Catecholaminergic Transmission Flashcards
Catecholamines include which three NTs?
Adrenaline.
Noradrenaline.
Dopamine.
What are the two structural components that all catecholamines consist of?
Catechol nucleus.
Amine group.
The synthesis of all catecholamines begins with the synthesis of what?
Dopamine.
How is L-dopa synthesised?
Tyrosine hydroxylase adds a hydroxyl group to tyrosine.
How is dopamine synthesised from L-dopa?
Dopa decarboxylase removes a carboxyl group from L-dopa.
How does tyrosine reach the brain to be converted into L-dopa and then dopamine?
Active transport.
What is the rate-limiting enzyme for dopamine synthesis?
Tyrosine hydroxylase (TH).
Why must TH be actively transported into the brain?
It must penetrate the BBB.
What can increase TH activity?
Catecholamine release through transcriptional, translational and posttranslational regulation.
How does chronic environmental stress affect TH expression?
Upregulates it.
Name three drugs that upregulate TH expression.
Caffeine.
Nicotine.
Morphine.
What class of drugs downregulate TH expression?
Antidepressants.
Peripheral administration of L-dopa can be used to increase dopamine synthesis to treat PD. Why?
This bypasses the TH rate-limiting step and penetrates the BBB.
Which transporter is used in reuptake of dopamine into the axon terminal?
DAT (dopamine transporter).
Which two enzymes break down dopamine after reuptake into axon terminal?
MAO (monoamine oxidase).
COMT (catechol-O-methyltransferase).
Name the two MAO isoforms.
MAOa.
MAOb.
Which NTs can MAO metabolise?
All catecholamines.
5-HT.
In which neurons is MAOa expressed?
Dopaminergic and noradrenergic neurons.
In which neurons is MAOb expressed?
5-HT neurons (axons contain MAOa).
Which MAO isoform has a higher affinity for dopamine?
MAOa = MAOb.
They have the same affinity.
Which MAO isoform has a higher affinity for noradrenaline and 5-HT?
MAOa.
MAO inhibitors (MAOIs) can be used to treat what?
Parkinson’s disease (PD).
Explain why MAOIs are used to treat PD.
MPTP is a dopamine neurotoxin that can cause PD.
It must be converted to MPP+ by MAOb before it can exert its toxic effects.
Selective MAOb inhibitor reduces oxidative stress.
Where is a membrane-bound form of COMT localised?
Catecholaminergic synapses.
What are the two main effects of COMT inhibitors?
Increase levels of dopamine and noradrenaline in synapses.
Prolong dopamine receptor activation.
Generally, COMT plays a smaller role in the catabolism of catecholamines compared to DATs. Where in the brain does COMT play a larger role and why?
Prefrontal cortex.
DAT is expressed at relatively low levels, so COMT may play a larger role.
Mutations in COMT may be associated with what?
Cognitive dysfunction.
Risk of psychiatric disorders.
Name the two dopamine (DA) receptor families.
D1-like.
D2-like.
Which two DA receptors belong to the D1-like family?
D1.
D5.
Which three DA receptors belong to the D2-like family?
D2.
D3.
D4.
How do the D1-like and D2-like DA receptor families differ structurally?
D1-like = long intracellular carboxy-terminal loop.
D2-like = large third intracellular loop.
What is the main role of D1-like DA receptors?
Stimulate the formation of cAMP and activation of protein kinase A (PKA).
What are the two main roles of D2-like DA receptors?
Decrease cAMP formation.
Modulate potassium and calcium ion currents.
What type of receptor are DA receptors?
GPCR.
Which G-proteins can D1-like DA receptors be coupled to?
Gaolf (G-alpha-olf).
Gas (G-alpha-s).
How do D1-like DA receptors affect excitability?
Increase excitability.
How do D2-like DA receptors affect excitability?
Decrease excitability.
What is an important target of D1-like DA receptors?
Dopamine- and cAMP-regulated phosphoprotein of 32 kD (DARPP-32).
