic symptoms with deficits in working memory and learning. At moderate doses, the proposed mechanism is disinhibition — ketamine inhibits inhibitory (GABAergic) neurons, producing net excitation that increases LTP and BDNF production, giving an antidepressant effect.
11. Propofol (a GABA_A positive allosteric modulator) increases Cl⁻ influx, making the membrane more negative and decreasing neurotransmission — reducing excitatory signalling by strengthening inhibition. High-dose ketamine (an NMDA antagonist) blocks the main excitatory NMDA-mediated pathway directly. Both routes reduce net excitatory neurotransmission — one by boosting inhibition, the other by blocking excitation — which is why increasing inhibitory tone and blocking excitatory transmission are both viable routes to anaesthesia.