Topic 3: Neurotransmitters and psychopharmacology Flashcards
The life-cycle of a NT/steps in synaptic transmission:
1 Synthesis.
2 Storage.
3 Release.
4 Diffusion across the synaptic cleft.
5 Binding to receptor.
6 Release.
7 Inactivation by enzymes (e.g. acetylcholinesterase cleaves acetylcholine into acetate and choline OR reuptake.
8 With re-uptake, inactivation OR re-storage in synaptic vesicles.
neurotransmitter V neuropeptide V hormone
neuropeptides (or ‘neuromodulators) are a special kind of NT that are synthesized in the cell body
neuropeptides are released through the dendrites and soma walls and all parts of the cell, and need multiple activation’s to be released, and when one cell fires the surrounding ones are encouraged to do so, and it diffuses widely, its more similar to a hormone, a spilling. Does gene altering stuff and last 20mins or longer, more for long term behavioral changes, and things like thirst hunger
e.g. oxytocin, vasopressin, insulin, glucagon
neuropeptides do not get re-uptook they diffuse away (and these large molecules are hard to make, bug influxes can temporarily exhaust supplies)
NT synthesized and released from the axon terminal, released by a single AP, doesn’t diffuse widely (just to those directly ahead), doesn’t change the genes of others, is very fast
hormones are like radio signals, anyone tuned in can pick it up, NT are like a phone call, only goes to one phone line, and NP are like a zoom call, go to a big area but still select (goes to specific areas of the brain, whereas hormones can go anywhere blood can carry them)
Sherrington
After Cajal discovered seperate neurons,
Sherrington showed that internal communication of a neuron was different to the kind of communication going on externally (e.g neurotrasmitter stuff in the synapses) which certainly confirmed Cajals hypothesis
together these two nearly simultaneous discoveries are the fathers of neuroscience
Main function of glutamate, GABA, ACh, dopamine, norepinephrine/epinephrine serotonin
glutamate, excitation
GABA, inhibitory
ACh, mainly excitation
dopamine,
norepinephrine/epinephrine
serotonin
Sherrington
After Cajal discovered separate neurons,
Sherrington showed that internal communication of a neuron was different to the kind of communication going on externally (e.g neurotransmitter stuff in the synapses) which certainly confirmed Cajals hypothesis
together these two nearly simultaneous discoveries are the fathers of neuroscience
how did sherrington show there was different communication inside and outside
testing dog relex to leg flexion reflex
he tapped and measured time
they already knew axon transmission goes at 40m/s
but the response went at 15m/s
it must have been slowed by the slower process of synaptic transmission.
a reflex arc goes from sensory neuron (afferent) to intrinsic neuron (within the spine - doesn’t go to brain -he tested by severing the dogs spinal chord-) to efferent motor neuron.
those three passes slowed it down
what is temporal summation, how did sherrington figure it out, and how does it relate to EPSP ex pos syn pot
the threshold of excitation for a postsynaptic neuron might not be reached (and is quickly decayed) but many quick simulations can trigger it (pinching the dog many times quickly)
this is temporal summation
excitatory post synaptic potential is this, the graded polerisation (partial polerisation) which can either increase or decrease the chances of an action potential with more stimulation it could be depolarising (sooner to activate - excitatory) or hyperpolerising (harder to activate - inhibitory)
sherringtons student Eccles measured this with electrodes on axons
IPSI is inhibitory postsynaptic potential
spatial summation and eccles finding about direction of stimulation
many stim at different places needed to cause AP
Eccles found direction matters if its going away from the cell body triggering dendrites in that direction it may not trigger AP where the other direction triggering dendrites one by one in the direction of the soma would aid AP activation
both spatial and temporal summation are about multiple stim on one neuron
IPSP how it works biologically confirmed by newer physiological studies
how sherrington showed this in the oldem days
inhibitory post synaptic potential is acheived by opening cloride ion channels or potassium ion channels, hyperpolerising the cell
(Cl- goes inside making it more -, K+ goes outside making it more neg inside, faster than the sodium potassium pump can normally bring leaky K+ in to keep it at -70mV, so it goes to below that, hence inhibitory)
sherrington saw the dogs alternate muscles extending when the reflex muscles flexed (and also the other three legs doing the opposite, necessary for the dogs balance)
he suggested there must be something inhibiting those alternate muscles while the reflex muscles were getting activated
IPSP’s dont propergate along an axon like AP does, they decay over time and distance always
maths of the nerous system, EPSP and IPSP
AP gets triggered when the summation at the axon hillock reaches -55mV/-50mV (about 20mV difference from normal)
more than just the summation of ESPS minus IPSP determine AP’s
some summate more or less readily
some have constant AP flow and EPSP just speed it up and IPSP just slow it down
some have multiple inputs at different places closer/furthur from the cell body affecting results
its a complex symphony boolean logic (ridgid true false statements, if A fires or B fires C fires but only if not D etc)
how neurotrasmitters are related to EPSP and IPSP
NT attach to proteins on the postsynaptic terminal which triggers the opening of sodium cloride or potassium channels, hence beginging the EPSP or IPSP process.
