NEUROTRANSMISSION + MODULATION Flashcards
Structure of a Neuron
Dendrites -> recipient of information from other neurons. Soma -> cell body contains the machinery that controls processing in the cell and intergrates information. Axon -> carries info from soma to the terminal boutons. terminal boutons -> found at the end of the axon, location of the synapse, communication point with other neuron
Neuronal membrane
boundary of soma, dendrites, axon, and terminal boutons separate the extracellular environment from the intracellular environment
Neuronal membrane structure
lipid bilayer (5nm) and protein structures. detects substances outside cell, allows access of certain substances into the cell (gated -> chemical or electrical) - cytoskeletal
Two different types of synapse
electrical synapse, chemical synapse
electrical synapse
very rare in adult mammals. found in retina. junction between neurons is very small. gap is spanned by proteins (connexins) which are used to communicate between the neurons (ions move freely).
Chemical Synapse
more common in mammals, junction between neurons longer, chemicals (neurotransmitters) are released from the presynaptic neuron to communicate with the post-synaptic neuron
Early work for chemical transmission
Loewi in 1920s -> application of fluid following vagus nerve stimulation slowed down heart rate,
What are different types of chemical synapses
axodendritic, axosomatic, axoaxonic
Chemical Synapse overview
neurotransmitter synthesis, transport, storage. depolarisation (action potential), open voltage-gated Ca+ channels, Ca+ influx, movement + docking of vesicles, exocytosis -> diffusion, interact with receptors, in/deactivation of neurotransmission.
Neurotransmitters
chemical that is used to transit information from the post-synaptic neuron to the post-synaptic.
Criteria for neurotransmitter
chemicals synthesised pre-synaptically, electrical stimulation leads to release of the chemical, chemical produces physiological effect, terminate activity.
Ionic receptor
opening of an ionic channel (typically). fast transmission leads to an immediate change in the post-synaptic cell.
Metabotropic receptor
activates an internal second messenger, indirectly affects function of post-synaptic cells.
Receptors vary in their:
pharmacology -> how drugs interact w specific receptors. agonist -> a drug producing cellular reaction. antagonist -> drug that reduces or completely blocks the activity of the agonist
Categories of neurotransmitters
Classical, Neuropeptides
Classical Neurotransmitters
amino-acid fast transmission (e.g., GABA and glutamate). monoamines (e.g., dopamine, serotonin), acetycholine. releases in local increase in Ca+
Neuropeptide transmissions
endorphin, pain relief etc. more intense stimulation necessary to release neuropeptides, more increase in Ca+. other small molecules (e.g. nitric acid).
Excitatory fast transmission
Ion channels open, movements of Na+ into the neurone. (e.g. glutamate receptors), depolarisation, excitatory post-synaptic potential (EPSP).
Inhibitory post synaptic potential (IPSP)
Ion channels move, movement of Cl- (e.g., GABAa receptors), hyperpolarisation, inhibitory synaptic potential
Metabotropic receptor
G-protein receptors in the intracellular side
Metabotropic receptor process
neurotransmitter binds to receptor and activates the G-protein (exchange GDP for GTP), G protein splits and activates into enzymes. the breakdown of GTP turns off G protein activity. Series of chemical reactions that leads to an amplification of the signal - second messenger system
Amplification
It is slower but it has a domino effect -> slow but bigger effects. Can activate multiple g-proteins and amplify the effect. Cascade of effects. Slower than inotropic receptor but bigger effect.
Neurotransmission deactivation
Neurotransmitters must be inactivated after use to remove them from the synaptic cleft. They use the reuptake transports. Also have deactivating enzyme and hydrolase the neurotransmitters. Both do the same things in different ways.
Autoreceptors
regulates synaptic transmission. Located on the presynaptic terminal, Respond to neurotransmitter in the synaptic cleft. Generally, they are G-protein coupled. don’t directly open ion channels. Regulate internal process controlling the synthesis and release of neurotransmitter. Negative feedback mechanism. Auto receptors are not the same as reuptake sites!
What is glutamate?
Major fast excitatory neurotransmitter in the CNS. Very widespread through the CNS. Activates different types of receptors -> mGLuR, NMDA, AMPA, Kainate.
