Chapter 4: Chemistry of Behavior: Neurotransmitters & Drugs

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I want you to close your eyes for a second.

Imagine it's April 1943.

The world is tearing itself apart in the Second World War, but we are zooming in on a very quiet, very sterile laboratory in Basel, Switzerland.

There's a man there, a chemist named Dr.

Albert Hoffman.

He's working for Sanda's Pharmaceuticals.

He's not trying to change the world and he's certainly not trying to start a counterculture revolution.

He's just doing his job.

Exactly.

He was looking for respiratory and circulatory stimulants.

He was working with ergot, which is this parasitic fungus that grows on rye.

It's actually quite toxic.

Historically, it causes something called St.

Anthony's Fire, gangrene.

But he was just trying to isolate compounds from it that might be medically useful.

It was just routine bench chemistry.

Until it wasn't.

On this particular Friday afternoon, Hoffman starts feeling,

well, off.

He describes it as a not unpleasant intoxication.

He feels restless.

His imagination is running a little wild.

He actually thinks he's coming down with something.

Yeah, a cold or the flu.

So he packs up his equipment and goes home to lie down.

And that is where the history of neuroscience takes a very sharp left turn.

Because, well, he didn't have the flu.

He lay down, closed his eyes, and instead of darkness or sleep, he was just bombarded by an uninterrupted stream of fantastic pictures.

He saw extraordinary shapes with, and this is his quote, intense kaleidoscopic play of colors.

It lasted for about two hours.

When he went back to the lab, he realized the only thing different about that day was this specific compound he had synthesized.

Lysergic acid, dithelomide 25, LSD.

He suspected he'd absorbed a tiny trace of it, maybe just through his fingertips.

But being a scientist, a suspicion isn't enough.

He had to prove it.

So three days later, April 19th, which is now known as Bicycle Day, he decided to perform a self -experiment.

And he measured out what he thought was a microscopic, a completely negligible dose, 250 micrograms.

Which is, it's hard to even picture.

That's that in perspective for you.

A standard aspirin pill is about 325 milligrams.

Hoffman took a dose thousands of times smaller than a headache pill.

He figured at this amount, nothing will happen.

Which was a massive, massive miscalculation.

Within an hour, he couldn't speak intelligibly.

He had to ride his bicycle home.

That's where the name comes from.

And the world just dissolved around him.

He felt like he was floating outside his own body.

He thought he was dying.

He thought he'd gone insane.

But what's so fascinating is that the next morning he woke up feeling completely refreshed.

Better than ever, in fact.

This story is wild.

But the reason we're starting here isn't just because it's a cool anecdote about the accidental discovery of LSD.

It's because of the scale.

How can a few millions of a gram of a powder completely hijack the reality of a grown man?

That is the essential question of Chapter 4 of behavioral neuroscience.

How does a tiny molecule, whether it's LSD or the caffeine in your mug right now, or the serotonin your brain is making this very second, how does that translate into experience?

How does chemistry become behavior?

So our mission today is to demystify that chemical soup inside our heads.

We're going to walk you through Chapter 4.

We'll start by breaking down the basic machinery of the synapse.

Then we'll meet the cast of characters, the neurotransmitters.

After that, we'll get into the foreign invaders, the drugs and exogenous substances.

And finally, we'll touch on the mechanisms of addiction.

And we should probably start with the proper terminology.

We are entering the world of neuropharmacology.

It sounds more intimidating than it is.

It's just the study of compounds that selectively affect the nervous system.

And in this world, there is a fundamental divide, the things you make and the things you take.

The make versus take distinction.

I like that.

It's a good way to frame it.

We have endogenous substances.

Endo means internal.

These are the neurotransmitters your brain produces naturally to send it signals, you know, dopamine, serotonin, glutamate.

And the take category.

That's everything else.

Those are exogenous substances.

XO, meaning from the outside.

These are molecules from the external world plants, animals, synthetic chemicals in a lab that by some coincidence of nature, happen to fit into the locks inside our brains.

Hoffman's LSD was exogenous.

Exactly.

But it worked because it mimics something endogenous.

It was a foreign key that just happened to fit a native lock.

It's kind of spooky when you think about it.

I mean, why does a fungus on rye bread produce a chemical that unlocks the human visual cortex?

That is one of the great mysteries of coevolution.

But to understand how the fungus hacks the brain, we first have to understand the hardware it's hacking.

You have to go right down to the level of the synapse.

Okay, let's set the stage.

In our last deep dive, we talked about the neuron like it was an electrical wire.

The signal, the action potential zips down the axon like a spark, but neurons don't actually touch, right?

They do not.