propergating channels are voltage opened
terminal channels at NT opened
how neurotrasmitters are related to EPSP and IPSP
NT attach to proteins on the postsynaptic terminal which triggers the opening of sodium cloride or potassium channels, hence beginging the EPSP or IPSP process.
propergating channels are voltage opened
terminal channels at NT opened
calcium as a unique extracellular ion
Ca2(+) acts similarly to sodium outside the cell, but does a 2nd messenger system
AP opens voltage opened Ca2 channels
Ca+ enters cell within 1-2ms vesicles open EXOCYTOSIS (endocytosis is where the left over vesicle bits of membrane are re used)
calcium also binds with and activates enzymes
these impact 2nd messengers which change the structure and function of cells
exocytosis
NT leaving presynaptic button
the vesicle binds to the presyn membrance and splits open release the NT into the cleft
1 Synthesis.
neuropeptides (“peptide NT”) synthesized in the cell body requiring mRNA then transported via FAST axoplasmic transport
stored in dense core vesicles. released like hormones, diffused from everywhere
smaller molecule neurotransmitters are made in the button.
(pre-curses and things needed for vesicles still made in cell body and transported by SLOW axo to the terminal button, where the smaller molecules are made package and stored)
stored in clear core vesicles
2 Storage.
in vesicles (all but NO get stored) stored in the terminal buttons
- Release
AP causes calcium channels to open and influx into the cell near the button
calcium binds with protein causing vesicles to DOCK and create a fusion pore openin in the membrane, releases the NT out via diffusion
4 Diffusion across the synaptic cleft.
super fast, picked up by dendrites
5 Binding to receptor.
this is where the magic happens, could be excititory or inhibitory, binds to a receptor site on the dendrites, casuing the opening of its sodium (of cloride, potassium or calcium) channels
sodium excitatory
cloride inhibitory
potassium inhibitory (more goes out)
6 Release.
NT separate off of postsynaptic terminals after mere miliseconds
UNDOCKING
7 Inactivation by enzymes
some NT diffuse away and get broken down by enzymes and cleaned up by COMT and glia
but some get reuptaken and recycled…
8 OR Re-uptake, and re-storage in synaptic vesicles.
presynapse sucks in left overs by transporter molecules
pulled up the axon by reterograde axoplasmic transport for recycling to occur
flexibility in NT release option
most neruons release many NT’s
some different from different branches of their axon
some one first another later
some one in summer one in winter
ionotropic vs metabotopic effects
ligand gated (NT gated) channels involved, ionotropic effects are quick and dacay quickly
mostly use glutamate GABA (sometimes glyceine and and Ach)
excitatory - glutamate
inhibitory - GABA
metabotropic effects are a sequence lasting a few seconds or longer
use seretonic, norephinephrine, dopamine (and also the others above)
a receptor protein goes through the membrane, when activated it bendsand on the inside is G protein(energy storing), it bends off and goes off and activates a second messenger e.g. cyclic AMP (where 1st messenger is considered to be the NT), this second messenger has effects of other arts of the cell (might impact chromosones or channels, whereas first messengers only impact on that one localised part of the membrane
ionotrpic better for quick processing eg sight and hearing, metabotrophic for slower eg taste arousal attention pleasure emotions smell pain
ionotropic vs metabotopic effects
IONOTROPIC = fast synaptic transmission ligand gated (NT gated) channels involved
Ionotropic effects are quick and dacay quickly
mostly use glutamate GABA (sometimes glyceine and and Ach)
excitatory - glutamate
inhibitory - GABA
these allow ions in, causing excitatory or inhibitory potentials
METABATROPIC = slow synaptic transmittion (indirect) “SECOND TRANSMITTOR SYSTEM
- a sequence lasting a few seconds or longer
- is with seretonic, norephinephrine, dopamine (and also the others above)
1) a metabotropic receptor cell protein goes through the membrane, when activated it bends and on the inside is G protein(energy storing) with GTP energy,
2) it bends off and goes off and activates
3) enzymes which causing the production of…
4) a second messenger e.g. cyclic AMP (where 1st messenger is considered to be the NT), this second messenger has effects of other arts of the cell (might impact chromosones or open other channels, whereas first messengers only impact on that one localized part of the membrane opening the channels directly)
sometimes G protein can just skip ahead and open channels producing a post synaptic potential
ionotropic better for quick processing e.g. sight and hearing, metabotrophic for slower e.g. taste arousal attention pleasure emotions smell pain
can also alter chromosones or protein productions
can even have involvement of a third messenger system, it can effect the sodium potassium pump, or open ion channels etc
nicotine
LSD
opiates
endogenous morphines
