Week 4: Neurotransmitters & Pharmacology Flashcards
The synapse
The junction between the terminal button of an axon & the membrane of another neurone
Allows information to be passed (transmitted) from one neuron to the other
Information travels in one direction (during sleep, there is a point where an AP may go ‘backwards’ resetting the neurone)
- Mitochondria in presynaptic neurone - provides energy for the vesicle movement Replace resting potential via sodium-potassium pump, requiring energy
Structure of synapse
Presynaptic axon
Terminal containing neurotransmitters , mitochondria, vesicles and other organelles
Postsynaptic ending
Receptor sites for neurotransmitters
Synaptic cleft - where diffusion of NTs takes place
Summation
- Need more than 1 synapse (summation) for the threshold potential to be reached, and forming an action potential
Synaptic transmission process: (6 steps)
- Action potential arrives at axon terminal triggering Ca2+ ions to move into cell
- Ca2+ ions cause the migration of vesicles (which contain NTs) to the pre-synaptic membrane
- The vesicles fuse to pre-synaptic membrane and break open emptying their neurotransmitters into the synaptic cleft (exocytosis)
- Neurotransmitters diffuse across the synaptic cleft towards the post-synaptic membrane
- Neurotransmitters bind to receptor sites on the post-synaptic membrane with ‘lock and key’ specificity – specific NT binds to specific receptors (NT’s trigger the opening of calcium channels = vesicle movement)
- This binding opens NT-dependent ion channels which change the excitability of the post-synaptic cell
Postsynaptic receptors (2 types)
Direct receptor (ionotropic)
* Binding site for a NT
* Ion channel opens when NT molecule binds
Indirect receptor (metabotropic)
* Only a binding site for a NT
* Activates enzyme
* Ion channel opens elsewhere
Postsynaptic potential
Postsynaptic potential = ions move across post synaptic membrane and alter the membrane potential
Depolarising (excitatory) = increased likelihood of AP (influx of sodium)
Hyperpolarising (inhibitory) = decreased likelihood of AP (outflux of potassium)
Depolarisation > threshold (-55mV) triggers AP
Chemical –> Electrical
Depolarisation vs hyperpolarisation
Depends on which type of ion channel in the postsynaptic membrane is opened by the neurotransmitters
Sodium - Na+ Potassium - K+ Chloride - Cl-
Sodium channels
Produce excitatory postsynaptic potentials
- Depolarises neurone from -70mv to -55mv (threshold) to -30mv
Move in (Think salty banana - there’s more NA+ on outside)
Potassium channels
Produce inhibitory postsynaptic potentials
- Through diffusion, K+ moves out of neurone
- Leads to repolarisation -> hyperpolarisation
Stops another AP forming during refractory period = inhibitory
Chloride channels
Cl- channels opens at rest = nothing happens (everything balanced)
Cl- channels open when neuron depolarised = Cl- ENTERS neuron = stabilisation - decreases the AP likelihood - hyperpolarised
Neurotransmitters (6)
- Acetylcholine (often abbreviated ACh)
- Dopamine
- Serotonin
- Norepinephrine (aka Noradrenaline)
- Glutamate
- GABA (gamma-aminobutyric acid) & Endorphins
Excitatory vs inhibitory
Excitatory - help propagate AP (e.g. glutamate)
Inhibitory - Reduce AP likelihood (e.g. GABA)
Acetylcholine (ACh)
- excitatory
- In PNS & CNS
- In ANS, release = regulate HR, blood pressure & gut motility PNS: neurons controlling muscle contraction, excretion of certain hormones
- Plays a role in muscle contractions, memory, motivation, sexual desire, sleep and learning. CNS: widespread - role in REM sleep, activating cerebral cortex, learning, memory
Alzheimer’s disease is associated with a lack of ACh in certain brain regions
Dopamine (monoamines)
Excitatory or inhibitory
Neuron cell bodies in midbrain ▪ Reward system including feeling pleasure, heightened arousal, and learning. ▪ Dopamine also facilitates focus, concentration, memory, sleep, mood and motivation.
▪ Dysfunctions of the dopamine system include Parkinson’s disease, schizophrenia, bipolar disease, restless legs syndrome and attention deficit hyperactivity disorder (ADHD)
Norepinephrine (monoamines)
▪ Epinephrine (aka adrenaline) and Norepinephrine
▪ Found in peripheral NS (autonomic NS) & CNS (pons & medulla) ▪ Also released into blood (as a hormone), causing blood vessel contraction & increased heart rate ▪ Responsible for “fight-or-flight response” to fear and stress. ▪ Stimulates body’s response by increasing heart rate, breathing, blood pressure, blood sugar, blood flow to muscles, heightened attention and focus. (Sympathetic NS) ▪ Excess epinephrine can lead to high blood pressure, diabetes, heart disease and other health problems. ▪ As a drug, epinephrine is used to treat anaphylaxis, asthma attacks, cardiac arrest and severe infections
Serotonin (monoamines)
Excitatory or inhibitory
Cell bodies of neurons in midbrain, pons, medulla Contributes to various functions, e.g., mood, eating, sleep, arousal, pain Regulation, anxiety appetite imbalances include seasonal affective disorder, anxiety, depression, impulsivity, fibromyalgia, and chronic pain.
▪ Medications that regulate serotonin and treat these disorders include selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs)
Peptides
▪ Endorphins. pain relievers - play a role in perception of pain. “feel good” feelings.
