Please enable JavaScript.
Coggle requires JavaScript to display documents.
Biopsych - Neurotransmitters (Y1) - Coggle Diagram
Biopsych - Neurotransmitters (Y1)
Structure of synapses - electrical and chemical communication
Neurotransmitter molecules are released from specialised sites known as synaptic vesicles on the buttons of the synaptic cleft where they induce EPSPs or IPSPs through binding onto receptors on the postsynaptic membranes
Astrocytes are also often found at synapses, forming a tripartite synapse (two neurons and astroglial cell) with all three cells communicating through synaptic transmission
Axoaxonic synapses are particularly important as they mediate presynaptic facilitation and inhibition, selectively allowing or preventing the postsynaptic neuron to fire
Advantage compared to PSPs is that they can influence one synapse rather than the whole neuron
Dendrodendritic synapses are also interesting due to their ability to travel in both directions
Axomyelenic synapses - axon synapses on the myelin sheath of an oligodendrocyte - new form of neuron-glia communication
Directed synapses - neurotransmitter release and reception are in close proximity
Non-directed synapses - site of release is distant from site of reception - neurotransmitters are released from varicosities (bulges) along the axon and its branches are widely dispersed to surrounding targets (string of beads synapses)
Synthesis, packing and transport of neurotransmitter molecules -
Large neurotransmitter molecules - neuropeptides - short amino acid chains (3-36) - synthesized in ribosomes on rough ER, packaged by Golgi complex into vesicles and transported by microtubules
Neuropeptide vesicles are larger and do not usually congregate near presynaptic membranes
Small molecule neurotransmitter - synthesized in the cytoplasm of the terminal button and packaged into synaptic vesicles through Golgi - cluster near presynaptic membrane
Neurons contain two neurotransmitters - coexistence - one large neuropeptide and one small molecule neurotransmitter in the small vesicle; often there are multiple small molecule neurotransmitters in the same neuron and the type of neurotransmitters a neuron releases can also change overtime
Process of neurotransmitter release: Exocytosis - at rest, neurons contain small molecule neurotransmitters congregated near the presynaptic membrane sections containing voltage gated calcium channels at a high concentration
When stimulated by APs, the channels open allowing Ca2+ into the button, and this entry triggers a chain reaction that causes synaptic vesicles to fuse with the presynaptic membranes and empty their contents into the cleft
Sodium and potassium - release of APs
Calcium and chloride ions - synaptic transmission, EPSPs and IPSPs
Release of neuropeptides - small molecules neurotransmitters are released with each AP pulse that causes an influx of calcium, whereas large molecules are gradually released in response to increases in the level of intracellular Ca2+ ions - coincides with increased neuron firing
Some vesicles do not fuse, but instead are released as packages into the extracellular space - often carry larger molecules between different neurons and glia in the CNS
Some transmitted molecules can induce persistent changes in gene expression through epigenetic mechanisms
Activation of receptors by neurotransmitter molecules: Each receptor is a protein containing binding sites for only particular neurotransmitters, and so they can only influence the cells that have receptors for them
Neurotransmitter is a ligand of its receptor (ligand - any molecule that binds to another)
Most neurotransmitters bind to several receptor types
Receptor subtypes - different receptor types that a neurotransmitter can bind too; a neurotransmitter has various subtypes residing in different brain areas that respond in different ways to the binding
One advantage of these receptor subtypes is that they enable one neurotransmitter to transmit different kinds of messages to different brain areas
Neurotransmitter binding to a receptor causes two different responses from the postsynaptic neuron, depending on whether the receptor is ionotropic or metabotropic
Ionotropic receptors - ligand-activated ion channels, metabotropic receptors - signal proteins and G-proteins
Ionotropic - associated in channel opens or closes immediately when the binding occurs, inducing an immediate PSP - in some neurons, EPSPs come from neurotransmitters opening sodium channels (depolarise), or IPSPs caused from neurotransmitters opening potassium or chloride channels (hyperpolarisation)
