Lecture 5 Flashcards
Discuss the two main effects of drugs, including why it can be complicated
Receptors
Psychoactive drugs—acting on synapses, exerting their effects
Don’t need to memorize these effects
Basic effects
Turning a neurotransmitter system up, or down
Can block reuptake—increasing signal, blocking enzymes can also cause increases, because the effect draws out—slower
Agonist
A drug that turns up a function in a specific neurotransmitter system
Not function of the brain, in fact, the opposite occurs
Antagonist
A drug that turns down a function in a specific neurotransmitter system
Other
E.g. transporter blocker, reuptake inhibitor, enzyme inhibitor
Small-Molecule Neurotransmitters
Glutamate neuron releases glutamate—they are named after their neurotransmitters
Most neurons don’t release more than one neurotransmitters—this is called co-occurrence
They will release one small-molecule (many are named after this) and a large molecule
Amino-acids
what is Glutamate
our primary excitatory neurotransmitters
Stains for glutamate receptors/enzymes will turn the entire brain to change color—they’re very common
Ionotropic receptors (glutamate is common)
AMPAR (glutamate receptor)
NMDAR (also allows calcium aside from sodium)
Kainate receptor
Metabotropic receptors
mGluR 1-8
Mostly positive modulator, increasing effect
Some are autoreceptor
Often not a great target for drugs—why
Cannot localize effect, changes the overall function of the brain, therapeutically impacts the whole system
Drugs: all glutamate antagonist—blocking signals, leading to a reduction of brain activity, sometimes leading to death
Barbiturates: common sedative, part of lethal injections
Nitrous oxide: laughing gas at the dentist office
Ketamine: is horse tranquilizer, sedative and dissolactive effects
Ethanol: drinking alcohol
Glutamate agonists—the glutamate system operates closer to an optimal functioning, so going beyond that wouldn’t help, just causing intense anxiety and seizures (too much brain activity)
Amino-acids
What is GABA
aka gamma-Aminobutyric acid
Primary inhibitory neurotransmitter
Ionotropic and metabotropic receptors
Ionotropic: GABA-a (chloride receptors)
Metabotropic: GABA-b
Drugs: All GABA agonists—drug that increases the function of GABA, which means you increase inhibition, and the brain becomes less active
Dampening the brain activity lessens anxiety
All the drugs are sedating
Benzodiazepines
Anti-anxiety medication
Xanax or ativan
Used recreationally for ages
Ethanol
Alcohol, decreases excitation and increases inhibition
Chloroform
Relatively fast, but not instant
Ether
Common gas anesthetic, used for surgeries but no longer used
Fun fact: Doctors used to throw ether parties
GABA antagonist, blocks inhibition and be very unpleasant
Glutamate agonists look a lot like GAB antagonists, etc.
Monoamines
What is dopamine*
Originates from two nuclei in the tegmentum
Substantia nigra pars compacta
Ventral tegmental area
Projects to some (but not all) brain areas
Mainly in the basil ganglia and some other structures
DA is also made in the hypothalamus
Here, it’s a hormone (not important to this course)
Precursor from diet: tyrosine (and phenylalanine)
Converted into DA via enzymes
Overlaps with norepinephrine
They are both catecholamines
Five DA receptors: D1R-D5R / D1-D5
All metabotropic
Some positive modulatory, some negative
The pleasure/reward molecule? (NO)
Motivation for brain stimulation?
1950s: Olds and Milner (1954)
Dopamine axons project from the Ventral Tegmental Area (VTA) to the Nucleus Accumbens (NAcc)
Created stimulation
conclusion that dopamine is related to pleasure
Caution: interpretation could go further than simply relating to pleasure
Drugs of addiction and dopamine
All addictive drugs directly or indirectly increase dopamine transmission
implication?
Amphetamine, cocaine, heroin, nicotine, oxycodone, ethanol, cannabinoids, and on and on
*directly increase DA transmission
Caution: little high using drug later on in the drug use cycle yet are so motivated to use it
Intense need to be satisfied but not necessarily pleasurable
Dopamine and Parkinson’s Disease (PD) (LOW DOPAMINE)
PD caused by the loss of the substantia nigra pars compacta (SNc)
Those dopamine neurons
Dopamine levels plummet
What we don’t see a strong relationship to pleasure
PD is a motor disorder
L-DOPA as gold standard PD treatment
L-DOPA can cross the blood barrier and is then converted to dopamine
Dopamine isn’t a super targetted system
PD, L-DOPA, and pleasure?
We see this in movement disorders but not loss of pleasure
loss of pleasure seen from lost of ability to move
Other PD drugs (e.g. D1 agonist)
PD drug side effects? (Not pleasure)
Related to impulsive behaviour
What about L-DOPA for healthy participants?