And this was a huge, huge debate in the early 20th century.

You had the sparks versus the soups.

The sparks thought electricity just arsed from one cell to the next.

And the soups.

They argued there had to be a chemical intermediary.

And well, the soups won.

Because of the gap.

Exactly.

The synaptic cleft.

It's unbelievably tiny, about 20 to 40 nanometers wide.

But to an electrical signal, it might as well be the Grand Canyon.

Electricity cannot jump through that salty fluid.

So when the action potential reaches the end of the line, the axon terminal,

the system has to switch modes completely.

It's a total conversion.

It goes from electrical to chemical.

So here's the play by play.

The action potential, this wave of electrical energy hits the terminal.

Okay.

This electrical surge changes the voltage across the membrane right at the end.

That voltage change is the trigger for a specific set of gates to fly open.

These are called voltage gated calcium channels.

Calcium.

Like for bone health.

The very same element.

The ion, colostrum plus a cell.

Outside the cell, there's a ton of calcium.

Inside, there's very little.

So when those gates open, calcium just floods in.

It rushes in like water through a broken dam.

And that's calcium influx is the signal.

It's the go signal.

It's the trigger for the main event.

Go do what?

Inside that axon terminal, floating around are these spheres called synaptic vesicles.

You can imagine them as little water balloons and they're filled with thousands of neurotransmitter molecules.

So they're just waiting for the signal.

They're docked and waiting.

When the calcium rushes in, it causes these balloons to migrate very rapidly to the absolute edge of the cell membrane.

And they pop.

In essence, yeah.

They fuse with the membrane and burst open,

spilling their chemical contents out into the gap, into the synaptic cleft.

The technical term for this process is exocytosis.

So now we have these chemical messengers, the neurotransmitters, just floating in that no man's land between the two cells.

Exactly.

And this all happens in microseconds.

The chemicals diffuse across the cleft to the other side, the post synaptic membrane.

And this is where the magic really happens.

This is where the signal is received.

The lock and key.

It's the classic analogy.

And it's a good one.

But let's refine it a bit.

On the receiving cell, there are these specialized protein structures called receptors.

The neurotransmitter molecule is the key.

And it has a specific shape.

A very specific shape.

It slots into the receptor.

But it's not just a static fit.

When that binding happens, the receptor protein physically changes shape.

It twists or contorts.

And that physical change is what triggers a reaction in the receiving cell.

Okay.

But keys are specific.

My house key doesn't open your car.

Absolutely.

Receptors are highly specific.

A dopamine receptor will completely ignore serotonin floating by.

But here's where we get into the pharmacology.

We have a broader term for any substance that binds to a receptor.

A ligand.

A ligand.

So that could be a drug or a natural chemical.

Exactly.

Now imagine a key that fits the lock and turns it, opening the door.

That is an agonist.

Most of your natural neurotransmitters are agonists.

They bind and initiate the normal effect.

Okay.

Makes sense.

But what if you have a key that fits into the lock perfectly, but it's bent?

Or it's a blank.

It slides in, but it won't turn.

And now the real key can't get in.

Exactly.

You've jammed the lock.

That is an antagonist.

CuraR, the famous aeropoison used by indigenous tribes in South America, works this way.

How so?

It's an antagonist for the acetylcholine receptor on your muscles.

It fits perfectly into the receptor.

It blocks the So your brain is sending the signal, contract, move your arm, but the message can't get into the muscle cell.

The lock is jammed.

The lock is jammed.

The result is complete paralysis.

That is terrifying.

So to recap,

an agonist mimics the natural transmitter and an antagonist blocks it.

Precisely.

And to make it even more complex, the locks themselves, the receptors, come in two very different styles.

The textbook breaks them down pretty clearly.

The fast ones and the slow The fast ones are ionotropic receptors.

These are built for pure speed.

The receptor protein itself is also an ion channel.

It's an all -in -one unit.

So when the key goes in?

The channel pops open immediately.

As soon as the neurotransmitter binds, the protein shape changes, the gate opens, and ions flow in or out.

It takes less than a millisecond.

This is crucial for things like muscle reflexes or, say, rapid visual processing.

And the slow ones?

Those are the metabotropic receptors.

These are more like a bureaucracy.

The neurotransmitter binds to the outside, but it doesn't open a channel directly.

There's a middleman.

A very important middleman.

It kicks a special protein on the inside of the cell called a G protein.

That G protein then wanders off to find an enzyme, which in turn creates a second messenger molecule, which then finally goes to open a channel or even change the cell's DNA expression.

Wow, that's a lot of steps.

Why would the brain use such a slow system?

Because it's amplified and long -lasting.

