Neurotransmission 2: dopamine, serotonin, acetylcholine Flashcards
Primary neurotransmitters and ‘neuromodulators’
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
Some neurotransmitters are ‘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)
- Neuromodulation is a neuron firing. To modulate the firing, you can fine tune it by increasing the firing
- On its own it probably isn’t going to do much
The Diffuse Modulatory Systems
Specific populations of neurons that project diffusely and modulate the activity of Glutamate and GABA neurons in their target areas.
- dopamine in the mid brain
- acetylcholine and serotonin in the brain stem
- noradrenaline in brain stem
They tend to be really widespread- they have massive actions on the brain
Dopamine neurons
- where are cell bodies?
- project into where?
- cell bodies in the midbrain
- project into the forebrain
What are the three different dopaminergic systems?
- what are the roles of the systems?
- what are their dysfunctions?
Nigrostriatal system (substantia nigra projections to neostriatum (caudate and putamen))
- 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 (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 (VTA projections to prefrontal cortex)
- role in functions such as working memory and planning.
- dysfunction: Schizophrenia
Dopamine step 1 and 2
1- Dopamine synthesis
Tyrosine (essential amino acid obtained in diet) →
(catalyzed by tyrosine hydroxylase (TH) (RATE LIMITING STEP/ slowest step)
L-Dopa →
(catalyzed by dopa decarboxylase)
Dopamine
2- Catecholamine storage
Loaded into vesicles
Drugs that affect dopamine synthesis and storage modulate behaviour
1) Reserpine
Impairs storage of monoamines in synaptic vesicles. (The vesicles remain empty resulting in no transmitter release upon activation)
2) L-DOPA
The precursor of dopamine, is 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)
3) AMPT (a-methyl-p-tyrosine)
- Inactivates TH (used experimentally – not in treatment)
- Allows less dopamine in neurons → less transmission
- Role and importance of neurotransmitter systems in behaviour revealed by drugs. (e.g. Reserpine was used to treat high blood pressure but caused depression)
Famous experiment- Reserpine
Rabbits don’t look like they’re alive
Don’t have any dopamine
People thought dopamine wasn’t a neurotransmitter but Carlsson said it is.
After giving reserpine to these rabbits, they gave loads of L-Dopa and then you have lots of dopamine back into vesicles again, dopamine can’t be released and you get these healthy rabbits again.
Important- to this day if you have parkinsons disease, you take L-Dopa and movement improves
However, after a while taking L-dopa when parkinsons progresses, it doesn’t have the same efficacy anymore
Reserpine was recently used to treat high blood pressure but eventually they found out it would cause depression.
Dopamine step 3 and 5
3- Dopamine release
- depolarization of presynaptic membrane
- influx of Ca2+ through voltage gated Ca2+
channels
- Ca2+ dependent vesicle docking and
Release
(Ca2+ dependent exocytosis)
4- Dopamine reuptake / metabolism
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-methyl-transferase (COMT)
Drugs that affect dopamine release and reuptake modulate behaviour
1) Cocaine, Amphetamine and Methylphenidate (Ritalin) - psychostimulants
- all block the reuptake of monoamines into terminals. More dopamine in synaptic cleft
- extended action of dopamine on postsynaptic neuron.
- cocaine blocks the dopamine from going back in and you will get dopamine accumulation. This means more action on postsynaptic neuron and increased dopamine transmission.
(Amphetamine reverses transporter so pumps out transmitter - uncontrolled release)
2) Selegiline – Monoamine oxidase B inhibitor
3) Entacapone – COMT inhibitor
- prevent the breakdown of catecholamines,
- increases the releasable pool
These drugs can have antidepressant activity (dopamine levels go up a bit) and can be used for treating Parkinson’s
The Serotonergic system:
1- what nuclei?
2- projections?
3- what project throughout the cerebral cortex?
4- raphe neurons?
5- function in?
1- Nine raphe nuclei (in brain stem) with diffuse projections
- each projects to a different part of the brain
2- Descending projections to cerebellum and spinal cord (pain)
Ascending projections (reticular activating system (with Locus Coeruleus))
3- Dorsal and medial raphe project throughout the cerebral cortex
4- raphe neurons
- fire tonically during wakefulness
- quiet during sleep
5- Function in:
- mood
- sleep
- pain
- emotion
- appetite
Serotonin step 1
1) Serotonin synthesis
Tryptophan (essential amino acid obtained in diet) RATE LIMITING
(tryptophan hydroxylase) →
5-hydroxytryptophan (5-HTP)
(Aromatic amino acid decarboxylase) →
Serotonin (5-hydroxytryptamine, 5-HT)
Tryptophan and mood:
- depletion diet: method of experimentally inducing a depressive state
- Enrichment: improving mood
Serotonin steps 2, 3 and 4
2) Serotonin storage
Loaded into vesicles
3) Serotonin release
Ca2+ dependent exocytosis
5) Serotonin reuptake / metabolism
- signal terminated by reuptake by Serotonin transporters (SERTs) on presynaptic membrane
- degraded by MAOs in the cytoplasm
Drugs that affect serotonin release and reuptake modulate behaviour
1- Fluoxetine (Prozac)
Blocks reuptake of serotonin (SSRI – selective serotonin reuptake inhibitor) – antidepressant / anti-anxiety
2- Fenfluramine causes the release of serotonin and inhibits its reuptake (has been used as an appetite suppressant in the treatment of obesity)
3- MDMA 3,4-methylenedioxy-methamphetamine (ecstasy)
Causes noradrenaline and serotonin transporters (SERT) to work in reverse releasing neurotransmitter into synapse/ extracellular space
Lets serotonin out of terminal and you get an excessive amount of serotonin in synaptic terminal and this will acutely boost mood.
Monoamine oxidase inhibitors (boost monoamines)
The cholinergic system
- in the periphery…
- in the brain…
- what other complex?
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
Pontomesencephalotegmental complex
cholinergic link between the brain stem and
basal forebrain complex
What neuron is in the striatum and the cortex?
What do each interneuron do?
Cholinergic interneurons in the striatum and the cortex
Each interneuron innervates 1000’s of local principal neurons and modulates their activity