▪ Released by hypothalamus and pituitary gland ▪ Inhibitors (opioid receptors)
▪ Low levels of endorphins may play a role in fibromyalgia and some types of headaches
Amino Acids (Glutamate)
- Glutamate
- Most common excitatory neurotransmitter
- Used by brain to synthesis GABA
- Most abundant neurotransmitter in brain
- Key role in cognitive functions like thinking, learning and Memory
- Imbalances in glutamate levels associated with Alzheimer’s disease, dementia, Parkinson’s, Huntington’s disease and seizures
Amino acids (Gamma-aminobutyric acid (GABA))
- Gamma-aminobutryic acid (GABA).
- Synthesised from glutamate and vitamin B6
- The most common inhibitory neurotransmitter of the nervous system, particularly in the brain.
- Regulates brain activity to prevent problems in the areas of anxiety, irritability, concentration, sleep, seizures and depression.
▪ Drugs that increase GABA in brain are used to treat epilepsy & calm trembling in Huntington’s disease
Neurotransmitter removal from synapse
- Reuptake: NT quickly pumped back into nearby glia or the axon terminal that released it
(via transporter protein)- Deactivation: NT destroyed (inactivated) by enzymes near receptors so it’s not recognized by receptor (acetylcholinase breaks down acetylcholine)
- Removal: diffuses into surrounding area (e.g., blood)
Psychopharmocology
Study of the effects of drugs on the nervous system and behaviour
Important field in neuroscience * Responsible for development of psychotherapeutic drugs to treat psychological & behavioral disorders
What are drugs?
Drugs are exogenous chemicals (not manufactured inside the body)
Unnecessary for normal functioning Alter molecular functions Effects are physiological or behavioural Natural vs artificial
Drugs and synaptic transmission: Agonist vs antagonist
Agonist: Facilitate/ mimic action of a NTs
Antagonist: Inhibit action of a NTs, block postsynaptic effects
Sites of drug action
Where drug interacts with molecules
Drugs affecting behaviour normally affect synaptic transmission
Mechanisms of drug action: 6 stages
- synthesis
- storage
- Release
- receptors
- reuptake
- destruction
Drugs 2. Storage
- alter NTs storage in presynaptic neuron
- modifies concentration in synaptic cleft
- transporter proteins in vesicle membranes move NT from cytoplasm into vesicles
- antagonist inactivate transporters
—> vesicles remain empty = can’t release NTs into synaptic cleft
Drugs: 3. Release
Changes neurotransmitter release from presynaptic cell
Modifies concentration in synaptic cleft
Modes of alteration 1. Prevent release of NT (antagonist) 2. Trigger NT release (agonist)
Drugs 1. synthesis
Alter neurotransmitter synthesis in presynaptic neuron
Modifies concentration in synaptic cleft
NT produced from specific precursor molecules (see diagram)
Enzymes required for change from precursor to NT (can act on the enzyme, may lead to no dopamine being produced)
Modes of alteration 1. Inactivate the enzymes (antagonist) 2. Introduce precursor molecules (mimicking) (agonist)
Drugs 4. Receptors
Act on neurotransmitter receptors
Modify postsynaptic potentials
Drugs: 5. reuptake
Modify removal of neurotransmitters from synaptic cleft
Change neurotransmitter concentrations in the cleft
Agonists reduce or block reuptake
Drugs: 6. Destruction
Modify neurotransmitter destruction in synaptic cleft
Enzymes typically inactivate neurotransmitters (agonist)
Enzyme Acetylcholinesterase (AChE) in postsynaptic membrane deactivates Ach
Neostigmine: inactivates AChE
ACh remains in synaptic cleft longer
Myasthenia Gravis
Reading: Ligand
A chemical that binds with the binding site of a receptor
Reading: binding site
The location on a receptor protein to which a ligand binds
Neurotransmitters are naturally occurring ligands
Reading: Dendritic spine
A small bud on the surface of a dendrite, with which a terminal button of another neuron forms a synapse.
Presence of mitochondria in terminal buttons: what does this suggest?
implies that the terminal button needs energy to perform its functions.
(There are also synaptic vesicles and microtubules for transport)
Reading: synaptic vesicles
small, bubble-like structures made of membrane and filled with molecules. A terminal button can contain from a few hundred to nearly a million synaptic vesicles
What causes vesicles to move?
Arrival of AP at presynaptic neuron = calcium released = vesicles move using energy —-> exocytosis —–> diffusion
Reading: Process after NTs have diffused across synaptic cleft?
Once binding occurs, the postsynaptic receptors open neurotransmitter-dependent ion channels (sometimes called ligand-gated ion channels), which allow the passage of specific ions into or out of the cell = depolarisation.
Direct ion-channel
Ion channel with its own binding site
NTs binds = ion channel opens
IONOTROPIC RECEPTOR
(E.g. ionotropic ion channels include sodium, potassium, chloride and calcium channels)
Indirect ion-channel
Ligand binding to some receptors does not open ion channels directly but instead starts a chain of chemical events.
METABOTROPIC RECEPTORS
(The NTs will be the 1st messenger, but there will be a second involved)
Reading: 2 types of postsynaptic potentials
EPSP’s
IPSP’s
- Determined by characteristics of the postsynaptic receptor, specifically the type of ion channel they open.
Reading: EPSP’s
Excitatory (depolarising) post-synaptic potential
e.g. Influx of sodium causes depolarisation
Reading: IPSP’s
Inhibitory (hyperpolarising) post-synaptic potential
e.g. efflux of potassium (K+) = hyperpolarisation. & influx of Chloride (Cl-) = hyperpolarisation