Metabotropic receptors - effects are slower to develop, longer lasting, more diffuse and more varied; each attached to a serpentine signal protein that winds through the cell membrane, and the receptor is attached to a portion of the signal protein outside the neuron, with the G protein attaching to a portion of the signal protein inside the neuron
When a neurotransmitter binds, a subunit of the G protein breaks away - depending on the G protein, the subunit will either move along with inside surface of the membrane and bind to a nearby ion channel, inducing an EPSP or and IPSP
Or, it may trigger a second messenger chemical to be synthesised (neurotransmitters are first) which then diffuses through the cytoplasm and influences neuronal activity
A neurotransmitter's binding to a metabotropic receptor can have radical, long lasting effects and there is also evidence of ionotropic receptors also having second messengers
Epigenetic mechanisms - strong evidence that the structure of both types of receptor and their functionality can be altered in this way
Autoreceptors - metabotropic receptors with unconventional characteristics; they bind to their neurons own neurotransmitter molecules and are located on the presynaptic membrane (not post) - function is to monitor the amount of neurotransmitter molecues in the synapse, stopping release when levels are high and increasing them when low
Small molecule neurotransmitters tend to be released into directed synapses for either receptor to act directly on ion channels - rapid brief excitatory or inhibitory signals to adjacent cells
Neuropeptides tend to be released diffusely, binding to all metabotropic receptors that act through second messengers - slow, diffuse, long lasting signals
Reuptake, enzymatic degradation and recycling - terminate the synaptic messages and prevent the neurotransmitter molecules staying active and clogging the cleft
Reuptake - more commonly used mechanism, neurotransmitters are immediately drawn back into presynaptic buttons through transporter mechanisms
Enzymatic degradation - neurotransmitters are broken down through enxymes, proteins which stimulate or inhibit biochemical reactions without being affected by them
Acetylcholine - main method, acetylcholinesterase
Terminal buttons are highly efficient - once released, neurotransmitter molecules or their breakdown products are drawn back into the button and recycled, regardless of how they are deactivated
Vesicles are also drawn back in from the presynaptic membrane and used to create new ones
Glia, gap junctions and synaptic transmission - glial cells such as astrocytes have been found to release chemical transmitters and have neurotransmitter receptors, conduct signals and influence synaptic transmission between neurons
Gap junctions - spaces between electrical synapses that are bridged by fine, tubular cytoplasm filled protein channels called connexins
connect cytoplasm of two cells, allowing electrical signals and small molecule second messengers to pass from one cell to the next - ions
Responsible for allowing electrical synapses to transmit signals rapidly using conduction of ions through the junctions, with the flow of ions triggering an AP in the next cell due to an influx of ions
Ceebral gap junctions - occur in all classes of cerebral cells, but most of them occur between cells of the same kind - many gap junctions connect astrocytes together in a glial network for example
Gap junctions between neurons tend to be more common between inhibitory interneurons of the same type - aim to synchronise the activities of one area
Astrocytic organisation - allows synchronisation of cells in a particular area; gap junctions on astrocytes tend to occur at the end of each process of coordination where it comes in contact with processes from adjacent astrocytes
Effects of chemical synapses - binding to receptors on postsynaptic side
Once it happens, it affects the membrane potential of the postsynaptic cell by allowing ions in or out
The movement of ions drives membrane potential to be more positive or more negative
If the binding causes positive ions to enter the postsynaptic cell, this will cause an increase in membrane potential
Postsynaptic cell is depolarized, which makes action potential more likely to happen (EPSP - excitatory post synaptic potential)
If the binding causes more negative ions to enter the postsynaptic cell, it causes a decrease in its membrane potential - hyperpolarised
Membrane potential is more negative making an action potential less likely - inhibitory postsynaptic potential (IPSP)