One neurotransmitter molecule can activate many G proteins, creating a huge internal cascade.

It's slower.

It can take seconds, minutes, even hours.

But the effect is much broader.

This is how we get things like mood changes or memory formation, things that need to stick around longer than a millisecond.

And I remember reading in the chapter that there isn't just one type of receptor for each chemical.

It's not like there is just the dopamine receptor.

Right.

Not even close.

That would be far too simple for the brain.

We have what are called receptor subtypes.

Okay.

For dopamine alone, we know of at least five major subtypes creatively named D1 through D5.

For serotonin, there are over a dozen, maybe 14 or more.

But why?

Why does the brain need 14 different ways to catch the exact same serotonin molecule?

It allows for a diversity of response.

Think about all the things serotonin is involved in.

Sleep, nausea, mood, anxiety, sexual function.

You don't want to fall asleep every time you feel happy.

Right.

By having different receptor subtypes located in different parts of the brain or that trigger different internal cascades, the exact same molecule can have completely different effects depending on which lock it finds.

And I'm guessing this is why drugs have so many side effects.

Bingo.

That's the central challenge of pharmacology.

Yeah.

If we design a drug to hit the serotonin receptor involved in depression, but it also happens to have a high affinity for the serotonin receptor subtype that controls your gut.

You might feel happier, but you're going to be nauseous.

Exactly.

This is the holy grail of drug design, trying to create molecules that are so incredibly specific, they only hit the one subtype we want without touching any of the others.

So we have the stage set,

the synapse, the calcium trigger, the vesicles, the lock and key receptors and all their variety.

Now we need to meet the actors,

the chemicals themselves, the endogenous ligands, the neurotransmitters.

And we absolutely have to start with the story of Otto Louis because this is one of the only times in science history where a Nobel Prize was essentially awarded for, wow, for having a dream.

It's a fantastic story.

It's 1921.

Otto Louis was obsessed with trying to prove chemical transmission.

He was convinced the soups were right.

He had a dream on Easter Saturday night.

He saw in perfect detail an experiment that would prove it.

So he woke up.

He woke up, scribbled some notes on a pad of paper and went back to sleep feeling triumphant.

I think we all know where this is going.

Of course.

The next morning he looked at the pad.

It's complete gibberish.

He can't read his own handwriting.

He said it was the longest, most frustrating day of his life.

But the dream came back.

Fortunately, yes, the dream came back the next night.

This time he didn't take any chances.

He got up at 3 a .m., went straight to his lab and performed the experiment on two frog hearts.

What was the experiment exactly?

It's beautiful in its simplicity.

He took two frog hearts and kept them beating in a saline solution.

Heart A was still connected to its vagus nerve.

He stimulated that nerve electrically and heart A slowed its beat down.

We already knew that would happen.

But then, and this is the genius part, he took some of the fluid from around heart A and transferred it to the container holding heart B.

And heart B had no nerve connection at all.

None whatsoever.

It was isolated.

But when that fluid from heart A hit heart B, it slowed down too.

So it wasn't the electricity that was slowing the heart.

It was something in the water.

Exactly.

They had to be a chemical messenger.

He called it vagus stuff, which just means vagus stuff.

We later identified it as acetylcholine or AA,

the first neurotransmitter ever discovered.

So let's break down acetylcholine.

Where does it live in the brain and what does it do?

In the brain, we find major clusters of cholinergic neurons in a region called the basal forebrain.

It's a really crucial system.

These neurons project their long axons to the hippocampus and the amygdala and also widely throughout the cortex.

And since the hippocampus is memory central, acetylcholine is profoundly involved in learning and memory.

And sadly, this is how we really confirmed its importance.

In Alzheimer's disease, these cholinergic neurons in the basal forebrain are some of the very first to wither and die.

And that loss of acetylcholine is directly linked to the memory loss we see in dementia.

It's a key hallmark of the disease.

In fact, you can create temporary memory loss in healthy people by giving them a drug like stapolamine, which is an acetylcholine antagonist.

It blocks the receptors.

So acetylcholine is the memory molecule.

Next up, the chapter introduces the monoamines.

This sounds like a 90s boy band.

It's a chemical family.

They're all modified from a single amino acid.

We break them down into two main subgroups.

You have the catecholamines and the indolamines.

Let's stick to the names people recognize.

Dopamine, the absolute celebrity of neurotransmitters.

Everyone wants more dopamine, but it's a bit misunderstood.

We actually have very few dopamine neurons in the grand scheme of things, maybe a million or so out of 86 billion total neurons, but they project everywhere and have huge influence.

And there are two main pathways you need to know, right?

