🧠 NEUROTRANSMITTERS 101: The Basics of Neurotransmission

 Ready to dive into the fascinating world of neurotransmitters? These tiny molecules are the chemical messengers that keep your nervous system humming—coordinating thoughts, movements, moods, and memories.

 Let’s explore how these molecules work and why they’re clinically meaningful. 🩺

🔹 What Are Neurotransmitters?

Neurotransmitters are chemical messengers released by neurons to communicate with other cells. They traverse synapses—the microscopic gaps between neurons, muscles, or glands—and either trigger or modulate the activity of the receiving cell.

• 🔥 Excitatory neurotransmitters push the receiving cell closer to firing an action potential (e.g., glutamate).
• 🧘 Inhibitory neurotransmitters dampen the signal, making the cell less likely to fire (e.g., GABA).

💡 Think of them as toggle switches in the brain—turning signals up or down to coordinate the body's responses.

🔹 The Neurotransmission Process: Step-by-Step Breakdown

Let’s walk through how neurons send a message, one step at a time:

1️⃣ Action Potential Arrival

A neuron becomes electrically excited. This voltage change travels down the axon to the presynaptic terminal—a bit like sending a signal down a wire.

🧠 Clinical tie-in: In diseases like multiple sclerosis, myelin damage impairs action potential conduction, disrupting neurotransmission.

2️⃣ Calcium Influx

Depolarisation opens voltage-gated calcium channels, allowing Ca²⁺ to flood in.

💡 Calcium isn’t just a structural ion—it’s the cue that “gets the party started” for neurotransmitter release.

3️⃣ Neurotransmitter Release

Calcium causes vesicles filled with neurotransmitters to fuse with the cell membrane and exocytose their contents into the synaptic cleft.

🧬 This step is impaired in certain toxins like botulinum toxin, which blocks vesicle fusion, leading to paralysis.

4️⃣ Binding to Receptors

Neurotransmitters bind to specific receptors on the postsynaptic membrane. This binding is like a lock-and-key mechanism.

🔗 Example: Acetylcholine binds to nicotinic receptors at neuromuscular junctions to trigger muscle contraction.

5️⃣ Cellular Response

Depending on the receptor activated:

• Excitatory signals might open Na⁺ channels and depolarise the postsynaptic cell.
• Inhibitory signals might open Cl⁻ channels to hyperpolarise it.

6️⃣ Signal Propagation

If threshold is reached, the postsynaptic neuron fires its own action potential—propagating the message onward.

7️⃣ Neurotransmitter Clearance

To prevent overstimulation, neurotransmitters are:

• Broken down (e.g., acetylcholine by acetylcholinesterase)
• Reabsorbed (reuptake) into the presynaptic neuron
• Diffused away

💊 Drugs like SSRIs block reuptake, prolonging serotonin’s mood-stabilizing effect.

🔹 Key Neurotransmitters to Know

Neurotransmitter	Function	Clinical Insight
Adrenaline	Fight or flight (SNS)	Linked to stress, panic attacks
Dopamine	Reward, movement	↓ in Parkinson’s; ↑ in psychosis
Serotonin	Mood, sleep, appetite	Targeted by SSRIs in depression
GABA	Main inhibitory	↓ in epilepsy; target of benzodiazepines
Acetylcholine	Learning, muscle action	↓ in Alzheimer’s; blocked in myasthenia
Glutamate	Memory & learning	Excitotoxicity in stroke, trauma
Endorphins	Euphoria, pain relief	↑ with exercise; mimic by opioids

🔸 Types of Receptors: Shaping the Signal

When a neurotransmitter is released, what happens next depends on the kind of receptor it binds to. These receptors are like cellular decision-makers, and they come in two main flavours: ionotropic and metabotropic

🪟 Ionotropic Receptors: The Rapid-Response Doors

Think of ionotropic receptors as fast-acting, automatic doors.