Shows flexibility - activity in one cell can inhiibit or excite activity in another
Effects depend on neurotransmitter and specifically, the receptor type
Neurotransmitter classes - three classses of small molucule; amino acids, monoamines and acetylcholine
Unconventional neurotransmitter as their mechanisms of action are unusual
Neuropeptides - one large molcule class
Amino acid neurotransmitters - fast acting, directed synapses in the CNS
Glutamate, aspartate, glycine and gamma-aminobutyric acid (GABA)
First three are consumed, the last one is synthesised by modification to the structure of the glutamate
Glutamate is the most prevalent excitatory neurotransmitter in the mammalian CNS
GABA is the most prevalent inhibitory neurotransmitter, but can be excitatory also
Monoamine neurotransmitters - synthesised from a single amino acid, slightly larger than amino acid neurotransmitters, more diffuse - present in small neuron groups located in the brain stem; neurons have highly branched axons with many varicosities (string of beads) from which they are diffused into extracellular fluids - 4 types
Epinephrine, norepinephrine and dopamine - catecholamines, serotonin is an indolamine
Catecholamines - synthesised from amino acid of tyrosine
Tyrosine converts to l-dopa, which then converts to dopamine
Neurons that release norepinephrine have an extra enzyme not present for dopamingeric reactions, and the dopamine is then converted into norepinephrine - these neurons are noadrgenergic
Neurons that release epinephrine have enzymes that release norepinephrine along with an extra enzyme that converts norepi into epi - these are adrenergic
Serotonin is an indolamine, and so is synthesised from the amino acid tryptophan
Dopamine systems - important role in emotion and cognition; has three pathways in the brain, with axon projections to various brain regions forming the following -
Mesolimbic pathway - ventral tegmental area (VTA) of the midbrain to the ventral striatum - reward and pleasure
neural activity occurs in response to rewarding stimuli
Strongly implicated in drug abuse and addiction - it you implant an electrode in a rat's brain to stimulate this pathway, the rat will repeatedly press a lever to receive direct stimulation on dopamine until it collapses
This is why mesolimbic dopamine system is involved in drug abuse - similar behavioral patterns
Apart from addiction, dopamine neurons are involved in many normal activities in daily life
Not only about drug addiction - also motivates us to do other things
Typical dopamine responses - burst to unexpected reward, response transfers to reward predictors, pause at time of omitted reward
Mesocortical pathway - VTA to prefrontal cortex - planning and short term memory
Nigrostriatal pathway - substantia nigra of the midbrain to dorsal striatum - motor functions, Parkinson's disease (caused by degeneration of this pathway)
Parkinson's disease - characterised by patients having difficulty controlling the movement of their body, they are slow and tremor
Loss of dopamine neurons in the nigrostriatal pathway in the midbrain
These neurons project to the basal ganglia and the thalamus, and these structures are important for regulating movement
Treatments rely on boosting the brain's dopamine levels with Levodopa (dopamine precursor)
Use of dopamine antagonists in schizophrenia
Serotonin: 5-HT; trypophan, an essential amino acid found in grains, meat, dairy products and chocolate
Produce in raphe nuclei (brainstem)
Serotonin gets projected widely across the cortex, and affects many brain regions
Has many functions - implicated in mood, sleep, body temperature, appetite and metabolism
Drugs used in treatment of depression and anxiety operate by increasing serotonin levels
On the contrary, by reducing serotonin level this can worsen depression etc
Acetylcholine - acetyl group added to a choline molecule - neurotransmitter at neuromuscular junctions, as many of the synapses in the ANS and at synapses in several CNS parts
Cholinergic neurons - breakdown through acetylcholinesterase
ACh - neurotransmitter at many sites within the brain and body, especially in the neuromuscular junction - binds to two receptor types; nicotinic and muscarinic receptors (ionotropic and metabotropic respectively)
Although ACh binds to both receptor types, only nicotine and muscarine bind to these receptors, hence their names (named after their neurotransmitter)
At the neuromuscular junction, ACh binds to the neuromuscular junction by binding to nicotinic receptors with built in ion channels
Once the binding happens, it quickly changes its conformation and allows Na+ to enter the cell, leading to a positive current / depolarisation