How do D1-like DA receptors amplify the PKA signal?
Inhibiting protein phosphatase 1 (PP1).
How do D1-like DA receptors affect potassium and calcium channels?
Inhibits voltage-gated potassium channels.
Inhibits inwardly-rectifying potassium channels (Kir).
Increases Cav1 (L-type) calcium channel currents.
Which G-protein are D2-like DA receptors coupled to?
Gai/o (G-alpha-i/o).
Which pathway do D2-like DA receptors inhibit?
AC-cAMP-PKA transduction pathway.
How do D2-like DA receptors affect potassium and calcium channels?
Activate inwardly-rectifying potassium channels (Kir).
Inhibit Cav1 (L) and Cav2.2 (N) channels.
Via membrane interactions of their Gby dimers.
What type of complex can D1-like and D2-like DA receptors form with each other?
Heteromeric complex.
D1/D2 heteromers are linked to what?
Calcium signalling via coupling with Gq and phospholipase C (PLC) transduction pathways.
What are psychomotor stimulants also known as?
Indirect dopamine agonists.
Why are psychomotor stimulants used to treat ADHD?
They block DAT or reverse its actions.
Describe the action of antipsychotic drugs.
Block D2 receptors in subcortical structures in the limbic forebrain.
Which two DA agonists are used to treat PD?
D2 agonists.
D3 agonists.
How are the cell bodies of dopaminergic neurons organised?
Into discrete clusters.
How are the cell bodies of dopaminergic neurons classified?
Alphanumerically into groups A8-A16.
Name the four major dopaminergic pathways.
Nigrostriatal.
Mesocortical.
Mesolimbic.
Tuberoinfundibular.
What is the nigrostriatal pathway involved in?
Motor planning.
Purposeful, voluntary movement.
What is the mesocortical pathway involved in?
Physiology of cognition and executive function.
Emotions and affect.
What is the mesolimbic pathway involved in?
Reward.
Incentive salience.
Pleasure.
Positive reinforcement.
What is the tuberoinfundibular pathway involved in?
Hormone regulation, mainly prolactin secretion.
Why does the substantia nigra appear dark in healthy (non-PD) individuals?
High neuromelanin content that forms from the L-dopa precursor in DA synthesis.
Describe the nigrostriatal pathway in a healthy (non-PD) individual.
Axonal fibres projected by A9 dopaminergic neurons in the substantia nigra innervate the striatum to provide the DA needed for proper regulation of the motor circuit.
Describe the nigrostriatal pathway in PD.
There is a significant loss of A9 dopaminergic neurons and degeneration of nigrostriatal fibres, leading to denervation of the striatum and depletion of its DA input.
What is the DA hypothesis for schizophrenia?
A dysfunctional midbrain dopaminergic system may play an important role in the cause of schizophrenia.
What is the evidence for the DA hypothesis for schizophrenia?
Amphetamine and cocaine increase DA levels, and their abuse can lead to psychosis.
Amphetamine exacerbates psychosis in schizophrenics.
PD patients taking L-DOPA sometimes show psychosis.
Name three positive symptoms of schizophrenia.
Hallucinations.
Disorganised speech.
Erratic behaviour.
Name three negative symptoms of schizophrenia.
Reduced expression of emotions.
Poverty of speech.
Social withdrawal.
Name three cognitive symptoms of schizophrenia.
Impaired executive function.
Impaired working memory.
Difficulty initiating goal-directed behaviour.
Which pathway of the midbrain dopaminergic system is thought to be involved in the expression of the positive symptoms of schizophrenia?
Overactivity of the mesolimbic pathway.
Which pathway of the midbrain dopaminergic system is thought to be involved in the expression of the negative and cognitive symptoms of schizophrenia?
Dysfunction of the mesocortical pathway.
Working memory requires which brain area?
The prefrontal cortex, specially the dorsolateral prefrontal cortex (DLPFC).
What can impair working memory?
Depletion of prefrontal cortex DA or blocking D1 receptors.
