Week 4 - topic 3 Flashcards
Common neurotransmitters and their general effects on the CNS and PNS
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Amino acid neurotransmitters
In the brain, most synaptic communication is accomplished by two amino acid neurotransmitters:
Glutamate = excitatory effects on cells.
Gamma-aminobutyric acid, or GABA = inhibitory effects on cells
Glutamate - production, storage and release
- Synthesised from a precursor amino acid (glutamine) by an enzyme (glutaminase)
- Glutamate is pumped into synaptic vesicles by vesicle glutamate transporters, and released from presynaptic neuron following an action potential
Glutamate - receptors
NMDA receptor, (ionotropic – controls calcium ion channel) (Voltage and neurotransmitter dependent ion channel - requires particular neurotransmitter for binding and particular charge to open) AMPA receptor, (ionotropic – controls sodium ion channel) Kainate receptor (ionotropic –controls sodium ion channel) Metabotropic glutamate receptor (metabotropic)
Glutamate - Reuptake and deactivation
Glutamate is removed from the synapse by excitatory amino acid transporters (reuptake) and broken down by enzymes (enzymatic deactivation)
If glutamate isn’t removed from the synapse, glutamate excitotoxicity occurs = prolonged overexcitation which damages neurons.
GABA - production, storage and release
- It is produced from a precursor (glutamic acid) by the action of an enzyme (GAD)
- GABA is pumped into synaptic vesicles by the vesicle GABA transporter, and released from presynaptic neuron following an action potential
- GABA-secreting neurons have an inhibitory influence to help keep brain stable
- A lack of inhibition might be related to seizure disorders
GABA - receptors
- GABAA receptors are ionotropic and control chloride channels (Cl-).
- They have at least five different binding sites, and other ligands (e.g. hormones) bind to these additional sites
GABA - Reuptake and deactivation
- GABA is removed from the synapse by proteins that are GABA transporters (reuptake).
- GABA is broken down by an enzyme (enzymatic deactivation)
Non-amino acid neurotransmitters
- Although amino acid neurotransmitters like GABA and Glutamate are widespread throughout the brain, other neurotransmitters (i.e. non-amino acid ones) are located in distinct pathways in the brain.
- Furthermore, whereas amino acid neurotransmitters are most concerned with information transmission, non-amino acid neurotransmitters tend have modulating effects.
Acetylcholine (ACh) - pathways
ACh functions in both the CNS and PNS PNS = primary neurotransmitter involved in muscle contraction CNS = found in specific locations and pathways: Dorsolateral pons (REM sleep - dreaming) Basal forebrain (facilitate perceptual learning) Medial septum (memory formation)
Acetylcholine (ACh) - production, storage and release
- Synthesised from two precursors (choline and acetyl coenzyme A) by an enzyme (ChAT)
- Loaded into vesicles by the vesicle ACh transporters and released from vesicles following an action potential
- Botox prevents the release of ACh when injected into a muscle. Also used to to treat migraines and severe muscle contractions.
Acetylcholine (ACh) - receptors
- Ionotropic ACh receptors stimulated by nicotine = nicotinic receptor (found in PNS)
- Metabotropic ACh receptors stimulated by muscarine (found in the mushroom Amanita muscaria) = muscarinic receptor (predominate in CNS)
Acetylcholine (ACh) - reuptake and deactivation
- Deactivated by the enzyme acetylcholinesterase (AChE) which is present in the postsynaptic membrane.
- Once broken down, ACh parts (choline) are returned to presynaptic neurons via reuptake via choline transporters.
- > Drugs are used to deactivate AChE.
e. g. AChE inhibitors used to treat myasthenia gravis (autoimmune, neuromuscular disease that causes weakness in the skeletal muscles)
Monoamine neurotransmitters
- Monamines are neurotransmitters produced in cell bodies mainly in the thalamus, hypothalamus, mid brain and brain stem, and whose axons project widely throughout the brain.
- Monoamine neurotransmitters include serotonin, dopamine, histamine norepinephrine, and epinephrine, all of which have wide ranging functions.
- For instance, you have probably heard about serotonin in relation to mood and depression, but it is also involved in digestion.
Dopamine (DA)
Produces both EPSPs and IPSPs
Impacts movement, attention, learning, and reinforcing effects of drugs
Dopamine (DA) - pathways
Originate from midbrain structures (substantia nigra and ventral tegmental area):
- Nigrostriatal system (movement control)
- Mesolimbic system (reward and reinforcement)
- Mesocortical system (memory and problem solving)
Dopamine (DA) - production
- Dopamine is a catecholamine - subclass of monoamines
- Producing catecholamines requires several enzymatic steps:
- > Precursor molecule which is modified slightly step by step to reach final shape
- > enzymatic process, modifications are made by enzyme
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Dopamine (DA) - storage and release
- Vesicle monoamine transporters move dopamine into synaptic vesicles for release into the synapse following an action potential.