At the end, neuronal firing causes muscles to contract
Brain functions - increasing levels of ACh in the brain increases learning and memory (reduction or blocking of ACh leads to deficits in these areas)
Implicated in the pathology of Alzheimer's disease, as neurons get destroyed, and drugs that temporarily improve symptoms are ones that increase ACh
Enzyme - Acetylcholinesterase breaks down ACh - medication for Alzheimer's suppresses this enzyme
Only a temporary relief - ACh increase slows down pace of memory decline patients
Unconventional neurotransmitters - soluble gas neurotransmitters such as nitric oxide and carbon monoxide
produced in neural cytoplasm and diffuse immediately through cell membrane into extracellular fluid and pass to nearby cells - happens due to them being soluble in lipids
They then stimulate the production of second messengers and are deactivated by being converted into other molecules - only exist for a few seconds
involved in retrograde transmission - postsynaptic back to presynaptic - function is to regulate presynaptic neuronal activity
Endocannabinoids - neurotransmitters similar to THC, the main psychoactive constituent in marijuana
Anandamide - produced immediately before release by fatty compounds in the cell membrane
Released from dendrites and cell bodies and they tend to have the most effect on presynaptic neurons, inhibiting synaptic transmission
Neuropeptides
100 identified - actions depend on amino acid sequence - 5 categories:
Pituaitary peptides - hormones release by pituitary
Hypothalamic peptides - hormones from the hypothalamus
Brain-gut peptides - neuropeptides in the gut
Opioid peptides - contains neuropeptides similar in structure to opium ingredients
Miscellaneous peptides - catch all category for other neurotransmitters not in the other 4 categories
Stored in the plasma reticulum in large, dense core vesicles; principle of divergence (not one to one mapping)
Main categories include brain and gut peptides, opioid peptides, pituitary peptides and hypothalamic releasing hormones
Oxytocin
Pro social neuropeptide; love hormone
Social bonding and warm feelings
Implicated in trust in social interactions
Maternal bond, childbirth and breastfeeding
Opioid peptides -
Widely distributed throughout the brain - endorphin is the one that is understood the best
High affinity for and lasting effects on opioid receptors in the brain
Endorphins are produced by the pituitary gland in response to pain and stress, but their release can also be triggered by exercise, eating spicy food, eating chocolate, having sex etc
Neuropeptides differ from those small molecule neurotransmitters as they produce a postsynaptic response with much slower onset but a much longer duration
Neuropeptides usually bind to metabotropic receptors
Neuropeptides can function as neuromodulators - modulate effects of another transmitter
Example - increase level of enzyme production so that there is enough of that enzyme to get rid of another neurotransmitter - with neuropeptides weaknening effects as a result
Or, it can reduce the production of enzymes so that there is less removal, and therefore more neurotransmitters remain in the synapse - neuropeptides enhance the effect
What defines a neurotransmitter? - synthesised and stored in presynaptic neuron, has to be released from the presynaptic axon terminal when an action potential comes to the end of an axon
When experimentally applied, must produce a response in the postsynaptic cell that is the same as the response produced by releasing neurotransmitters into the synapse naturally
There must be some retrieval mechanism to remove it out of the synaptic cleft
Pharmacology of synaptic transmission and behaviour -
Impact of drugs on neurotransmitters - drugs are either responsible for facilitating or inhibiting activity
Drugs that faciliate effects are agonists
Drugs that inhibit the effects of a neurotransmitter are antagonists or receptor blockers
Common steps of neurotransmitters - synthesis neurotransmitter
Storage in vesicles
Breakdown in cytoplasm of any neurotransmitter that leaks from vesicles
Exocytosis
Inhibitory feedback from autoreceptors
Activation of postsynaptic receptors
Deactivation
Impact of agonists on the normal process - drug increases synthesis of neurotransmitter molecules, making more of them
Drug increases number of neurotransmitter molecules through destorying degrading enzymes
Increases amount in terminal buttons
Bind to autoreceptors and stop inhibition
Binds to PS receptors and either activate them or increase neurotransmitter effects