That's right.

The book lays them out clearly.

First is the mesostretal pathway.

It starts in a part of the midbrain called the substantia negra, which means black substance, and it sends its axons to the basal ganglia.

What's that one for?

This is all about motor control, movement.

When you decide to reach out and pick up your coffee cup, this pathway is firing to make that smooth and coordinated.

That's Parkinson's disease.

Parkinson's is caused by the progressive death of these specific dopamine neurons in the substantia negra.

That's why you see the tremors, the rigidity, the difficulty initiating movement.

And pathway two, this is the one people usually mean when they say dopamine hit.

This is the famous one, the mesolimbocortical pathway.

It starts in a nearby area called the VTA, the ventral tegmental area, and it projects to the limbic system, especially a spot called the nucleus accumbens and also to the cortex.

This is the reward pathway.

This is the reward and reinforcement pathway.

It's the system that tells your brain, that was good, pay attention, do it again.

So food, sex, winning at a video game, and crucially, drugs.

This is the exact pathway that gets hijacked by addiction, which we'll get to later.

Next in the monoamine family,

norepinephrine, also called noradrenaline, if you're in the UK.

These neurons are found in a tiny, tiny spot in the brainstem called the locus coruleus, which is Latin for the blue spot.

The blue spot.

Yeah, it literally looks bluish and unstained tissue.

And despite being microscopic, it broadcasts to virtually the entire brain.

It's the brain's alarm system, controls arousal, alertness, and mood.

So when you hear a loud bang and you suddenly snap to full attention, that's a massive surge of norepinephrine flooding your cortex.

And the last of the big three monoamines, serotonin.

Its chemical name is 5 -hydroxy tryptamine, or 5 -HT.

It's an endolamine made from the amino acid tryptophan, the stuff in Turkey that supposedly makes you sleepy.

And where is it made?

In the raffi nuclei, which are these clusters of cells all along the midline of the brainstem.

Again, it's a tiny number of neurons, maybe only 200 ,000.

But their axons reach out and influence billions of other cells.

Serotonin is the great regulator.

That's a great way to put it.

It manages sleep states, mood, anxiety, even hunger.

It's the primary target for drugs like Prozac and other modern antidepressants.

If dopamine is the go signal for reward, serotonin is often the stabilizer, the mood modulator.

Before we leave this cast of characters, the chapter mentions the really weird ones, the rule breakers, the gas

the soluble gases like nitric oxide or NO.

Not laughing gas, right?

Now that's nitrous oxide, N2O.

This is nitric oxide.

And it's completely baffling if you just learned the standard textbook rules of neurotransmission.

Okay, rule one, neurotransmitters are made in advance and stored in vesicles.

Well, nitric oxide is a gas.

You can't put it in vesicle.

It would just leak out.

So the brain makes it on demand right when it's needed.

It's just in time manufacturing for the neurotransmitters are released from the axon terminal and bind to receptors on the post synaptic membrane.

Nitric oxide doesn't bother with receptors.

It's a gas.

So it just goes right through the cell membrane and interacts with enzymes inside the target cell.

And what's the biggest role it breaks directionality.

Most signals are one way pre synaptic to post synaptic.

Nitric oxide often functions as a retrograde transmitter.

It diffuses from the post synaptic neuron, the receiver backwards to the pre synaptic neuron.

Wait, it goes backwards.

Why?

It's a feedback signal.

It essentially tells the sending neuron, hey, message received loud and clear.

This is an important connection.

You can strengthen it now.

We think this retrograde signaling is a key physical mechanism for how memories are solidified in the brain.

It's part of neuroplasticity.

The gas is the confirmation receipt, a confirmation receipt that tells the sender to upgrade the connection.

Yes.

Okay, we have the machine, we have the principles of neuropharmatology.

I want to go back to my original question about the aspirin versus the LSD.

Why is one tiny speck of acid so much more potent than a giant pill of aspirin?

It comes down to two key properties that are really important to distinguish,

affinity and efficacy.

Okay, breaking down for us.

Binding affinity or just affinity is about stickiness.

It's a measure of how strongly a drug binds to a receptor.

Think of it like magnets or Velcro.

So a high affinity drug is like super glue.

Exactly.

Even if there are only a few molecules of a high affinity drug floating around, they will find their target receptor and latch on tight.

They won't let go easily.

LSD has an incredibly high affinity for certain serotonin receptors.

So that's why you need so little of it.

It finds the target and stays there.

Right.

A low affinity drug is more like a weak magnet.

It bounces on and off easily.

So to get the same effect, you need a much higher concentration, a bigger dose, just to keep enough of the receptors occupied at any given moment.