nicotinic receptors are a type of Ach receptor, that are abundant on dopamine releasing neurons increasing reward messages in the nucleus accumbuns
LSD is similar to seretonin and attaches to it, sending crazy pleasure messages and overwriting sensory inputs eg hallucinations
opiates attach to endogenous morphine receptors blocking pain (analgesia), ‘endorphine’ is the shortened version. enhance immune functioning, reward effects
get them from excersize, chocolate, chilli, massage
ways of inactivating
diffusing breaking down reuptake autorecpetors reverse transmitters
neuropeptides arent inactivated, they diffuse away
NT can be;
ACh is broken into acetate and choline by aceytellcholinesterase (“(l)ets-eraze”). The choline is reuptook and join acetate in the terminal button to form new ACh
even though this recycling is good, it will eventually diminish supply with enough stimulation
regular re-uptake of the whole NT as special transporter proteins. this is how it goes for serotonin and the catelcholamines (dopamine epinephrine and norepinepherine)
breakdown by an enzyme COMT, eventually exiting through blood and urine (the “compt-troller”)
Autoreceptors - a type of metabotropic receptor. They are on the presynaptic neuron, they involve G ptoteins and 2nd messengers. They look at how much NT is relased and manage it, causing more or less to be released
Reverse transmitters in receptor cells send the message back “thats enough” e.g. NO and protons in the retina (hydrogen ions)
drugs and transporters amphetamines cocaine ritalin SSRIs canabanoids haloperidol (anti-psychotics) MDMA
amphetamines and cocaine inhibit transporters of dopamine serotonin and norephinephrine (prolonging the effects because re-uptakers are inhibited)
dopamine to much accumulating so is broken down by COMT instead and eventually the brain cant produce enough to replace (low come down)
methylphenidate (ritalin) and cocaine block the re-uptake of dopamine (cocaine much faster up and down)
canabanoids released by post synapse bind to receptors on the pre synapse (reverse transmission), activating them so saying to the pre-syn cell ‘that’s enough thanks’. these slow glutamate and GABA, excitatory and inhibitory things are all told “that’s enough” even if they never released. can reduce anxiety
anti-psychotics block receptors of dopamine stopping the message altogether
MDMA releases more serotonin and dopamine
electrical synapses
gap junctions 2 synapses directly touch with pores always open and large enough for sodium and others to pass straight into the next cell
useful for essential rhythms like breathing
animal escape mechanisms
axo-axonic synapses
2 axons can be neighbors and have synapse communication
it modulates NT release
dendro-dendritic synapses
a connection between 2 dendrites
these neurons don’t have long axons like normal
for organizing groups of neurons
amino acid Neurotransmitters: glutamate GABA glycine aspartate
small molecule NT clear core vesicles, formed in button
glutamate (primary excitatory)- found in the oldest organism (nearly all animals have all the same NT as current humans do). Usually bind to AMPA and NMDA receptors (important for learning) glutamate excitotoxicity (too much calcium) can cause enzymes to destroy, implicated in alzheimers, ALS MS
GABA (inhibitory) - opens CL- channels, balancing,
GABA-A (Alpha) have 5 binding sites, benzos barbituates steroids (progesterone) all bind to these receptors and promote feelings of relaxation
glycine - common inhibitory found in spinal chord
aspartate
a modified amino acid: acetylcholine
has its own category
small molecule NT clear core vesicles, formed in button
- excitatory (mostly) as it opens sodium gates
binds to cholinergic pathways
binds to ionotropic nicotine receptors
and metabotrophic muscarine receptors
associated with learning memory and REM, also implicated in Alzheimers
important for PNS muscular conctractions
is synthesized by choline acetyl transferase binding the per-cursers
monoamines: indolamines and catecholamines
are a kind of modified amino acids, involved in slow metabotropic transmission
big molecules, synthesized in cell body
the indolamines; serotonin, also called 5HT (excititory) (from the precursor tryptophan - tryptophan hydroxylase changes it to 5HT)
9 serotonin receptors
mood regulation, eating, sleep, arousal and pain and gastro functioning, there are seretonin receptors in the gastro tract
and the catecholamines; dopamine, norephinephrine (blood vessels), epinephrine (heart rate) also vigilance, energy supplies etc might also enhance learning, is released in emotional times (related to plasticity)
synthesis of catecholamines; tyrosine (food) - L-dopa (by tyrosine hydroxylaze) - made into Dopamine which can be synthesized into norepinephrine which then also goes to epinepherine
there are 5 dopamine receptors (D1, D2, D3, D4, D5)
dopaminergic systems;
nigrostriatal system movement and automatic behaviours
mesolimbic - rewards
mesocortical - planning and problem solving. in the frontal lobes, may be involved in attention.