Does not directly impact good mood
Dopamine and schizophrenia (HIGH DOPAMINE)
Schizophrenia medications are dopamine D2R antagonists
Block dopamine receptors
The better the antagonist is the better it blocks dopamine receptors
Dopamine theory of schizophrenia
Hallucination, delusions, and disorganization
Do individuals with schizophrenia have higher baseline pleasure? (NO)
Monoamines
What is Norepinephrine*
(aka Noradrenaline)
Both a hormone and neurotransmitter!
Where it’s released differs, in the blood as a hormone or for the brain
As NT, it originates in brain stem region called the locus coeruleus
“The blue location”
NE projects all over the brain
Alot of DA just goes to the basil ganglia while these go everywhere
Two main receptor types (⍺1-2, β1-3) with subtypes & sub-subtypes
All metabotropic (GPCRs)
slower-acting , g-proteins
NE and epinephrine act similarly, on same receptors
Bind to the same receptors that do mostly the same thing, can treat them as the same system
Causes heterosynaptic facilitation (via heteroreceptors)
Look back at last lecture, acts on pre-synaptic
Baseline levels in wakefulness/arousal
Enhancement of memory by stress/emotion
Brain’s fight-or-flight
What is serotonin*
Still in Monoamines
Originates from a nuclei that runs along the reticular formation
referred to the Raphe (Seam) nuclei
Long and spread out, like the seam of your shirt
They project all over the brain; esp. cortex, thalamus, cerebellum
thalamus in particular
Lots of receptors—15 types
The only exception of one receptor is ionotropic—but all others are metatropic
the latin term for seam, long and spread out like the seams of your pants
what is SSRIs*
Selective serotonin reuptake inhibitors (SSRI)
aka SSRIs, e.g. Prozac (fluoxetine)
For depression (but also anxiety and even OCD)
“Chemical imbalance” theory of depression
“Depression is due to chemical imbalance”
Jay says they don’t measure your chemicals in the hospital
History of monoamines implicated in mood disorders
Someone in the 70s wrote this statement suspecting it but people took the first half of the statement and ran with it
Block serotonin from being removed from the synapse
SSRI block transporters, spend more time in the synapse to bind to the receptors, working as a serotonin agonist
Effects of SSRIs quick, improvements slow
Chemcially they work quickly, blocking transporters
But takes up to 1 month to take effect
SSRI efficacy
Major problem in publication bias (not all results in studies are published, only those with impressive results)
Limits our ability to make sense of the data
Now drug is on the market and allowed everyone to make studies about it
Original meta-analyses: SSRIs no better than placebo for mild to moderate depression
May help with major depression
Effect size is relatively small
What are Hallucinogens*
Psychedelic drugs like LSD, DMT, psilocybin etc. are serotonin receptor agonists!
Potent serotonin agonist, mimic serotonin
Radical changes to our conscious perception and thoughts
Perceive patterns, radical changes BUT MINIAL EFFECTS ON MOOD (implication?)
Youre increasing serotonin but not increase mood, not euphoric and not addictive
Recent reexamination of psychedelics’ therapeutic value: end of life care, PTSD, addiction, and more
Serotonin: not simply a “mood molecule”
What is Acetylcholine*
The first neurotransmitter discovered, acetylcholine is crucial at the neuromuscular junction, where it facilitates muscle activation
Acts like a dendrite
Acetylcholine also plays a role in overall levels of attention and wakefulness in the basal forebrain
Overall levels of stimulation
Nicotine is an acetylcholine receptor agonist, stimulating acetylcholine receptors
Muscles are covered in nicotine receptors
We learn about nicotine first, then receptors after
A large amount of nicotine—you would feel sick, you activate smooth muscle
The only reason the name is different is because the naming conventions of scientific findings —whatever comes first is named, even when later on they discover that they do the same thing
What are Endocannabinoids*
Endocannabinoids
Recently discovered neurotransmitter system
Endocannabinoids are neurotransmitters that travel in the opposite direction from dendrites to axons, known as retrograde transmission (like going in the same lane, but opposite direction)
They are efficient at crossing membranes and slipping through, they don’t sit around doing nothing—and weaken synaptic connections
THC (in cannabis) is a cannabinoid receptor agonist, while CBD’s mechanism is less clear
Weird one: this neurotransmitter comes from the dendrites, not axons
You will make them on demand in the dendrites, and they travel backwards to the axons
Don’t memorize names—just that there’s two neurotransmitters in the same system
What is Adenosine*
Adenosine
Ties in ATP production—producing cellular production
Levels of adenosine build up across a day
All of our cells across the brain have receptors to receive this signal—that adenosine is building up
These adenosine receptors are coupled with g-proteins, and are largely inhibitory
Building across the day —> inhibition is building up across the day
Responsible for daytime sleepiness
Multiple systems are active for sleep, but adenosine drives the feeling of sleepiness
Caffeine/theophylline
Both of these bind to adenosine receptor, and blocks the effect of adenosine
Which makes us feel more awake
Adenosine receptors
Thorough out the cells, all across the brain
G-protein, inhibition
Adenosine responsible for daytime sleepiness
What are Endogenous Opioids*
AKA Endorphins (AKA Endogenous morphine)
These are large neurotransmitters that bind
Just understand that these are multiple neurotransmitters, despite being called an opioid
The gold standard for pain relief
As opposed to other avenues
Morphine and fentanyl—all opioids—bind to opioid receptors
An agonist drug
The health crisis happening in BC right now—outnumbering all other accidental deaths, car crashes, Covid-19, etc.