• When a neurotransmitter binds to an ionotropic receptor, it directly opens a channel in the cell membrane.
• Ions (like Na⁺, K⁺, Cl⁻) rush through, immediately changing the electrical charge inside the cell.
• If enough positive charge enters (like Na⁺), the neuron might fire an action potential.

⏱️ Speed: Very fast—milliseconds. The signal is almost instant.

🧠 Example:

• GABA_A receptors open chloride channels when GABA binds, making the cell more negative and inhibiting firing.
• These are targets of benzodiazepines, which boost GABA's calming effects—explaining their rapid sedative action in anxiety or seizures.

🧠 Knowing the receptor type helps explain drug effects. Benzodiazepines enhance GABA_A directly via ionotropic receptors—quick sedation.

🔁 Metabotropic Receptors: The Chain Reaction Switches

These receptors are more like a master switch that kicks off a chain reaction inside the cell.

• Instead of opening ion channels directly, metabotropic receptors activate G-proteins inside the cell.
• This sets off a cascade of intracellular events—like releasing second messengers (e.g., cAMP), modifying enzymes, or opening channels indirectly.
• The effect is more modulatory, fine-tuning how excitable or inhibited the cell becomes.

⏳ Speed: Slower—seconds or more. But the effects can last longer and be more complex.

🧠 Example:

• Serotonin 5-HT_1A receptors and dopamine D₂ receptors are metabotropic.
• These are targets for SSRIs and antipsychotics, respectively—explaining their delayed onset and nuanced actions in mood and psychiatric disorders.

🔸 Mapping the highways: Neurotransmitter Systems & Pathways

Neurotransmitters aren’t just floating randomly in the brain—they travel along dedicated neural circuits, kind of like electrical highways connecting key regions. Each pathway has a purpose, and if traffic is disrupted, you get symptoms.

Let’s explore the most important systems:

🧠 1. Dopaminergic System: The Multi-Lane Highway

Dopamine doesn’t have just one job—it acts differently depending on where it’s released. Here are the three major routes:

🚗 a. Nigrostriatal Pathway

• Route: From substantia nigra to the striatum (basal ganglia)
• Function: Controls voluntary movement
• Clinical Relevance: Degenerates in Parkinson’s disease, leading to tremor, rigidity, and bradykinesia

💡 Think of dopamine here as the brain’s motor oil—when it dries up, movement becomes stiff and sluggish

💡 b. Mesolimbic Pathway

• Route: From ventral tegmental area (VTA) to limbic system
• Function: Involved in reward, pleasure, and motivation
• Clinical Relevance: Overactive in schizophrenia—may contribute to hallucinations and delusions

🔔 This system helps explain why dopamine spikes are linked to addiction and compulsive behaviours—it’s the “wanting” system.

🧩 c. Mesocortical Pathway

• Route: From VTA to the prefrontal cortex
• Function: Supports executive function, decision-making, and cognition
• Clinical Relevance: Dysfunction may contribute to negative symptoms of schizophrenia—e.g., flat affect and poor planning

📚 This pathway is important in balancing emotion and thought—impaired dopamine here can make thinking dull and motivation low.

😴 2. Serotonergic System: The Mood Regulator

• Origin: Raphe nuclei (brainstem) project widely across the brain
• Function: Regulates mood, sleep, appetite, and pain perception
• Clinical Relevance:

• ↓ serotonin linked to depression and anxiety
• Target of SSRIs (e.g., fluoxetine), which block serotonin reuptake

🌙 When serotonin is low, emotional regulation falters. SSRIs keep serotonin in the synapse longer, improving mood over time.

🧘‍♂️ 3. GABAergic System: The Brain's Brake Pedal

• Function: GABA is the main inhibitory neurotransmitter
• Distribution: Found throughout the CNS
• Clinical Relevance:

• ↓ GABA leads to seizures and anxiety
• Enhanced by benzodiazepines, which increase inhibitory signalling

🔌 GABA is like a circuit breaker—it prevents overactivity in the brain. Without enough, the nervous system goes into overdrive.