also important for the release of prolactin
melatonin
histamines (debated)
can be inhibitory (except seretonin - only excitatory)
nor-ephinephreine and epinephrine are the NT words, noradrenaline and adrenaline are the hormone words
the pathways in the brain are called noradrinergic pathways
they are released from the adrenal medulla
LARGE molecules, stored in dense molecules = NEUROPEPTIDES
endorphins substance P neuropeptides Y oxytocin corticotrophin releasing hormone thyrotopin releasing hormone growth hormone releasing hormone
peptide hormones
amino acid chains endorphins substance P neuropeptides Y - hunger oxytocin vassopressin - water retention and blood pressure
corticotrophin releasing hormone
thyrotopin releasing hormone
growth hormone releasing hormone
released from the hypothalamus
endocannabinoids, synthesised by fats rather than amino acids
increase appitie, reduce nausea, analgesia
change perception time visual auditory
reduced memory concentration (canabis use)
purines: ATP
adenosine
not included by lecturer
gases: NO, nitric oxide
(different from nitrous oxide (N20) - dilates blood vessels, released by many neurons so in highly active brain areas there is more NO so blood knows where to go
unlike other NT, NO is not stored, but produced and released instantly
Viagra facilitates erections by targeting NO receptors
involved in immune response
retrograde messenger during learning and memory
can do longer term changes to pre synaptic cell
AGONIST V ANTAGONIST
Agonist - facilitates NT
increases likelihood the NT will activate a post-synapse
facilitates synthesis and release
Antagonist - oppose NT
prohibits production or transmission
blocks receptors
drugs and NT synthesis
auto-receptors detect high or low levels, slowing or increasing synthesis
L-Dopa is an agonist that increase synthesis by providing a per-curser
antagonists on synthesis can prevent pre-cursers or breakdown needed enzymes
PCPA inhibits enzyme needed for seretonin production
drugs and transport and vesicles
no example for agonist
antagonist - inactivate vesicle transporters, so the vesicles stay empty e.g. RESERPINE (although aparently according to game acts as an agonist for dopamine)
drugs and neurotransmitter release
agonists and neurotransmitter release; bind with proteins facilitating fusion to the membrane and release into the cleft
(black widow venom, ACh release over stimulated - painful muscle spasms and cramps)
antagonist and release;
preventing fusion to the membrane and release e.g. botox prevents ACh making the face muscles paralysed
drugs and receptors
drugs can attach to the receptors in a competitive or non competitive way
competitive/DIRECT = blocking the receptor hole
- direct agonists, mimic neurotransmittors perfectly (e.g. nictotine on ACh)
- direct antagonist, receptor blockers, blocks the site and doesn’t open ion channels (e.g. chlorpromazine blocks dopamine receptors) (curare - hunting darts ACh is blocked, muscle paralysis)
non-competitive/INDIRECT = multiple receptor sites, the drug can attach and there is still room for the NT, and they can have agonist/antagonist effects there
indirect agonist = helps ion channel opening (diazapam/valium - facilitas GABA relaxing anxiety)
indirect antagonist = hinders the NT’s channel opening (PCP & ketamine reduce NMDA glutamate receptors - slowing muscular control (less glutamate) causing hallucinations etc)
drugs and deactivation of NT
agonist, will bind to the enzyme that breaks down the NT, stopping it from breaking it down
e.g. neostigmine
drugs and reuptake
agonist; cocaine prevents transporters of dopamine, SSRI’s prevent re-uptake of serotonin
antagonist
drugs and autoreceptors
agonists; block autoreceptors, inhibiting the inhibitory effect of the autoreceptor
antagonists; facilitate autoreceptors, meaning they slow the release of NT
individual differences in drug effects
- size of person
- repeated use triggers b process compensation, receptors decreasing or increasing (withdrawal effects)
- sensitization and desensitization habituation/tolerance,
learn the precursers;
to monoamines
1 catecholamines
&2 indolamines
G-group
GABA glutamate & glyceine
neuropeptides
soluble gases
acetylcholine
catecholamines - tyrosine
indolamines - tryptophan
GABA glutamate & glyceine -from amino acids
neuropeptides (oxytocin, cholecystokinin CCK neuropetide Y hypothalamic hormones
soluble gases NO: L-Arginine
acetylcholine: by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA
retrograde NO effects
can go in and change the cells capability retrograde communicators can go in and change what the cells can do, make them more receptive, different NT could be accepted etc, area of budding research