Glutamate synthesis process
Synthesized in nerve terminals from glucose or glutamine. Loaded and stored in vesicles by vesicular glutamate transporters. Released by exocytosis (Ca+ dependent mechanism). Acts at glutamate receptors on postsynaptic membrane
Reuptake by excitatory amino acid transporters (EEATs) in the plasma membrane of presynaptic cell and surrounding glia
Different receptors for glutamate
Based on their pharmacology – three types of ionotropic receptor have been described that respond to glutamate
NMDA, AMPA, and Kainite ->
They are named based on the agonists selective for them.
What is AMPA receptor
Ionotropic receptor -> Binding of glutamate leads to the opening of a Na+ channel (slight K+ permeability) and hence depolarization. Selective agonists -> AMPA. Antagonist -> CNQX, DNQX
NMDA receptor?
Ionotropic receptor -> permeable to Na+, K+ and Ca2+, Binding of glutamate -> nothing happens!, Voltage dependent blockade.
Resting membrane in NMDA
At resting membrane potential (-65mV): Glutamate binds, Channel opens. Blocked by Mg2+
Depolarised membrane in NMDA receptor
At depolarised membrane (-30mV), Mg2+ pushed out of pore, Channel is open, Ion movement, Further depolarization, Different ‘kinetics’ from AMPA receptor (open much longer)
Features of AMPA receptor
AMPA (and kainite) receptors -> Fast opening channels permeable to NA+ and K+ (it is a glutamate receptor)
Features of NMDA receptor
slow opening channels, permeable to Ca2+, as well as Na+ and K+. but also requires: glycine as a co-factor (no glycine, no activation!) And gated by membrane voltage.
NMDA receptors are only activated in an already depolarised membrane in the presence of glutamate.
NDMA receptors - dysregulation
NMDA receptors also blocked by phencyclidine (PCP, angel dust) and MK801 which both bind in the open pore. (these are drugs btw lol). Blockade of NMDA receptors in this way produces symptoms that resemble the hallucinations associated with schizophrenia (associated with reduced NMDAR function). Certain antipsychotic drugs enhance current flow through NMDA channels
Glutamate excitotoxicity
Caused by excessive Ca2+ influx into the cell which activates calcium dependent proteases and phospholipases that damage the cell.
This kind of cell damage occurs after stroke and chronic stress.
What is GABA?
GABA (gamma aminobutyric acid). Major inhibitory neurotransmitter. Activates an ionotropic receptor (GABAa receptor) which opens a chloride channel (Cl-) leading to hyperpolarisation (IPSP).
GABA synthesis overview:
GABA is synthesized from glutamate. GABA is loaded and stored into synapses by a vesicular GABA transporter. GABA is released by exocytosis (Ca+ dependent mechanism) GABA acts at ionotropic GABAa and metabotropic GABAb receptors on post-synaptic membrane.
GABA cleared from synapse by reuptake using transporters on glia and neurons including non-GABAergic neurons.
What are GABAa receptors?
GABAa ionotropic receptors: Ligand gated Cl- channel -> Fast IPSPs!
what are GABAb receptors?
metabotropic receptors: G protein coupled receptors -> Indirectly coupled to K+ and Ca2+
-> Channel through 2nd messengers. -> (opens k+ channel, closes Ca+ channel) -> Slow IPSPs
Dysregulation of neurotransmitters
Too much glutamate/too little GABA = hyperexcitability (could lead to epilepsy), excitotoxicity. Too much GABA = sedation/come (at right doe, drugs increase GABA transmission can be used to treat epilepsy).
What is cerebral ischemia?
The metabolic events that retain the electrochemical gradient are abolished. Transporters release glutamate from cells by reverse operation. Excitotoxic cell death
GHB gamma-hydroxybutyrate
date-rape drug! A GABA metabolite that can be converted back to GABA by transmission. Increases amount of available GABA
Moderate dose like alcohol, but too many leads to unconsciousness and coma.
Death from alcohol?
quite drunk = BAC of 0.2 – 0.3, death = BAC of 0.35 – 0.5. but typically, one passes out before ingesting lethal dose.
GABAa receptors in drug use
Complex receptor with multiple binding sites. -> Drugs binding at GABA binding site.
What is muscimol?
GABAa receptor agonist drug (mushroom popular in siberia)
What are the two GABAa receptor antagonist?