The issue is the toxicity
EX. Fentanyl is much stronger than heroin, which is much stronger than morphine
Opioid antagonist
Counteracting the effects—naloxone
The effects of naloxone are fast—for only about 20 minutes
Receptors are found directly in the spinal cord and basal ganglia
Pain is a valuable signal sometimes (EX. taking care of your arm and hand when you get burned)—but not all the time (EX. when you’re in the heat of the moment and you need to focus)
Is dopamine the “pleasure molecule”?*
Fluctuating dopamine levels—parkinson’s = low levels
L-DOPA = better movement
No fluctuation in baseline levels of pleasure
Schizophrenia—positive symptoms like hallucinations and delusions
High basel;ine dopamine does not equal higher baseline level of pleasure
Psychostimulants
The emergence of psychosis
Symptoms close to schizophrenia
Important for movement, motivation, learning as related to movement and motivation
Important for levels of arousal, attention, executive function
More on all of these later
It is NOT the pleasure molecule!
Example one: Separating pleasure from motivation rat experiment
Example two: Dopamine and reward prediction error
Is norepinephrine the “memory molecule”?*
Norepinephrine’s Role in Memory: Norepinephrine (NE), also known as noradrenaline, is a neurotransmitter and hormone involved in the brain’s stress and fight-or-flight response. During intense or emotionally charged events, norepinephrine is released, enhancing memory consolidation—specifically, it makes emotionally significant memories more salient and easier to recall later. This evolutionary mechanism ensures that people remember potentially dangerous or life-threatening situations (e.g., flashbulb memories) to avoid them in the future.
Evolutionarily useful
During intense events, you have to stay alert on dangerous situations, you don’t want to forget this
Flashbulb memories, “whatever is happening right now is important, hang onto it”
but…
Post-traumatic stress disorder (PTSD) and propranolol
High levels of norepinephrine that creates very strong memories of trauma
Intrusive and very negative, may leads to dissociation from even the smallest trigger
Propranolol (norepinephrine receptor antagonist, aka noradrenergic receptor antagonist, aka “beta blockers”)
Not for your brain but for your heart, reduce heart-rate by blocking beta receptors for norepinephrine and noradrenaline
Potential PTSD treatment via reconsolidation
Working memory → stored into long term memory (process of consolidation)
When you retrieve a memory, you lay it down and reconsolidate the memory, when you do so, they’re flexible and can be distorted and we fill in gaps through reconstructions
The idea is to take advantage of this through propranolol
You give them propranolol in therapy session then ask them to recount and talk about the trauma to be reconsolidated to be calmer with the norepinephrine blocked
Memories aren’t gone but modified
What are the ethics?
Main source of cases done in the military as they can’t say no to their superiors
Is it like Eternal Sunshine of the Spotless Mind?
Not really, but not entirely unalike
Side effects: if you have heart conditions, slowing it down can be dangerous
Is serotonin the “mood molecule”?*
Serotonin does come in turkey (or tofu, anything with lots of protein)—from tryptophan
To get across the blood-brain barrier, you need both tryptophan and carbohydrates to move
If only tryptophan is there, it’s hard to get into the brain
Low carbs, high protein diet—Serotonin depletion effects
Human studies done where people live in a lab for a few days
Condition 1: eating food provided by the lab
Condition 2 (control): eating food you regularly would eat
Condition 3: eating food that is slightly chemically altered to prevent you from getting any tryptophan
Selectively reduced levels in a serotonin in your brain
Strongest effect is in cognitive flexibility
Stroop task: identifying word red with color blue (colors don’t match with word content)
This is a task of cognitive flexibility
How do you study aggression: punishing other players way more severely when serotonin is depleted (but you don’t see a decrease in mood)
Even though serotonin is related to mood
In a general population
In follow-up studies
Participants with no history of mental illness or depression (but some participants had family history)
People with no depression (but family history) showed lower mood when showed serotonin depletion when having a tryptophan-reduced diet
People with no depression (and no family history) showed no effects on mood
