CHAPTER 2 LECTURE NOTES
- There the communication between neurons so the primary side of action in which a neuron in
which neurons communicate is at the synapse
- so here you can see we have a presynaptic cell and we have a postsynaptic cell our actual
potential will travel down our Axon of the presynaptic cell once it is in the terminal button
button or the pre synaptic terminal that action potential will initiate the influx of calcium so
calcium will come in here and that is what actually activates the vesicles and causes them to
fuse with the cell membrane.
- once they fuse with the cell membrane they release their neurotransmitters those
neurotransmitters travel across the synaptic cleft and bind to receptors on the post synaptic cell
and these the binding is specific so these receptors have specific neurotransmitters that that
they bind to they will bind to more than one neurotransmitter.
othey tend to have a neurotransmitter that they find the best with and so if that’s
dopamine we would say this this is a dopamine receptor and following that binding this
will produce a an effect in our postsynaptic neuron
▪effect might be opening a channel it might be activating a second messenger
system.
- binding does have an effect on that receptor.
- GET PICTURE so this is just an electron microscope picture of a synapse so you can see this little
area here so that’s the synaptic cleft presynaptic membrane postsynaptic membrane and these
are what are are called Omega figures
othis is what happens when the vesicle binds with the membrane so here this presynaptic
cell would be releasing neurotransmitter into the synaptic gap travels across the gap
binds to receptors in the postsynaptic cell and here are our vesicles so all of these are
vesicles containing neurotransmitters packaged and ready to be released in the post
synaptic cell so we have about 100 different types of neurotransmitters most
neurotransmitters are produced near the synaptic cleft there’s are some exceptions.
▪they’re stored in the vesicles that’s for the protection of the neurotransmitters
cause we have enzymes inside the cell that could break them down and also for
the protection of the presynaptic cell so
•for example dopamine if release within the cell will actually kill the
dopamine cell so when the action potential reaches the synapse
calcium comes rushing into the cell and that is what signals the best
cycles to fuse with the membrane then releasing neurotransmitter into
the synaptic cleft so let’s talk about the types of receptors that that we
have on our postsynaptic cell so this is a postsynaptic receptor and we
would call this receptor a ligand gated receptor because it’s opened by a
ligand and a ligand is just a word for a chemical messenger so a
neurotransmitter is a specific type of ligand OK so here let’s say that this
is acetylcholine so we have a RC coline molecule it’s been released by
our pre synaptic cell it’s binding to a receptor on her post synaptic cell
so we have a binding site here where it fits in activates our receptor it
opens and sodium comes rushing in right so and that’s gonna change
the voltage of our postsynaptic cell which in turn changes the
probability that the cell will fire right so if it’s if it’s sodium it’ll increase
the probability that it fires if this was chloride it would decrease the
probability that it would fire OK so again this is a post synaptic receptor
and it’s changing the post synaptic potential right so the potential just
refers to the voltage inside the cell so we’re changing that we if it’s
again if it’s positive we’re making the inside of the cell more positive
and this is a ligand gated perceptor so we have two different types of
ligand gated receptors we have the ionotropic which is what we just
talked about right and we have the metabotropic So what makes the
metabotropic or sometimes called G coupled proteins different is that
again we have the the ligand or our neurotransmitter it’s gonna bind to
an area within to a a binding site in our receptor but this time instead of
the action of the receptor occurring at the binding site it’s gonna occur
at a second location so this binding well activated G protein which in
turn releases a second messenger that second messenger goes to
another location so in this case that is a ion channel so activates that ion
and sodium comes into the cell so this producing an epsp or excitatory
postsynaptic potential increasing the voltage of the cell increasing the
probability that the cell we’ll fire now second messenger systems can do
other things right so they can go into the nuclei and they can alter the
production of proteins they can upregulate the production of different
types of receptors so they’re much more flexible they have a lot more a
lot more roles that they can fulfill so let’s look in general at the
difference between ionotropic perceptors and metabotropic receptors
so ionotropic receptors are fast right we saw that they don’t need that