Bicuculine, pricrotoxin
Drugs increasing GABA activity in reducing anxiety
Agonist -> anxiolytic substances -> alcohol, barbiturates.
Indirect agonist -> benzodiazepines (BDZ) (also anti-convulsant).
Antagonist -> anxiogenic drug -> flumazenil (also used to reversing sedation due to BDZ overdose). These drugs all act at the GABAa receptor, ionotropic receptor. Changing the kinetics.
what are Barbiturates?
anxiolytic. relaxation and stress relief drug. Poor therapeutic ratio. Small difference between therapeutic dose and overdose. High suicide risk in emotionally unstable patients. Long-term treatment leads to dependence and withdrawal. Thus, only used for severe insomnia, seizures.
Benzodiazepines
Discovered in 1960s, First, benzodiazepine was chlordiazepoxide (Librium), Shortly after that diazepam (Valium) became the major treatment for anxiety disorders. It acts as an anxiolytic, anticonvulsant, sedative, muscle relaxant, amnestic.
Pros and Cons of Benzodiazepines
Advantages -> Good, fast acting anxiolytics. Large therapeutic window
Disadvantages -> May cause dependence.
Effects potentiated by alcohol.
Primary neurotransmitters:
Glutamate and GABA - the main workhorses of the brain -> Directly mediate the transmission of information between neurons either via activation (excitation, EPSPs) or inactivation (inhibition, IPSPs) of post-synaptic targets
What are neuromodulators?
some neurotransmitters are known as neuromodulators. Affect the response properties of a neuron (e.g., release, excitability). Do not carry primary information themselves, e.g. dopamine, serotonin, noradrenaline, acetylcholine. (others: histamine, neuropeptides).
Nigrostriatal system?
dopamine system -> substantia nigra projections to neostriatum (caudate and putamen)) -> has a role in movement. Dysfunction -> Parkinson’s disease (destruction of DA projections from SN to basal ganglia). Huntington’s disease -> destruction of DA target neurons in striatum.
Mesolimbic system?
dopamine system -> ventral tegmental area projections to nucleus accumbens (NAcc)) -> role in reinforcement (reward) dysfunction -> Addiction - most drugs of abuse lead to enhanced DA release in the NAcc
Mesocortical system?
Dopamine system. Ventral Tegmental Area projections to prefrontal cortex -> role in functions such as working memory and planning. Dysfunction -> Schizophrenia
Dopamine Synthesis
Tyrosine (essential amino acid obtained in diet) -> Catalysed by tyrosine hydroxylase (TH) -> rate limited step (or slowest step) -> L-Dopa -> catalysed by dopa decarboxylase -> Dopamine.
Catecholamine Storage -> loaded into vesicles.
What is reserpine?
drug that affect dopamine synthesis. Reserpine -> impairs storage of monoamines in synaptic vesicles (the vesicles remain empty resulting in no transmitter release upon activation).
What is L-DOPA?
one of the drugs that affect dopamine synthesis. the precursor of dopamine, used as a treatment, for Parkinson’s disease (Bypasses rate-limiting TH step – dopa decarboxylase converts it into dopamine increases the pool of releasable transmitter).
What is AMPT?
drug that affect dopamine synthesis. AMPT (a-methyl-p-tyrosine) inactivates TH (used experimentally – not in treatment)
Role and importance of neurotransmitter systems in behaviour revealed by drugs (e.g., reserpine was used to treat high blood pressure but caused depression).
Dopamine release overview:
Depolarization of presynaptic membrane. Influx of Ca+ through voltage-gated Ca+ channels. Ca+ dependent vesicle docking and release (Ca+ dependent exocytosis). Signal terminated by reuptake into the axon terminal by transporters powered by electrochemical gradient (dopamine transporters (DATs)). In the cytoplasm dopamine is -> Reloaded back into vesicles. -> Enzymatically degraded by Monoamine oxidases (MAOs) or catechol-O-methyltransferase. (COMT)
Drugs that affect dopamine release/reuptake
Cocaine, amphetamine, and methylphenidate (Ritalin) – psychostimulants. All block the reuptake of mono-animes into terminals – more dopamine in synaptic cleft. (Amphetamine reverses transporters so pumps out transmitter – uncontrolled release)
What is Selegiline?
monoamine oxidase B inhibitor
What is entacapone?