And what about efficacy?

Efficacy is what happens after the drug binds.

Does it actually do anything?

An agonist has high efficacy.

It binds, turns the lock, and opens the door wide.

An antagonist, on the other hand, might have very high affinity.

It sticks to the lock perfectly, but it has zero efficacy.

It doesn't turn the lock at all.

So a perfect antagonist is super sticky but totally useless at opening the door.

It's just a plug.

It's a perfect plug.

Now, putting these two concepts together helps us understand drug safety.

And this is where the textbook introduces the dose -response curve.

I remember this graph.

If you're looking at the book, it's this S -shaped curve.

Right.

On the x -axis, you have the dose of the drug, and on the y -axis, you have the response or effect.

You give a little bit of the drug, and nothing much happens.

Then you hit a certain point, and the effect shoots up rapidly.

Then at the top, you give more and more drug, but the effect plateaus because all the receptors are already saturated.

And this gives us a really important number, the ED50.

The effective dose for 50%.

It's the dose at which the drug shows half of its maximal effect, or the dose that is effective for 50 % of the population, depending on how you measure it.

It's a useful benchmark for a drug's potency.

But there's a scarier curve we can also plot.

Yes.

We can also plot the toxic or lethal effects of a drug to find the LD50, the lethal dose, for 50 % of the subjects, usually in animal studies.

And the space in between those two curves.

That is the therapeutic index.

And this is one of the most important concepts in pharmacology.

It's the safety window, the gap between the dose that helps you and the dose that hurts you.

So a wide therapeutic index is good.

Very good.

For something like marijuana, the therapeutic index is massive.

The ED50 and the LD50 are miles and miles apart.

But for something like heroin or many anesthetic drugs.

The window is terrifyingly narrow.

Yes.

The dose that produces the desired effect is uncomfortably close to the dose that can stop your breathing.

That's a narrow therapeutic index, and it makes the drug much more dangerous.

Now, here's a phenomenon every coffee drinker or really any regular drug user knows about.

The first time you drink a real espresso, you're buzzing, you're vibrating.

A year later, you can drink a triple shot and then go take a nap.

Why does the drug stop working as well?

That is tolerance.

And it's so important to understand that tolerance isn't just a psychological thing, like you're just getting used to it.

It is your body physically and biologically fighting back.

Your body hates being out of balance.

It's all about maintaining homeostasis.

Your body views a drug as a disturbance, an assault on its normal equilibrium.

So it deploys countermeasures.

The first line of defense is metabolic tolerance.

What's that?

That's your liver and other organs getting better and more efficient at hunting down and destroying enzymes.

So even though you took the same dose, less of the active substance actually makes it to your brain.

And what happens if the drug does make it past the liver to the brain?

Then you get functional tolerance.

This is the brain itself changing its own hardware to compensate.

If you are constantly flooding your system with an agonist, let's say an opiate,

the brain basically says it is way too loud in here, and it starts physically removing receptors from the cell membrane.

It takes the ears off the wall so it can't hear the signal.

That's a great analogy.

We call it downregulation.

With fewer receptors available, you now need more drug to get the same level of stimulation.

And does the opposite happen?

Yes.

Absolutely.

If you take an antagonist that blocks receptors for a long time, the brain says, I can't hear anything.

Is anyone there?

And it responds by sprouting more receptors to try and catch any tiny signal it can.

That's called upregulation.

It makes the system more sensitive.

And this explains withdrawal, doesn't it?

It explains it perfectly.

Imagine you've been drinking alcohol, which is a depressant, every day for years.

Your brain has fought back against this constant sedation by upregulating its excitatory systems.

It's added more go signals to fight the alcohol's stop signals just to keep you functioning.

So you're basically running with the brake pedal pushed down, but your foot is also slammed on the accelerator to compensate.

Exactly.

Then one day, you suddenly stop drinking.

You take your foot off the brake.

But your other foot is still flooring the accelerator.

Precisely.

The alcohol is gone, but all those extra compensatory go signals are still there.

Your brain is now massively hyper -excitable.

You get the shakes,

anxiety, hallucinations, seizures.

Withdrawal is essentially the body's compensatory mechanism laid bare because the drug that caused it is suddenly gone.

That makes perfect, if terrifying, sense.

The counterweight is still pushing, but the original weight is gone.

Exactly right.

All right.

We have arrived.

Part four, the grand drug tour.

We are going to walk through the major classes of psychoactive drugs, explaining exactly what they do to the machine we've just spent so much time describing.

Let's start with the drugs that are used to treat madness,

antipsychotics.

Right.

For a long time, schizophrenia was just a black box.