second messenger system they don’t have to go to a second location
they can open a channel and they can close a channel very very quickly
metabotropic receptors on the other hand while they’re slower they
also their effects tend to last longer so that makes sense if we’re
changing gene if we’re altering gene regulation that is going to last
much longer so we’re turning on and off jeans propagating down
regulating protein production a number of other things but they tend all
of those things tend to last longer so in general we would say that they
could cause or alter the biochemical reactions within the neuron so just
as a review we have our ligand gated channels we just talked about so
they’re gonna be activated by a neurotransmitter which is a ligand and
that is gonna change the voltage of our cell right so those ions that
come in are going to diffuse across the cell and that eventually if we
have enough of those could activate a voltage gated channel so this
channel is opening in response to the change in voltage right the change
in ions versus the ligand gated channel which is opening in response to a
neurotransmitter I remember these voltage gated channels are only at
the Axon hillock and the Axon because they’re involved with the
production of an action potential whereas these ligand gated channels
are involved with the production of a E PSP or an IP SP so a post
synaptic potential change let’s talk about these postsynaptic potentials
so we can either have a excitatory postsynaptic potential or an
inhibitory post synaptic potential so either an EPS P or an IP SP an EPS P
is always going to increase the neurons firing right because it's causing
the cell to get more positive therefore it’s getting closer to that gated
threshold so increases neuronal firing it’s always due to sodium influx so
that’s easy and it depolarizes itself so that’s what I was saying about
increasing the voltage right so it’s depolarizing the cell when the cells
are resting potential it’s negative OK so and I PSP or an inhibitory
postsynaptic potential is going to decrease neuronal firing and it could
be due either to potassium leaving the cell so if we’re losing positive
ions the inside the cells becoming more negative and therefore it’s
getting further away from that that gated threshold or it could be due
to chloride ions coming into the cell so if we’re adding negative ions the
cells becoming more negative so we would say that it’s hyperpolarizing
the cell so that would decrease the probability that our cell fires so it’s
important to remember though that this is a graded potential so unlike
the action potential which is all or nothing we can have a very small E
PSP or a large epsp we can have a very small ipsp or very large ipsp so
that’s why we say that it’s a graded potential OK so let’s talk about
signal termination so once we’ve released a neurotransmitter it crosses
the synaptic cleft it binds to a receptor what happens then does it just
continue to bind to the receptor does it have its effect you know to
Infinity or what happens so you may have guessed they hit the signal
does get terminated but let’s talk first about why that’s important right
so why is it important that that signal not just continue one of the
reasons is temporal resolution so you know that’s especially important
if we’re talking about something like motor output so if I’m playing the
piano for example my thing and I give the signal for my for my finger to
move it needs to move right then and then the signal needs to go away
so I can pull my finger back up because I have the next key to hit right so
temporal resolution it’s very important so we have two methods of
turning off in our transmitters one is free uptake so we have these
proteins that are on the presynaptic cell and they’re kind of like little
vacuum cleaners that are specific to particular neurotransmitters so for
example the that protein is is specific to dopamine so it’s a that stands
for dopamine transporter protein cert is is particular for serotonin so it’s
a serotonin transporter protein and these can be some sites of actions
for different drugs and we’ll talk about those in a little bit the second
method of signal termination is enzymatic deactivation so acetylcholine
esterase is the best example of the most well known example of this
because we know we’ve known about it for such a long time and one of
the reasons for that is because it’s actually in the periphery so we could
study it in frogs while the frogs still alive because it’s working at the
neuromuscular junction so just to give you an idea of how powerful
ascetic calling esterase is 1 molecule could metabolize more than 5000
molecules of acetylcholine each second so that’s why our our motor
coordination is so good we’re able to we’re able to execute a movement
and have really really good temporal resolution all thanks to our
received calling esterase so I’m sure they would say it’s a team effort
though there’s some neurons involved you know eating your wheaties
