Neural Communication II Flashcards
how does neuronal trasmission begin in the axon terminal?
- axon ends in terminal boutons (buttons) that have vesicles filled with neurotransmitters
- action potential travels to bouton and depolarizes
- causes voltage-gated Ca++ channels to open
- Ca++ causes vesicles to fuse with membrane
- neurotransmitters are released into the synapse
- dendrite membrane has receptors that fit with neurotransmitters
- receptors are often just closed channels that open when they bind with neurotransmitters
- also called ligand-gated ion channels
what are the different types of receptors?
- ionotropic receptors (ligand-gated ion channels)
- metabotropic receptors (GPCRs)
what are ionotropic receptors?
- let ions cross, ligand-gated ion channels
- activate EPSPs and IPSPs by allowing ions to cross the membrane
- excitatory (depolarize) - Ca crossing
- inhibitory (hyperpolarize) - Ch crossing (Chloride)
- fast, transient effect - when neurotransmitter is no longer binded, effect is gone
what are metabotropic receptors? what happens when neurotransmitters bind to them?
- signalling proteins: G-protein-coupled receptors (GPCRs)
- don’t directly change voltage or allow ions to cross, they have a metabolic effect
- neurotransmitters bind and G proteins break off and activate in the cell
- activate or inhibit process in the cell
- they modulate the cell and modulate signals
- slow, longer lasting effect
what are some examples of modulatory effects of metabotropic receptors?
- can activate signalling molecules
- can change transcription and translation
- can open or close other channels
- cause signal cascades
what are the common receptor locations?
- postsynaptic side - most common (dendrite)
- presynaptic - on the axon
what are some examples of receptors that are on the pre-synaptic side?
autoreceptors and heteroreceptors
what are autoreceptors and what do they do?
- usually GCPRs and have an inhibitory effect
- accepts it’s own released neurotransmitters (dopamine)
- uses negative feedback to make sure not too many neurotransmitters are released
what are heteroreceptors and what do they do?
- modify how the synapse works
- binds to a different neurotransmitter than the one released by the axon
- also modular, increases or decreases neurotransmitter activity (the amount released)
- affect lingers for a little
in what ways are neurotransmitters cleaned up?
diffusion, enzymatic degradation, re-uptake
how does diffusion work to clean up neurotransmitters?
- neurotransmitters just float away
- not the best solution because they’ll bind to other receptors
- only happens when the goal is for the neurotransmitter to bind to other targets
how does enzymatic degradation work to clean up neurotransmitters?
- enzymes break down neurotransmitters into components (COMT, MAO)
- not the best solution either because we have to use energy to make the neurotransmitter again
how does re-uptake work to clean up neurotransmitters?
- transporters push molecules back into the cell (back in axon) and back into the vesicles
- DAT - transporters on the membrane pack the neurotransmitter into the axon
- VMAT2 - transporters on the vesicles pack the neurotransmitter into the vesicles
- done in both the pre-synaptic side and the astrocytes
what are the two main drug types?
- agonist - increase effects in neurotransmitter system
- antagonist - decrease effects in neurotransmitter system
what is glutamate?
- the primary excitatory neurotransmitter that is used throughout the brain
-
ionotropic receptors
- AMPAR - binds to AMPA drug
- NMDAR - binds to NMDA drug (also allows calcium in, important for learning)
- kainate receptor
-
metabotropic receptors - some are excitatory, and some are inhibitory
- mGluR
- our autoreceptor on the axon is a metabotropic receptor
- effect depends on what Glutamate binds to, it’s not always excitatory
- often not a great target for drugs because it’ll affect the whole brain
what are some glutamate antagonists? what does it mean to be a glutamate antagonist?
- means we decrease glutamate activity, which decreases overall brain activity
- barbiturates - lethal injection
- nitrous oxide - laughing gas
- ketamine - “horse tranquilizer”
- ethanol - drinking alcohol
- at lower levels → relaxation, at higher levels → diminished consciousness, less brain activity
- agonists don’t work because glutamate already works at a very high level - too much = extreme anxiety and even seizures
what is GABA?