But in the 1950s, we stumbled upon the first generation of antipsychotics drugs like chlorpromazine.

We call them typical antipsychotics or neuroleptics.

How did they work?

We didn't know at first, did we?

Not exactly, but we figured it out.

They are potent antagonists of dopamine D2 receptors.

They block a specific subtype of dopamine receptor.

So this led to the theory that schizophrenia is just too much dopamine activity.

That was the famous dopamine hypothesis.

By jamming the D2 receptors, these drugs were very effective at stopping the hallucinations and delusions, what we call the positive symptoms of schizophrenia.

But remember our conversation about receptor subtypes and side effects?

Blocking dopamine everywhere is going to cause problems.

Big problems.

Patients would develop severe movement side effects that looked a lot like Parkinson's disease.

Tremors.

Rigidity.

Because the drugs were blocking dopamine in the motor pathways, not just the emotional and cognitive ones.

So that led to the next generation.

Yes, the atypical antipsychotics.

These are a bit messier pharmacologically.

They still block D2 but usually with a lower affinity.

And crucially, they also block certain serotonin receptors, especially the 5 -HT2A subtype.

And that combination is better?

It seems to be.

That dual action appears to reduce the nasty movement side effects and can also help with the negative symptoms of schizophrenia,

like social withdrawal and flat emotions, which the first generation drugs didn't touch.

Okay, moving to probably the most commonly prescribed category of psychoactive drug today, antidepressants.

The history here is a real ladder of innovation.

We started in the 50s with the MAOIs monoamine oxidase inhibitors.

Those monoamine oxidase.

It's an enzyme that lives inside the neuron.

And its job is to chew up and break down neurotransmitters like dopamine, norepinephrine, and serotonin after they've been reabsorbed.

The MAOIs, while they inhibited that enzyme, they killed the eater.

So more neurotransmitter was left untouched, ready to be released again.

Exactly.

Levels of all the monoamines went up.

But these drugs had really dangerous interactions with certain foods.

The cheese effect.

You couldn't eat aged cheese or drink red wine.

Right.

Because those contain a substance called tiramine, which MAO also breaks down.

Without MAO, tiramine levels could skyrocket and cause a hypertensive crisis.

So we moved on to the tricyclics, which block the reuptake pumps.

But they were also kind of dirty drugs with a lot of side effects.

And then came the revolution.

The SSRIs.

Prozac, Zoloft.

Selective serotonin reuptake inhibitors.

The key word there is selective.

They were designed to very specifically target the reuptake pumps, or transporters, for serotonin only.

So if you imagine a little vacuum cleaner on the presynaptic neuron that's sucking unused serotonin back up.

The SSRIs basically cut the power cord on that specific vacuum.

They leave the vacuums for dopamine and norepinephrine alone.

So the serotonin stays in the synaptic gap longer.

It stays in the gap, accumulates, and has more time and more opportunities to bang on the postsynaptic receptors.

It effectively boosts the serotonin signal.

Next up, anxiolytics.

The drugs for anxiety.

Valium, Xanax, Ativan.

These are mostly from a class called the benzodiazepines.

And they work on the brain's main inhibitory system, GABA.

GABA is the universal brake pedal.

It's the primary off switch in the adult brain.

But benzos are clever.

They don't press the brake pedal themselves.

They're what we call allosteric modulators.

Meaning?

They bind to a different separate site on the GABA receptor.

And when they bind, they change the shape of the receptor protein, so that when the natural GABA molecule comes along, it binds better and more effectively.

So they're not the brakes.

They're like brake boosters.

They grease the wheels for the brakes.

That's a perfect analogy.

They make the GABA receptor stay open for a longer duration when GABA binds to it.

This allows more negative chloride ions to flow into the cell, which hyperpolarizes it, making it much harder to fire an action potential.

It turns down the volume on the whole brain.

That's why they reduce anxiety, but also cause sedation.

Now for the heavy hitters.

The opiates.

Morphine, heroin, fentanyl.

Humans have used opium from the poppy plant for thousands of years for pain and euphoria.

But it wasn't until the 1970s that scientists asked a very obvious question.

Why?

Why on earth do our brains have receptors for a chemical from a poppy plant?

And the answer wasn't, so we can get high.

No.

The only logical reason was that we must make our own internal version of morphine.

And they found them.

They're called endogenous opioids, or more commonly, endorphins.

Which is a contraction of endogenous morphine.

Exactly.

So when you go for a long run and get that runner's high and feel less pain, that's your brain releasing its own internal opiates.

And where do these drugs work?

They bind to several subtypes of opioid receptors.