COMT inhibitor. Prevents the breakdown of catecholamines, increases the releasable pool, these drugs can have antidepressant activity and can be used for treating Parkinson’s.
The serotonergic system
Nine raphe nuclei (in the brainstem) with diffuse projections – each project to a different part of the brain. Descending projections to cerebellum and spinal cord (pain). Ascending projections (reticular activating system (with Locus Coeruleus)). Dorsal and medial raphe project throughout the cerebral cortex. Raphe neurons -> fire tonically during wakefulness, quiet during sleep. Function on -> mood, sleep, pain, emotion, appetite.
Serotonin Synthesis overview
Tryptophan (essential amino acid obtained in diet) -> hydrolysed into > 5-hydroxytryptophan (5-HTP) -> hydrolysed by aromatic amino acid and decarboxylase -> serotonin (5-hydroxytryptamine, 5-HT).
Tryptophan and mood
It is the amino acid responsible for serotonin synthesis. depletion diet, method of experimentally inducing a depressive state. Enrichment -> improving mood.
Serotonin release/reuptake
Serotonin storage -> loaded into vesicles.
Serotonin release -> Ca+ dependent exocytosis
Serotonin reuptake/metabolism -> signal terminated by reuptake by serotonin transporters (SERTs) on presynaptic membrane -> degraded by MAOs in the cytoplasm.
Drugs affecting serotonin release/reuptake
Fluoxetine, fenfluramine, MDMA
What is fluoxetine?
drug that blocks reuptake of serotonin (SSRI – selective serotonin reuptake inhibitory) – antidepressant/anti-anxiety.
What is Fenfluramine?
drug that causes the release of serotonin and inhibits its reuptake (has been used an appetite suppressant in the treatment of obesity.
what is MDMA?
ecstasy -> causes noradrenaline and serotonin transporters (SERT) to work in reverse releasing neurotransmitter into synapse/extracellular space.
What is the cholinergic system?
In the periphery -> acetylcholine (ACh) at neuromuscular junction (NMJ) -> and synapses in the autonomic ganglia. In the brain -> basal forebrain complex -> projections to hippocampus and cortex. Cholinergic interneurons in the striatum and the cortex -> each interneuron innervates 1000s of local principal neurons and modulates their activity.
What is Pontomesencephalotegmental cortex?
cholinergic link between brain stem and basal forebrain complex.
Acetylcholine synthesis:
made from chlorine (amount of chlorine is rate limiting step).
Acetycholine release/reuptake:
Storage -> loaded into vesicles. Release -> Ca+ dependent exocytosis. Metabolism -> rapidly degraded (hydrolysed) in synaptic cleft by acetylcholinesterase. -> chlorine is transported back into the presynaptic terminal and converted to acetylcholine. acetylcholinesterase is made by the cholinergic neuron, secreted into synaptic cleft and associated with the axonal membrane.
Drugs affecting release/reuptake of acetylcholine
Acetylcholinesterase inhibitors, Botulinum and tetanus toxins, botox
What is acetylcholinesterase inhibitors?
block the breakdown of ACh thus prolonging its actions in the synaptic cleft. E.g., physostigmine. -> treatments for Alzheimer’s disease, Myasthenia gravis (autoimmune disorder, AchR’s destroyed).
What is Botulinum and tetanus toxins?
(from bacteria Clostridium botulinum and tetani respectively) -> blocks the docking of vesicles by attacking SNAREs – no release.. (Inhibiting the release of Glycine at these sites “disinhibits” the cholinergic neurons so they continuously fire resulting in permanent muscle contraction, ‘lock jaw’)
What is Botox?
affects acetycholine release. Botox acts directly at synapse in NMJ . The muscles lose all input and so become permanently relaxed.
Disorders of the cholinergic system
myasthenia gravis, alzheimers disease, addiction, schizophrenia
What is myasthenia gravis?
autoimmune disease -> destroys cholinergic receptors in the muscle - muscle weakness and eventual loss of muscle activity.
What is Alzheimer’s disease?
loss of cholinergic neurons in the basal ganglia - possibly underlies deficits in memory associated with the disease -> Drugs that increase acetylcholine help (e.g. donepezil)