- primary inhibitory neurotransmitter that is used throughout the brain
- has both ionotropic and metabotropic receptors
- GABA-A - ionotropic Cl- receptor, which makes cell more negative and inhibits (IPSPs)
- GABA-B - metabotropic receptor causes inhibition
- also not a great target for drugs but better than glutamate because it isn’t as universal in the brain
what are some gaba agonists? what does it mean to be a gaba agonist?
- means we increase gaba activity, which decreases overall brain activity
- benzodiazepines - anti-anxiety medication
- ethanol - drinking alcohol
- chloroform - used to make people lose consciousness
- ether - an anesthetic previously used
- at lower levels → relaxation, at higher levels → diminished consciousness, less brain activity, death
- antagonists don’t work very well, would result in anxiety, just like glutamate agonists
what are amines? what are some examples?
- small molecule neurotransmitters that are metabotropic and play a modulatory role
- released into brain area and hit many neurons
- dopamine (DA), epinephrine (adrenaline), norepinephrine (noradrenaline), serotonin (5-HT), histamine
where does dopamine originate from?
- originates from two nuclei in the tegmentum
- substantia nigra pars compacta - axons go to basal ganglia
- ventral tegmental area - axons go to basal ganglia and other brain areas
- projects to some (but not all) brain areas
- DA also made in hypothalamus, where it is a hormone
where do we get dopamine from?
-
precursors from diet: tyrosine - in foods with high amino acid content, protein (and phenylalanine)
- converted from tyrosine and phenylalanine into DA via enzymes
- overlaps with norepinephrine, they are both catecholamines
what are the dopamine receptors like>
- five dopamine receptors: D1R-D5R / D1-D5
- all metabotropic
- some positive modulatory, some negative
what is the olds and miler experiment? what did it tell us about the role of dopamine?
- Olds and Milner (1954) - meant to target the brainstem, but mistakenly hit a bundle of axons from ventral tegmental area (VTA) to nucleus accumbens (NAcc) in rats brain
- when a rat hit a lever, it stimulated axons that released neurotransmitters (dopamine)
- rat would hit the lever until they passed out
- researchers came to the conclusion that dopamine → pleasure
what was the study done in response to the olds and milner study? what did that study tell us?
- same study was done on humans, they self-stimulated dozens of time in a day
- they said they felt somewhat unpleasant
- clicking the button made them feel like they were gonna remember something on the tip of their tongue
- concluded that dopamine does not equal pleasure
what relationship does dopamine have with drugs of addiction?
- all addictive drugs directly or indirectly increase dopamine transmission
- what they all have in common is that using them makes you more likely to seek them in the future
- levels of pleasure don’t get higher than the first couple hits, but people keep doing it
- people chase the initial feelings of euphoria
what are some drugs that increase dopamine transmission?
- amphetamine and cocaine directly increase dopamine transmission
- heroin, nicotine, oxycodone, ethanol and cannabinoids indirectly increase dopamine transmission
how does Parkinson’s disease relate to dopamine? what does this tell us about dopamine and pleasure?
- Parkinson’s is associated with loss of dopamine in substantia nigra pars compacta (SNc)
- loss of dopamine results in a loss of voluntary behaviour, but NOT a loss of pleasure
- there is a relationship between Parkinson’s and levels of pleasure, but is strongly correlated to motor skills
- think that it may not be from loss of dopamine, but the loss of autonomy
what is the treatment for Parkinson’s? what does this tell us about dopamine and pleasure?
- L-DOPA is a Parkinson’s Disorder treatment
- DOPA is already created in the brain
- when we insert L-DOPA into brain, the brain will create dopamine
- L-DOPA treatment improves motor function but doesn’t necessarily increase pleasure
- D1 agonists have been used in the past, but too much of them and too much L-DOPA have negative side effects (impulse problems)
- shopping and shoplifting compulsivity, severe gambling, hyper-sexuality
- when you give L-DOPA to healthy participants, it has no impact on positive mood
how does schizophrenia relate to dopamine? what does this tell us about dopamine and pleasure?