🧠 4. Glutamatergic System: The Brain’s Accelerator

• Function: Glutamate is the main excitatory neurotransmitter
• Role: Essential for learning, memory, and synaptic plasticity
• Clinical Relevance:

• Excessive glutamate leads to excitotoxicity (neuronal damage seen in stroke or trauma)
• Linked to neurodegeneration in diseases like ALS and Alzheimer’s

⚡ Glutamate activates cells—but too much can be destructive, like revving an engine until it overheats.

💪 5. Cholinergic System: The Motor and Memory Messenger

• Origin: Basal forebrain and brainstem nuclei
• Function:
• In the brain: regulates attention, learning, and memory
• At the neuromuscular junction: triggers muscle contraction
• Clinical Relevance:

• ↓ acetylcholine in Alzheimer’s disease
• Target of acetylcholinesterase inhibitors (e.g., donepezil)

💡 It’s also the first neurotransmitter you meet when studying anatomy—the one that makes muscles move.

Each of these systems forms the basis of many neurological and psychiatric conditions. 

💊 Neurotransmitters and Drugs: Decoding the Synapse

Drugs often work by modifying neurotransmission—either amplifying or dampening the chemical signals that neurons send. By learning a few core mechanisms early, students can make sense of why drugs help, how they cause side effects, and what symptoms they’re targeting.

Let’s simplify the major ways drugs interact with neurotransmitters:

🔁 1. Reuptake Inhibition

After a neurotransmitter acts on the receptor, it’s usually reabsorbed by the presynaptic neuron to “reset” the system. Some drugs block this reuptake, leaving the chemical in the synapse longer.

• Example: Selective Serotonin Reuptake Inhibitors (SSRIs) like fluoxetine
  → Keep serotonin in the synapse longer
  → Used to treat depression and anxiety
  → Effect is gradual, not instant (takes weeks)

💬 Imagine the signal lingers like background music—it keeps nudging the neuron gently.

🚪 2. Receptor Agonists

Some drugs mimic neurotransmitters and bind directly to the receptor, activating it.

• Example: Levodopa is converted into dopamine
  → Boosts dopaminergic signalling in Parkinson’s disease
  → Helps restore motor control
  → Side effects may include involuntary movements (dyskinesia)

🧠 You’re adding more “key copies” to open the right locks—especially useful when neurotransmitter levels are low.

🧘‍♂️ 3. Receptor Modulation

Instead of turning receptors fully on or off, some drugs enhance or inhibit receptor sensitivity.

• Example: Benzodiazepines bind to GABA_A receptors
  → Increase GABA’s inhibitory effect
  → Used in anxiety, insomnia, and seizures
  → Quick calming effect

💡 They don’t open the door themselves—they help GABA open it more easily

✂️ 4. Enzyme Inhibition

Enzymes often break down neurotransmitters after use. Blocking these enzymes extends their action.

• Example: Donepezil (used in Alzheimer’s disease)
  → Inhibits acetylcholinesterase
  → Preserves acetylcholine, supporting memory and attention

🔍 Like turning off the vacuum cleaner that clears the neurotransmitter—it gives acetylcholine more time to work.

⛔ 5. Receptor Antagonists

These drugs block receptors so neurotransmitters can't bind. Often used to dampen excessive signalling.

• Example: Haloperidol blocks dopamine D₂ receptors
  → Used in schizophrenia to reduce hallucinations/delusions
  → Can cause side effects like muscle rigidity

🚧 The brain’s signal is trying to deliver a message—but the receptor is locked shut

🧠 Why It Matters

Understanding drug mechanisms give you:

• A framework to predict therapeutic effects
• Insight into side effects by identifying which neurotransmitter pathways are disrupted
• The ability to start linking symptoms, drugs, and systems into a clinical narrative

Neurotransmitter Changes Through Development and Ageing 👶🧠🧓 

Neurotransmitters aren’t static—they shift dramatically depending on age, brain development, and even life stage. Understanding these changes helps explain why behaviour differs in children, teenagers, adults, and older adults, and how this relates to mental health and neurological disease.