Blocks deactivation of neurotransmitter molecules by blocking degradation or reuptake
Impact of antagonistic drugs - drug blocks synthesis of neurotransmitter molecules
Drug causes neurotransmitter molecules to leak from vesicles and be destroyed by degrading enzymes
Drugs block release of transmitters from terminal buttons
Activates autoreceptors and inhibits neurotransmitter release
Receptor blocker
Applications - nicotinic receptors at neuromuscular junctions - agents such as botox and atropine used to paralyse patients for surgery and for cosmetics; acetylcholine release blocked
Pleasure and pain - endogenous receptors of endorphins and enkephalins - how opioid binding to the brain suggests brain naturally searches for it
Tremors and mental illness - antipsychotic drugs for schizophrenia; atypical and typical to reduce severity of psychosis - blocking D2 and D3 receptors
Dopamine agonists produce a condition that resembles schizophrenia and so antagonistic drugs to this would be effective
Similarly, dopamine agonists help Parkinson's disease, which is caused by degeneration of the main dopamine pathway in the brain
Life cycle of a neurotransmitter - needs to be stored and created in the presynaptic cell
Neurotransmitters are built from precursors (molecules which form the building blocks from our diets
Precursors transported to the brain and enzymes convert them into various neurotransmitters
Production - uptake of precursors and synthesis (exact process differs based on neurotransmitter)
Small molecule neurotransmitters created at axon, with enxymes acting on precursors
Neuropeptides made in rough ER on ribosomes transported by Golgi apparatus to the axon terminal for release
Storage - neurotransmitters stored in vesicles (neuropeptides in dense core vesicles)
Release - after being stored in vesicles, neurotransmitters wait for the arrival of an action potential to come to the axon terminal
Action potential causes calcium ions to enter the terminal, causing vesicles to move to the membrane of the axon terminal
The vesicle that fuses with the membrane and releases neurotransmitter into the synaptic cleft and binds to receptors (excytosis)
Diffuse across cleft and bind to receptors
Receptor binding - after release from presynaptic axon terminal
Neurotransmitter diffuses across the synaptic cleft to bind with receptors on postsynaptic side
Receptor - membrane protein with binding sites for a neurotransmitter, and are named after their agonists (chemicals that bind to activate that particular receptor)
Pharmacology - which transmitters and other similar chemicals can bind to the receptor
Kinetics - duration of effects; each neurotransmitter has multiple receptors (divergence)
Effects -
Affect membrane potential by allowing ions in or out of a cell - positive is an EPSP (depolarisation, negative is hyperpolarisation and an IPSP
Ionotropic receptors - transmitter gated ion channel, directly opens or closes its ion channel - directly connected to one
When a neurotransmitter binds to this receptor, the receptor protein changes its conformation, creating an opening for ions to travel through
This mechanism changes the membrane potential of the postsynaptic cell
Fast effect on receptor structure
Local or short term effects
EPSP or IPSP depends on the ion channel coupled with the receptor - if allows Na+ in, it depolarises, if allows Cl- to enter, it will hyperpolarise
Depends on receptor properties not the neurotransmitter itself
Metabotropic receptor - G-coupled protein receptor; indirect effects, no ion channel and so activates a G protein instead (a second messenger) - if neurotransmitter is first messenger, it triggers a G protein to send message to an ion channel - indirectly connected to ion channel
It diffuses inside the cell and binds to the bottom of the ion channel, making the channel open from the inside
Apart from binding to ion channel, the G protein exerts a wide range of different effects on the postsynaptic cell
Deactivation - various mechanisms such as reuptake, enzyme degradation and diffusion
Inactivation by enzyme - ACh acts on receptors:
ACh is decomposed by acetylcholinesterase
Choline is reabsorbed and will be used again in the future
The whole process of ACh release, action and destruction takes about 5-10ms (efficient)
Destruction and recycling is extremely fast to keep the postsynaptic neuron ready for the arrival of the next new stimuli
Autoreceptors on presynaptic terminal allows the regulation of the neurotransmitter by binding it to the synapse, allowing record of how much has been released so it can then be terminated