all that stuff but none of it would be possible without
acetylcholinesterase OK so we’ve been alluding to this all along but the
but I wanna go ahead and put it out there formally is the fact that the
rate of firing so the action potentials are due to the summation of both
IPS’s and E PSP’s you’ll hardly ever have a situation where you only have
one or the other OK so so this is what that might look like if you did
though right so we have only EPS base that would be sodium coming
into the cell from every area right so we have all of these cells synapsing
on our cell they’re all saying fire with their neurotransmitters they’re all
opening sodium channels so that means that the that the threshold for
excitation right that temperature at which those voltage gated channels
open will be reached relatively quickly here OK so that’s an EPS B but
what tends to happen is you have both right so you have some cells
which are inhibitory cells saying don’t fire so they’re opening those
chloride channels they’re opening those potassium channels so those
are inhibitory they’re hyperpolarizing the cell and that is being summed
with excitatory signals right so it’s the summation of that here at the
Axon hillock that determines whether the cell fires or not at the end of
the day all we have to do is increase our voltage beyond the the
threshold for those voltage gated sodium channels here in the Axon
hillock OK so so the neural integration can occur a couple of different
ways so the first is is a temporal summation so this is where we have
activation occurring in quick succession so those presynaptic cells are
firing one after the other very quickly and so you get to have an addition
right so temporal summation of EPS fees so they’re combining on top of
each other to get to the threshold OK so if we just had one it would go
here and then go back down but because we have one fire and then
another fires it gets to add on top of what happened with the previous
cell so you can see here our EPS P that didn’t really reach the threshold
right so we have one here and then we have two and then we have
three and with the three on top of each other we reach threshold
however keep in mind if we had three like this one that were spread
apart then the voltage would go down and then back up and down and
it would never reach this threshold OK the other is spatial summation so
this is where you have multiple cells that are firing at different areas on
your synapse OK so unlike the same cells firing multiple times this is
different cells firing in different areas on your on your post synaptic cell
so they actually have the same result because it allows you to add those
PSP's up to get to threshold but they're via a different mechanism right
and in reality they usually actually occur together so usually you’re
getting both temporal and spatial summation OK so here is an example
of that so temporal summation here we have the same synapse that’s
firing multiple times right so that’s temporal and here is spatial where
we have multiple synapses firing at the same time Each of these will
produce an action potential and her post synaptic cell OK let’s move on
and talk about neurotransmitters so like I said we we probably have
hundreds of neurotransmitters but you know we’ll probably only really
talk about a dozen in this class it’s it’s helpful to know these
neurotransmitters within their family right so the amino acids glutamate
and GABA are going to be the ones that we talk about the most OK so
and actually these are probably the two most important
neurotransmitters in the entire nervous system um just because they’re
ubiquitous right so glutamate is going to be our primary excitatory
neurotransmitter so it’s always excitatory it’s everywhere OK GABA is
going to be our primary inhibitory neurotransmitter so it’s always
inhibitory and again it’s everywhere it’s all over the brain and that’s why
any drug that activates are blocks glutamate or GABA is going to have
huge effects on the brain so it has it’s kind of like a sledgehammer to
the brain they say so you’re affecting almost every structure if you’re
messing with these two neurotransmitters OK so a modified amino acid
will talk about acetylcholine so I’ve already mentioned that because
acetylcholine works at the neuromuscular junction your monoamines
within monoamines we have serotonin which is its own little subdivision
so it’s an indoleamine and then we also had the catecholamines so
that’s gonna be dopamine neuropil nepheline and epinephrine right so
these guys these three they well I’ll show you that in just a second but
they actually have a similar pathway like a synthesis pathway OK and
then our neuropeptides so these are gonna be our endorphins
substance P neuropeptide Y tons of others right so these are going to be
our opiates endogenous opiates of course purines so this is going to be
ATP at Denison and then gases so we only know one nitric oxide but we