🧒 Childhood: Building the Synaptic Blueprint

• During early development, the brain lays down massive numbers of synapses—far more than needed.
• Neurotransmitters like glutamate (excitatory) and GABA (inhibitory) help sculpt these circuits.
• Interestingly, GABA starts out excitatory in the developing brain due to higher intracellular Cl⁻—this flips as chloride transport changes.
• Acetylcholine helps support attention and motor learning during this foundational phase.

📚 Clinical tie-in: Disruptions in neurotransmitter signalling during this time may contribute to neurodevelopmental disorders like ADHD or autism.

👩‍🎓 Adolescence: Dopamine’s High-Speed Ride

• Dopamine activity surges in the mesolimbic pathway, which controls reward and motivation.
• This can explain risk-taking behaviour, emotional swings, and susceptibility to addiction.
• Prefrontal areas (e.g., those using serotonin and dopamine) lag in development—hence impulsivity and poor inhibition.

🧠 Clinical tie-in: Understanding this helps students contextualize teenage behaviour and mental health vulnerability during this time.

🧑‍🦳 Adulthood & Ageing: Neurochemical Refinement and Decline

• In healthy adults, neurotransmitter systems stabilize and become more efficient.
• With ageing:

• Acetylcholine declines, especially in regions like the hippocampus—contributing to memory loss
• Dopamine levels drop, which may lead to reduced motor control and slower reward processing
• Serotonin and GABA may also decline subtly, affecting sleep, mood, and stress regulation

🧠 Clinical tie-in: Age-related changes underpin conditions like Alzheimer's (acetylcholine deficit), Parkinson’s (dopamine loss), and late-onset depression (serotonin imbalance).

🧩 Neurotransmitters in Context: the case of Jake

Meet Jake

Jake is a 68-year-old retired geography teacher who comes to his GP with a few concerns. Over the past year, he’s noticed:

• A persistent tremor in his right hand, especially when resting
• Slowed movements (“I feel like my limbs are stuck in glue”)
• Occasional freezing of gait when trying to initiate walking
• A softened voice and reduced facial expression

Jake’s cognition is intact, and he reports no depressive symptoms. Neurological exam shows stiffness, rigidity, and a pill-rolling tremor. Jake feels mentally sharp but says his body “isn’t cooperating.”

This constellation of signs—bradykinesia, rigidity, and a classic pill-rolling tremor—is characteristic of Parkinson’s disease, a progressive neurodegenerative condition resulting from dopaminergic dysfunction in a key motor pathway.

🧩 Dopamine and the Nigrostriatal Pathway

The motor symptoms Jake experiences arise from a loss of dopamine-producing neurons in the substantia nigra, which project to the striatum in the nigrostriatal pathway. Dopamine normally fine-tunes the balance between excitation and inhibition in basal ganglia circuits. It acts via metabotropic D₁ and D₂ receptors, orchestrating movement through complex G-protein cascades.

Without sufficient dopamine, inhibitory signals dominate:

• Motor initiation is impaired
• Movements become slow and rigid
• Tremors develop due to disrupted feedback control

This explains Jake’s “body not cooperating”—his neural circuits are receiving distorted signals.

🧠 How does Parkinson’s differ from essential tremor?

While both conditions involve tremor, they’re clinically distinct:

Feature	Parkinson's Disease	Essential Tremor
Tremor Timing	Occurs at rest	Occurs during movement
Other Symptoms	Bradykinesia, rigidity, postural instability	Usually no other neurological signs
Response to Levodopa	Improves motor symptoms	Usually no effect
Cause	Dopamine loss in nigrostriatal pathway	Thought to involve cerebellar-thalamic circuits
Age of Onset	Typically ≥60 years	Can begin earlier

💊 Treatment: Replacing Dopamine

Jake is prescribed Levodopa, the gold standard for Parkinson’s therapy. Levodopa is a dopamine precursor capable of crossing the blood-brain barrier, where it is converted into active dopamine to restore signalling.