- dopamine theory of schizophrenia → unusually high levels of dopamine
- individuals with schizophrenia do not have higher baseline pleasure
- dopamine receptor (D2R) antagonists treat schizophrenia (block dopamine)
- the more effective D2R antagonists were in the brain, the better they treated schizophrenia by blocking D2R
what did Salamone’s T-maze task tell us about dopamine, pleasure, and motivation?
- had a maze that was designed so that low effort = low reward and high effort = high reward
- control - rats usually go for high effort and high reward option
- dopamine antagonist - rats go for low effort and low reward instead
- if DA was pleasure, they would be at a deficit for pleasure and would want to get the higher reward
- in reality, DA antagonist made them less motivated to go for the high effort, high reward
- giving a dopamine antagonist = decreased motivation but not pleasure
how do we know that dopamine release is related to reward prediction error?
Schultz et al. (1990s) - study on Pavlovian learning, classical conditioning
- at first, DA neurons fire for unexpected rewards
- then, they start associating the light with grape juice (reward)
- then, DA neurons only fire to the stimuli that predicts the reward (light)
- another condition where the light goes up but no reward is given: the neurons still go off when the light turns on, but they go silent when the predicted reward is not delivered
- dopamine goes up when something unexpectedly good happens, and goes down when something unexpectedly bad happens
what is the reward prediction error and how is dopamine release related?
reward prediction error - when an outcome is better or worse than expected
- dopamine release is related to reward prediction error
- when something better than what we expect happens, dopamine rises
- when something worse than what we expect happens, dopamine decreases
what does dopamine actually do?
- important for movement, especially motivated movement
- important for learning as related to movement and motivation
- important for levels of arousal, attention, executive function
- it is NOT the pleasure molecule
what is norepinephrine? how does it impact memory?
- works very similarly to epinephrine, both are hormones and a neurotransmitters
- originates in brain stem region called the locus coeruleus
- norepinephrine projects all over the brain
- affects baseline levels in wakefulness and arousal and also fluctuate according to stress
- enhances memory based on stress/emotion, arouses brain areas and gets the system ready to better remember things
- affects flashbulb memories, vivid memories of a time that was emotionally charge
- evolutionarily useful, things that are stressful or emotional are the most valuable
what are norepinephrine receptors like?
- has two main receptor types (⍺1-2, β1-3 - alpha and beta) with subtypes & sub-subtypes
- all metabotropic (GPCRs)
- causes heterosynaptic facilitations via heteroreceptors
how has propranolol been used in relation to PTSD? explain why it works.
- PTSD is a result of the strong emotions and strong memories caused by norepinephrine
- propranolol (beta blockers) is a norepinephrine receptor antagonist, originally used for heart conditions
- take propranolol and recount traumatic event while body is relaxed, memory is supposed to be reconsolidated differently (can treat PTSD)
- the reason this might work is that memories are fragile and malleable when they are recounted over and over again
- talking about the memory again brings it into working memory, put it into long term memory differently
in what other context was propranolol used as treatment?
- also tried this treatment of people who recently had a breakup
- made them think of how their significant other was a jerk
- resulted in less heartbreak
what is serotonin? what are its receptors like?
- primarily released from the raphe nuclei (brain stem)
- projects all over the brain, especially the cortex, thalamus, cerebellum
-
precursor: tryptophan in amino acid rich foods (protein)
- can’t get across blood brain barrier without carbs, which means serotonin decreases
- serotonin depleted when tryptophan is taken away or prevented from absorption
- there are 15 receptor types, almost all are metabotropic (modulatory)
what happens when serotonin from diet is depleted?