actually have a gas in the the nervous system that acts as a
neurotransmitter all right so this is the pathway I was talking about and
you can see four for dopamine neuropil nepheline and epinephrine they
are using the same synthesis pathway so for example if I if I increase the
amount of dopa then I would increase the amount of each of these
neurotransmitters right because they’re all using the same pathway so
this is actually what they do with in the case of patients with Parkinson’s
disease they can’t give they can’t give dopamine because dopamine is
too large to pass the blood brain barrier so they give the precursor for
dopamine and the drug is actually called L dopa so it increases the
amount of dopamine in the system which helps alleviate some of the
symptoms of Parkinson’s because it is due to the death of dopamine
cells so it’s basically like saying all the cells that are still there we’re
going to make sure that they’re firing as much as they can OK so here’s
serotonin and of course it requires tryptophan so that has to come from
your diet that’s where the myth that eating Turkey causes you to get
sleepy because it has tryptophan eating overeating in general almost
anything will cause you to get sleepy because you’re activating your
parasympathetic nervous system but you know don’t let little things like
facts get in the way OK so you don’t have to memorize all this by any
means I just wanted to give you a look at a synapse and see all of the
different ways that drugs can actually act at a synapse to alter to alter
how that cell is communicating OK so so here’s an example this is what I
was talking about with L dopa right so like adding a precursor for a
neurotransmitter can can that can act as what we call an agonist
becausee it increases what that neurotransmitter would already be
doing right so if we add this precursor it means we have more dopamine
activity making it an agonist we could actually inhibit nerd a
neurotransmitter so some toxins will do that with acetylcholine so they
inhibit the release of the neurotransmitter you could stimulate the
postsynaptic receptors so that would be a classic agonist you could
block the postsynaptic receptor so that would block the effects of the
drug you could actually block the uptake of the neurotransmitter so you
can see that here cocaine for example blocks the reuptake of dopamine
so that means more dopamine stays in that synaptic cleft um which is
where it gets its euphoric effects serotonin reuptake inhibitors or SSRI’s
that’s their mechanism of action as well so they’ll block the cert protein
remember so the serotonin re uptake protein and that causes more
serotonin to stay in the synapse so elite which alleviates depressive
symptoms drugs can also act within the cell and the synaptic cloth to
interfere with enzymes that would usually break them down so that’s
what MAOI’s do so it’s a type of antidepressant they are monoamine
oxidase inhibitors so remember your monoamines were dopamine
neuropil nepheline and epinephrine so it blocks the enzyme that would
normally break them down which means that you have more activity of
of those neurotransmitters that are actually available in the system so
that’s how monoamines work so you could sorry that’s how MAOI’s
work you could you can look at this just read through it look at all the
different areas where where drugs can be activated but I just wanted to
give you guys an idea of like what’s possible at just at the synapse so it’s
pretty cool OK so we talked about neurotransmitters neuropeptides are
kind of like a special case a special type of neurotransmitter but they’re
a little bit different so instead of and sorry just to give you an idea of of
what this includes it would include like beta endorphins RC tosin
vasopressin but they’re a little different than neurotransmitters because
so for example there they’re synthesized in the cell body instead of the
presynaptic terminal so wherever we said most neurotransmitters are
synthesized in the the in the presynaptic terminal they’re released from
dendrites and sometimes the cell bodies and the sides of the axons so
very different than what we see with neurotransmitters which are
released at the Axon terminals there they tend to be released whenever
this cell is repeatedly depolarized so not just getting to that threshold to
produce an action potential and then you have the release you have to
have multiple depolarizations in a row in order to activate the release or
neuropeptide they tend to act on neighboring cells so those cells that
are literally in their area as opposed to neurotransmitters which are
acting on cells that they synapse on so and because they’re being
released just outside they’re being released by the dendrites of the cell
body and the Axon like they just diffuse across the extracellular space so
beyond what you would see with the synapse so that means they have
said that that diffuses across a wide area right whereas with