But a key area for pain relief is the periaqueductal gray, a region in the brain stem.

Activating these receptors there effectively disconnects the brain's emotional response to a pain signal.

The signal might still be coming from your foot, but your brain doesn't care as much.

But because these receptors are also in the reward centers, they cause intense euphoria and are highly addictive.

Let's talk about a more controversial one.

Marijuana.

Kinabendoids.

The main psychoactive ingredient is THC, or tetrahydrocannabinol.

For a long time, the science was murky.

We thought maybe it just messed with cell membranes in a general way.

But in the 1990s, we found the specific receptors,

CB1 and CB2.

Which again beg the question, why do we have them?

What's the endogenous version?

The first one we found was named anandamide.

It was named after the Sanskrit word ananda, which means bliss.

That is a much more beautiful name for a molecule than acetylcholine.

What does our natural bliss molecule do?

Well, just like the gas transmitters, it's a rule breaker.

Anandamide is a lipid, a fat, so it's not stored in vesicles.

It's made on demand and just slides through membranes.

And it also acts as a retrograde messenger.

It goes backwards, from the receiver to the sender.

Yes.

And it typically inhibits the release of other neurotransmitters.

It acts as a kind of dimmer switch all over the brain.

It's involved in modulating memory formation, sometimes by promoting the forgetting of non -essential information.

And it powerfully stimulates appetite.

The munchies are scientifically validated.

Absolutely.

The hypothalamus, which controls hunger, is incredibly rich in CB1 receptors.

Okay, let's wake things up.

Stimulants.

Nicotine, cocaine, amphetamine.

Nicotine is pharmacologically quite simple.

It mimics acetylcholine.

It binds directly to a subtype of acetylcholine receptors called nicotinic receptors, which are found on muscles, but also all over the brain's cortex.

It's a direct agonist.

And that's what increases heart rate and makes you feel more alert.

Exactly.

Now, cocaine is different.

It's a reuptake inhibitor like the antidepressants we talked about.

Much more powerful.

Much more.

Cocaine blocks the transporters, the vacuum cleaners, for all the monoamines.

But it has a particularly powerful effect on the dopamine transporters in the reward circuit.

It just stops the recycling of dopamine.

So the happy chemical gets stuck in the on It floods the synapse and keeps stimulating the receptors over and over, causing that immediate intense euphoria.

And amphetamine.

Methamphetamine.

Amphetamine is like cocaine's meaner, stronger, older brother.

It does two things.

First, like cocaine, it blocks dopamine reuptake.

But second, and this is the big one, it also gets inside the presynaptic terminal and makes the synaptic vesicles leaky and it reverses the transporter, actively forcing the neuron to dump its entire reserve of dopamine into the synapse.

So it doesn't just block the vacuum, it empties the entire bank vault onto the street.

Kicks the doors open and throws all the money out.

It causes a massive unnatural flood of dopamine.

This is why it's so potent and also why the crash is so devastating.

You've literally depleted your entire ready supply of dopamine.

It can take days for the system to recover and rebuild it.

And finally, the most common psychoactive drug on the planet.

Alcohol.

Alcohol is deceptive because its effects are biphasic.

Meaning two -phase.

Right.

At low doses, in phase one, you get the buzz.

It feels like stimulation.

But what's actually happening is that alcohol is inhibiting your inhibitory systems first, particularly in the prefrontal cortex.

It inhibits the inhibition.

Yes.

It turns off the don't say that or don't do that filter in your brain.

Removing a break feels like hitting the gas.

But as the dose increases, you enter phase two.

It starts acting as a depressant all over the brain.

It enhances the function of GABA receptors, just like a benzodiazepine.

So it's boosting the breaks.

It's boosting the breaks.

And at the same time, it's blocking the receptors for glutamate, which is the brain's main excitatory gas pedal.

So you're boosting breaks and cutting the gas.

The combined result is sedation, loss of coordination as it hits the cerebellum, memory loss, and eventually at high enough doses, unconsciousness and respiratory depression.

And lastly, to bring it full circle, let's revisit Dr.

Hoffman, the hallucinogens.

Right.

The classic hallucinogens LSD, psilocybin from up rooms, mescaline from the peyote cactus.

These are primarily serotonin agonists.

They have a very high affinity for the 5 -HT2A receptor subtype, which is found in high concentrations in the visual cortex.

And that's what creates the visual effects.

Yes.

We think they disrupt the normal filtering of information and create a kind of cross -talk between brain regions that don't usually communicate so directly.

Hearing colors and seeing sounds.

Synesthesia.

Exactly.

But the chapter also distinguishes another class, the dissociatives, like PCP and ketamine.