- serotonin depleted when tryptophan is taken away or prevented from absorption
- don’t necessarily see mood go down, but we lose cognitive flexibility
- increases impulsivity and aggression
- found that for people who had no family history with depression, serotonin depletion did not result in mood change
- people with a family history of depression experienced decrease in mood when serotonin was depleted
what are SSRIs and how do they work?
Selective Serotonin Reuptake Inhibitors
- medication used for depression that makes serotonin floats in synapse for longer, acts as serotonin agonist
- prozac/fluoxetine
- SSRIs are selective, but also affect DA and NE systems
- effects of SSRIs in the brain are quick (45min-1 hour), but improvements are slow (2 weeks)
how effective are SSRIs?
- producers of fluoxetine didn’t publish studies on it’s usefulness
- there was a significant publication bias
- original meta-analyses determined that SSRIs are no better than placebo for mild to moderate depression
- may help with major depression but effect size is relatively small
- 80% of doctors said they’d prescribe it to a patient but only 40% said they’d take it themselves
what are hallucinogens? what do they tell us about serotonin and mood?
psychedelic drugs that act on serotonin receptors (agonists)
- LSD, DMT, psilocybin
- radical changes to our conscious perceptions and thoughts, minimal effects on mood
- 1/3 of people on psilocybin said it’s the most eye-opening, amazing experience
- 1/3 of people also said it was extremely anxiety provoking
- have been useful in end of life care, PTSD, addictions, and more
- serotonin is not simply a mood molecule
- serotonin organizes cortical networks that see and feel patterns in the sensory world
- serotonin agonists cause the brain to find patterns that don’t exist
what is acetylcholine?
- first discovered neurotransmitter
- seen at the neuromuscular junction - used for muscle contraction
- also in the basal forebrain
- related to wakefulness and attention
how is nicotine related to acetylcholine?
- nicotine is a acetylcholine receptor agonist
- lots of acetylcholine receptors in the gut, too much nicotine causes lots of activation in that muscle and causes discomfort
what are endocannabinoids?
- two neurotransmitters that bind to two different receptors (GPCRs)
- bind to metabotropic receptors and are inhibitory
- weaken the connection between two cells at a synapses
- same system that is used when we are trying to forget things
where are the endocannabinoid neurotransmitters stored, and why?
- neurotransmitters are produced in the dendrite
- retrograde transmission - move from dendrite to axon
- aren’t stored in the vesicles because the molecules are good at getting across membrane
- instead, enzymes make and release neurotransmitter from the dendrite when the drug enters
- cannabis (THC, CBD) is a cannabinoid receptor agonist
- there is a relationship between cannabis use and problems with long-term memory retention
what is adenosine?
- byproduct of metabolic activity (ATP), not necessarily a neurotransmitter
- phosphate groups break off of ATP until there are none left, and it’s just adenosine
- brain is covered in adenosine receptors, they are metabotropic and inhibitory
- adenosine receptors bind (inhibitory) and makes us tired during the day
- may be the reason for daytime sleepiness
how does caffeine interact with the adenosine system?
-
caffeine/theophylline - molecules bind to adenosine receptors, are antagonists
- block the inhibition, make us feel more awake
- tolerance builds up as cells adapt and add more adenosine receptors
- need more caffeine to keep us awake
- experience caffeine withdrawals in the mornings
- after about a month of no coffee, body will recognize that there is too much adenosine
- extra receptors will be removed
what are endogenous opioids?
- giant peptide neurotransmitters that are also called endorphins (endogenous-morphine)
- are used as pain killers
- receptors are all GPCRs (inhibitory and metabotropic)
- Mu and Delta receptors
- receptors found in spinal cord, periacqueductal grey (PAG), nucleus accumbens, more
- we have a release of endogenous opioids when body is trying to avoid pain in stressful situations
- ex. mom in a car accident with a broken leg saves their child before passing out
what exogenous opioids mimic the endogenous opioid neurotransmitter system?
- heroin - opioid agonist
-
fentanyl - even stronger opioid agonist
- can be fatal if dosing is wrong
-
naloxone - opioid antagonist
- used to treat people