neurotransmitters the receptors are just on the post synaptic zone so
the adjacent postsynaptic cell so they act very differently so some of the
effects that neuropeptides are responsible for are things like hunger
right like pair bonding that would be like oxytocin but those things are
things that are going to last a long time right they’re not things that are
super quick like like go see with the searchline right so they have much
longer lasting effects OK I just wanted to talk just a little bit about the
variations in receptors we see so you might get the impression that if
you’re talking about a serotonin receptor every serotonin receptor looks
exactly like it turns out that most of these neurotransmitter systems
have different types of receptors so this is just this is serotonin right so
five HT is the the abbreviation for serotonin so we’ve had five HT one
through 7 within one and two we have different subtypes within those
right and these have these all have different characteristics they behave
differently and you find them in different areas of the brain right I think
don’t quote me on this but I think 5 HT 2A is the audit receptor so it’s
always found on the presynaptic cell and it’s always inhibitory so
inhibiting further release of their of of serotonin so if you
pharmacologically if you target that particular subunit or that particular
subtype of receptor then you know you’re going to be if you’re
activating it then you know you’re going to be decreasing the amount of
serotonin released which is pretty cool once you get into like
pharmacology and actually like targeting these specific receptor
subtypes you can do some really neat stuff OK so this is the same thing
here but we’re looking at these are GABA receptors so GABA receptor
subtypes there’s actually last time I checked there was like 26 different
types of GABA receptor subtypes and scientists are really interested in
this because GABA is is one of the neurotransmitters that is affected by
alcohol so people who study alcohol use disorders are interested in the
fact that you know alcohol has a bunch of different effects and those
effects are being mediated by specific subtypes of GABA so for example
here you can see we can use the key down here look at A1A1 seems to
be really important for addiction it’s also important for the amnesia
effects of GABA the anti convulsant effects and the sedative effects
right so ostensibly using this we could actually let’s say so let’s say that
we wanted to block the anxiolytic effects of alcohol we could just block
these A2 receptors and you would have alcohol working the way it
usually does but blocking the anxiolytic effects I don’t know why we’d
ever want to do that but we could we could do that we could also block
the amnesia effects of course if we did that we’d be blocking the the
reinforcing effects so that might not be very good there was actually
talk of trying to develop a a drug that could be taken with alcohol that
would block the withdrawal effects but of course there’s some serious
you know ethical implications there right we don’t want to like create a
permissive factor for people to be able to drink more OK so I mentioned
earlier that I mentioned earlier that the different subunits are
distributed differently throughout the brain and so this is just
demonstrating that with again GABA receptors so here are the different
some of the most common types of GABA receptor subunits and you
can see where they’re most concentrated in the brain now this is a rat
brain so it looks a little bit different but you can see for this A1 we have
and down here It tells you what it’s involved with sedation addiction
anterior grade amnesia but you can see there’s tons of it in the cortex
this is the olfactory bulb and then we can go back we can go down here
and look at A2 and see the same thing but you can see they’re just in
different places in the brain they it seems like they have different
functions in different places which is cool again because if we have a
drug we can we can specifically try to target these different subunits
and have more specific effects rather than like alcohol which effects all
of them and acts as kind of a sledgehammer to the brain like it does
everything it affects all of the systems OK so so some of the effects of
drugs that bind to these receptors right because you know we don’t
have we don’t have true nicotine receptors in our brain we have
acetylcholine receptors it’s just that acetylcholine looks a lot like
nicotine right like structurally the molecules look really similar so
nicotine is kind of hijacking those systems that are there OK so so one of
the questions that you start out with if you have a drug it has sycho
active properties is what neurotransmitter system is it working through
OK so if it’s a hallucinogenic drug for example most hallucinogenic drugs
work through the serotonin system 2A receptors I think are particularly
vulnerable to hallucinogens and like I said nicotine stimulates the