How are they different?

They don't work on the serotonin system at all.

They are antagonists for NMDA receptors, which is a critical type of receptor for glutamate, our main excitatory neurotransmitter.

By blocking these receptors, they seem to disconnect the sensory inputs from the higher level conscious mind.

You feel detached, floaty, removed from your body and from reality.

We've covered the fun in the medicine, but we have to end this tour on the dark side of all this.

Addiction, part five.

It really is the elephant in the room for so many of these substances.

And it's important to recognize that our scientific understanding of addiction has shifted massively over the decades.

We started with the moral model.

Right.

Which basically said,

you're an addict because you have weak character and poor morals.

It just blamed the victim.

Thankfully, we moved on to the disease model, which views addiction as a medical condition, a pathology of the drain.

Then there was the physical dependence model.

Yes.

The idea that people keep using a drug mainly to avoid the horrible pain of withdrawal.

And this explains opiate addiction pretty well.

The withdrawal is physically agonizing, but it didn't explain cocaine addiction very well.

Cocaine withdrawal is mostly psychological depression, anxiety, not physically painful like heroin withdrawal.

Yet people relapse constantly, which led us to the current prevailing view, the positive reward model.

This model says that addiction is fundamentally a disorder of learning.

It's a hijacking of the brain's natural reward system.

And we learned this from rats in a box.

We did.

If you put a catheter in a rat's brain and give it a lever that it can press to self -administer a dose of cocaine, it presses the lever.

It presses it thousands of times.

It will ignore food.

It will ignore a sexually receptive mate.

It will cross a painful electric grid to get to the lever.

It will press that lever until it dies of exhaustion or starvation.

It's clearly not pressing the lever to avoid pain.

It's pressing because the drug has short -circuited the reward system.

It has short -circuited the mesolimbocortical dopamine pathway, specifically the release of dopamine in the nucleus accumbens.

The wanting system.

Exactly.

Neuroscientist Kent Barrage makes a crucial distinction between liking a drug and wanting it.

Dopamine isn't the pleasure chemical.

It's the motivation chemical.

It's wanting.

And these drugs stimulate that wanting system with a power and speed that no natural reward, not food, not sex, ever could.

The brain learns one thing.

This is the most important thing in the universe.

Get more.

So how do we treat it?

I mean, if the brain's hardware is literally rewired and hacked by the drug, can we ever patch it?

It's incredibly difficult.

We have agonist therapies like giving methadone to an opiate addict, which is a safer, slower opiate to taper them off.

We have antagonist therapies like naltrexone, which blocks the opiate receptors so you can't get high.

But the chapter ends by mentioning a new frontier that sounds like straight out of science fiction.

A vaccine.

Vaccine.

For cocaine.

How would that even work?

The idea is to create a vaccine that stimulates your immune system to build antibodies that specifically recognize the shape of the cocaine or heroin molecule.

Okay, wait.

So if I have this vaccine in my system and then I try to snort cocaine?

The cocaine molecules enter your blood stream.

The antibodies, which are now circulating in your blood, immediately swarm the cocaine molecules and latch on.

And then what?

The antibody cocaine complex is now a huge, bulky molecule.

It's far too big to pass through the blood brain barrier.

So the drug never even touches the brain.

It never reaches the brain.

You feel absolutely nothing.

No high, no reward.

The entire reinforcement loop is chemically severed before it can even begin.

That is incredible.

It's like putting a biological firewall on your brain.

It's showing a lot of promise in animal trials.

It changes the entire paradigm from a battle of willpower to a matter of immunology.

Wow.

We have covered so much ground.

From a forgotten fungus in a Swiss lab in 1943 to a potential vaccine for addiction.

It really highlights the central theme of this whole chapter.

We are electrochemical beings.

Our thoughts, our feelings, our moods, our darkest addictions, and our highest moments of creativity.

At the most fundamental level, it's all just molecules binding to receptors.

And that line between a drug and a medicine is much, much thinner than we like to think.

It's often just a matter of dose, context, and intent.

As the chapter points out, we're still clinging back to Hoffman's discovery.

LSD was first explored as a way to model psychosis, but now clinical research is looking at hallucinogens again, this time as powerful tools for treating disorders like severe depression and PTSD.

So the key that locks you in can also be the key that sets you free.

It all depends on which lock you turn and how you turn it.

It shows how our understanding is constantly evolving.

A fantastic and provocative thought to end on.

Thank you for listening to this massive deep dive into the chemistry of behavior.

It was a true pleasure.

This has been the Last Minute Lecture Team.

You are now armed with the basics of neurochemistry.

Use them wisely.

Sign off.