Dopamine (DA) - receptors
Five Metabotropic types of receptors
D1, D2, D3, D4, and D5
Dopamine (DA) - reuptake and deactivation
- Dopamine transporters remove dopamine from the synapse (reuptake)
- Several drugs serve as dopamine agonists: amphetamine, methamphetamine, cocaine, and Ritalin.
- Deactivation of catecholamines is regulated by an enzyme called monoamine oxidase (MAO)
Norepinephrine (NE) - pathways
- Norepinephrine is found in both the CNS and PNS
- The most important system originates in the locus coeruleus located in the dorsal pons – related to vigilance
- catecholamine subclass
Norepinephrine (NE) - production, storage and release
- very similar process as dopamine, synthesised from the dopamine molecule using a second enzyme
Differences:
- NE is synthesised in the synaptic vesicle
- Most neurons releasing NE release it via axonal varicosities (beadlike swellings of the axonal branches)
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Norepinephrine (NE) - receptors
- Four types of adrenergic receptors (norepinephrine and epinephrine)
- All metabotropic
- Found in neurons in CNS and in various organs of body
Norepinephrine (NE) - reuptake and deactivation
- Norepinephrine transporters remove excess norepinephrine from the synapse (reuptake)
- Excess norepinephrine is deactivated by an enzyme called monoamine oxidase, type A.
Serotonin (5-HT) - pathways
- Serotonin = regulation of mood, control of eating, sleep (and dreaming), arousal, and pain regulation
- Clusters originate in the raphe nuclei of the midbrain, pons, and medulla
- > Dorsal raphe project to cerebral cortex + the basal ganglia
- > Median raphe project to cerebral cortex + part of the hippocampal formation
Serotonin (5-HT) - production, storage and release
- Synthesised from an amino acid
- Loaded into synaptic vesicle by vesicle monoamine transporter
- Released from axonal varicosities
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Serotonin (5-HT) - receptors
- At least nine different types of serotonin receptors (autoreceptors and postsynaptic receptors).
- All are metabotropic except one.
- the ionotropic receptor is involved in nausea and vomiting and helps with production of IPSP’s
Serotonin (5-HT) - reuptake and deactivation
- Serotonin transporter removes 5-HT from the synapse (reuptake)
- Drugs that inhibit uptake of serotonin play important role in treatment of depression (e.g. Prozac)
- 5-HT can be deactivated by monoamine oxidase (enzymatic deactivation).
Histamine
- Found in only one place in the brain: the tuberomammillary nucleus (TMN), located in the posterior hypothalamus
- Histamine plays important role in wakefulness
- Drugs that block histamine receptors (antihistamines) cause drowsiness
Histamine - production, storage and release
- Produced from an amino acid precursor by the action of an enzyme
- Stored in vesicles and released following an action potential
Histamine - receptors
- CNS contains H1, H2, H3, and H4 receptors
- Antihistamines act as antagonists at histamine receptors
Peptides - production, storage and release
Produced from large polypeptide precursor molecules
that are broken into smaller neurotransmitter molecules
by special enzymes.
• Synthesis of peptides occurs in the soma
• Vesicles containing the peptides are delivered from the
soma to terminal buttons by axoplasmic transport
Peptides - production, storage and release part 2
Many terminal buttons have two types of synaptic
vesicles (e.g. one with a peptide and one with a
monamine, or acetylcholine) = co - release.
• Peptides regulate sensitivity of presynaptic or
postsynaptic receptors to the neurotransmitter
Peptides - production, storage and release part 3
Peptides are released from all parts of the terminal
button
• Some molecules go to the synaptic cleft - others go to
receptors on other cells nearby
Several types of peptides
• Most peptides are neuromodulators
• Some peptides are neurotransmitters (e.g.
endogenous opioids)
Peptides - receptors
• Several neural systems activated when opioid receptors are
stimulated
• Analgesia (pain relief)
• Inhibition of defensive responses such as fleeing and
hiding
• Reinforcement (can lead to opioid abuse)
• Direct agonists = Heroin
• Direct antagonists = Naloxone (drug that blocks opiate
receptors which can treat opioid overdose)
Peptides - deactivation
Peptides are deactivated by enzymes but there is no
reuptake process
Lipids
- non-soluble in water
- Substances derived from lipids (fat like molecules) can transmit messages within or between cells
- Endocannabinoids – natural ligands for the receptors that THC also activates (active ingredient in marijuana).
- > Anandamide
Lipids - production, storage and release
- Lipid neurotransmitters like anandamide appear to be synthesized on demand.
- They are not stored in vesicles, only produced and released when needed
Lipids - receptors
- Two types of cannabinoid receptors, CB1 and CB2
- Both are metabotropic
- Found on terminal buttons of glutamatergic, GABAergic, acetylcholinergic, noradrenergic, dopaminergic, and serotonergic neurons > regulate neurotransmitter release
- > THC exerts analgesic effects by stimulating CB1 receptors in the PNS
- > Paracetamol also acts on these receptors
Lipids - deactivation
- Anandamide is deactivated by the enzyme FAAH
- Because the enzyme is inside the neuron, the anandamide is transported back into the cell for deactivation via anandamide transporters