acetylcholine receptors and there’s a reason for this like nicotine is
produced by tobacco plants because bugs have acetylcholine receptors
and so eating the nicotine makes the bugs sick because it activates their
acetylcholine receptors and it acts as kind of like a toxin for them so
we’re basically just smoking you know bug toxins so that’s nicotine
opiates they attach to our endogenous opiate receptors so again those
are neuropeptides we talked about earlier and those are there for a lot
of different reasons one is for is for pain right so to decrease pain if you
get cut your body you feel the pain and then your body releases
endorphins and it numbs that pain but also for just enjoying things right
like eating ice cream or going for a walk you’re releasing endorphins
doing those things and so that increases the probability that you’ll do it
in the future and keep you alive OK and then last methylphenidate so so
methylphenidate is is Ritalin right and so its mechanism of action is is
similar to both methamphetamine and cocaine it just has a different
time course and so that’s why it’s not it doesn’t have a propensity to be
addictive if you take it the way you’re supposed to so it blocks that
dopamine reuptake transporter allowing more dopamine to to stay in
the system so of course we could talk about like a million drugs but I
just wanted to talk about a few and give you guys a feel for like
matching up the drug with the the neurotransmitter system responsible
for its effects OK family negative feedback systems in the brain so in
general negative feedback is is accomplished two ways one is through
autoreceptors and I’ve casually mentioned those a couple of times so
autoreceptors are receptors that detect the amount of
neurotransmitter being released and inhibit further synthesis and
release so they respond to the neurotransmitter that’s released by OK
so if this is the pre synaptic cell and this is the post synaptic cell these
are under transmitters they are going to go up to this autoreceptor right
and they’ll bind here and the more binding you get the more they sell
says OK back off we’ve released enough leave it alone so if we block this
for example that means we can’t get that feedback and the cell will just
keep firing right but if we activated it for example then we would
release less neurotransmitter so again the autoreceptor is on the
presynaptic cell and it’s going to respond to neurotransmitter released
by that cell and it will whenever it’s activated it will decrease the
amount of neurotransmitter being synthesized and the amount that’s
being released OK so that’s how it’s a negative feedback so we can also
have a negative feedback on the post synaptic cell so this is going to be
a receptor that responds to stimulation by releasing a chemical that
travels back to the presynaptic terminal where it inhibits further release
so nitric oxide and and and the means which are the endogenous THC
chemicals do this right so endocannabinoids so we have
neurotransmitter being released and then the postsynaptic cell is
releasing these endocannabinoids and they go back and bind with the
presynaptic cell and tell that cell to stop releasing neurotransmitter so
this is essentially what marijuana does is you take it and it’s activating
these presynaptic cannabinoid receptors and then causing the the
reduction of neurotransmitters like other types of neurotransmitters
from being released so but keep in mind this is the exception rather
than the rule right so this is the exception because this
neurotransmitter is being released by the postsynaptic cell right it’s not
packaged in vesicles it’s not made ahead of time it’s actually made on
demand so as soon as the cell starts getting too many too much
activation it’ll start putting together endocannabinoids which it releases
and goes to the presynaptic cell and says hey that's enough take It easy
no need to keep firing basically and finally the last exception we’re
going to talk about here is the gap junction for a synapse so most most
synapses are going to be they’re gonna have a gap or a sorry a synaptic
cleft there right so and our neurotransmitter has to be released it goes
into the septic club and then binds to a receptor right so that’s most of
them there are very few special purpose synapses that operate
electrically rather than through neurotransmitters so that means that
whenever the cell fires so you have an action potential that sodium just
rushes through to the next cell do you see this here so we have we have
the sodium ions going through this channel and then they go through an
adjacent channel on the postsynaptic cell and cause of depolarization of
this cell and this causes the any cells that are synapsing this way using a
gap junction they can operate as if as if they’re one because every time
this cell fires this cell fires right so but again that really is the exception
rather than the rule
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