It’s given with Carbidopa, which blocks peripheral conversion, ensuring more levodopa reaches the brain and reducing side effects like nausea.

Dopamine acts on metabotropic receptors, meaning the effects are slower but sustained—perfect for regulating motor activity over time.

Initially, Jake improves:

• His movements are smoother
• Tremor lessens
• He walks with more ease

But over time, dopamine replacement becomes less predictable.

🧠 Why does Levodopa eventually become less effective?

While Levodopa replenishes dopamine, its long-term use is limited by several factors:

• Progressive neuron loss: As Parkinson’s advances, fewer dopamine-producing neurons remain to convert Levodopa into usable dopamine.
• Receptor desensitization: Dopamine receptors may become less responsive over time due to chronic stimulation.
• Short half-life: Levodopa wears off quickly, leading to motor fluctuations—periods of good mobility (“on”) followed by stiffness (“off”).

This is why patients may develop “on-off” phenomena or dyskinesia—a sign that the system’s capacity to regulate dopamine smoothly is declining.

⏳ Disease Progression and Treatment Challenges

Levodopa's effectiveness can diminish over time. Jake may eventually experience “on-off” phenomena, where mobility suddenly freezes, or develop dyskinesia—involuntary jerking movements—when dopamine levels surge.

In some cases, excessive stimulation of non-motor dopamine pathways may cause hallucinations or mood changes, reflecting the mesolimbic system’s involvement in reward and perception.

🧠 What explains hallucinations in Parkinson’s patients on dopamine therapy?

Hallucinations aren’t uncommon with long-term dopaminergic treatment. Here's why:

• Dopamine doesn’t only work in movement—it also modulates perception and emotion through the mesolimbic pathway.
• Excess dopamine stimulation in this system can lead to sensory misinterpretation, like visual hallucinations or delusional thinking.
• The risk increases with:
  • Higher doses of dopamine agonists
  • Advancing age and cognitive decline
  • Longer disease duration

This shows the importance of understanding dopaminergic pathways beyond the basal ganglia.

🧓 Age and Neurotransmission

Jake’s case also illustrates how ageing affects neurotransmitter systems:

• Dopamine levels decline naturally with age, even without disease
• The cholinergic system also deteriorates, affecting memory and learning
• These changes reduce reserve capacity, making older adults more susceptible to movement disorders, cognitive decline, and altered drug responses

Understanding these shifts provides context for why diseases like Parkinson’s emerge and how their management must adapt over time.

Jake’s journey connects multiple layers of neuroscience—from neurotransmitter function and receptor biology to clinical pharmacology and age-related physiology. It shows how the brain’s chemical messengers shape not just our movement, but how we respond to illness, adapt to treatment, and age over time.

💡 Why Does This Matter?

Understanding neurotransmission lays the groundwork for clinical neurology, psychiatry, and pharmacology. Whether it's the tremor in Parkinson’s or a seizure in epilepsy, the root is often disrupted signalling.

By grasping how neurotransmitters function, you’ll be equipped to:

• Recognise symptoms in context of synaptic dysfunction
• Predict drug actions based on neurotransmitter targets
• Build strong neural networks—for both patients and neurons 😉

📦 Want to learn more?

• 📝 All posts on the nervous system →
• 📝 Structure and function of the CNS →
• 📝 Pathophysiology of seizures →
• 📝 Understanding seizure classification →
• 📝 Localisation of seizures →
• 📝 Neurotransmitters 101 →
• 📝 Consciousness and how we can lose it →
• 📝 Clinical cases in seizure localisation →
• 📝Principles of seizure management →
• 📝Neurotransmitters on drugs! →
• 📝A beginner's guide to EEG →
• 📝A beginner's guide to neuroimaging →