What is thought to underlie brain stimulation reward?
Projections from the VTA to the nucleus accumbens.
All addictive drugs activate which DA system?
Mesocorticolimbic.
Which three types of “reward” have been shown to increase extracellular levels of DA in the nucleus accumbens?
Natural reward, e.g. food.
Electrical self-stimulation.
Systemic administration of drugs of abuse.
The tuberoinfundibular pathway transmits DA from where to where?
From the hypothalamus to the pituitary gland.
In the tuberoinfundibular pathway, blocking D2-like DA receptors can result in what?
Increase in the plasma levels of prolactin.
What can an increase in the plasma levels of prolactin lead to?
Gynaecomastia = enlargement of breast tissue in both sexes.
Galactorrhoea = milky discharge from the nipples, unrelated to normal lactation, in both sexes.
Where is noradrenaline synthesised?
Synaptic vesicles.
How is DA converted into NA?
A hydroxyl group is added to DA by dopamine beta-hydroxylase (DBH).
Which three main actions does NA regulate?
Attention.
Impulsivity.
Autonomic function.
Where is adrenaline synthesised?
In the axon terminal.
How is adrenaline synthesised from NA?
Phentolamine N-methyltransferase (PNMT) adds a methane group to NA.
What are the three main effects of adrenaline on the PNS?
Increases heart rate.
Constricts blood vessels.
Relaxes airways.
Which transporter pumps adrenaline into synaptic vesicles?
Vesicular monoamine transporter (VMAT).
In which neurons does adrenaline occur?
A small number of central neurons, all located in the medulla.
What is the rate limiting enzyme for the production of NA and adrenaline, and why?
Tyrosine hydroxylase.
Both NA and adrenaline are synthesised from DA, and TH is the rate limiting enzyme for DA synthesis.
Which transporter is responsible for the reuptake of NA into the terminal?
Noradrenaline transporter (NAT).
Which two enzymes break down NA and adrenaline?
MAO.
COMT.
Which branch of the nervous system do most adrenergic drugs target?
ANS.
True or false: adrenaline and NA use the same receptors?
True.
Are adrenoreceptors ionotropic or metabotropic?
Metabotropic.
Name the five adrenoreceptor subtypes.
a1 (alpha-1).
a2.
B1 (beta-1).
B2.
B3.
Which adrenoreceptor subtypes are postsynaptic noradrenergic receptors?
a1.
B1.
B2.
B3.
Are postsynaptic noradrenergic receptors excitatory or inhibitory?
Excitatory.
Which adrenoreceptor subtype is a presynaptic autoreceptor?
a2.
Is the presynaptic a2 autoreceptor excitatory or inhibitory?
Inhibitory.
Do all subfamilies of adrenoreceptors couple to the same G-protein?
No. Each subfamily preferentially couples to a different type of G-protein.
How does the presynaptic a2 autoreceptor function in a negative feedback loop to modulate signalling between neurons?
Release of NA into synaptic cleft causes diffusion of transmitter and activates presynaptic a2 autoreceptor.
This inhibits further synthesis of NA and blocks the release of more transmitter.
Name four NA-dependent functions.
Attention focusing and shifting.
Memory formation.
Stress response and mood regulation.
Sleep-wake cycle and circadian rhythm.
Which region of the brain is vital in the regulation of sleep, arousal and attention?
Locus coeruleus (LC).
How is the LC involved in anxiety?
In response to threat, LC firing may increase anxiety by releasing NA in the amygdala and other regions of the limbic forebrain.
Why are beta-adrenergic receptor antagonists being investigated as interventions to decrease the intensity of traumatic memories in PTSD?
Stimulation of beta-adrenergic receptors in the amygdala results in enhanced memory for stimuli encoded under strong negative emotion.
This facilitates the recall of stimuli that predict danger.
Where are the cell bodies of noradrenergic neurons found?
In the LC.
Which four areas do ascending LC projections innervate?
Hypothalamus.
Amygdala.
Hippocampus.
Cortex.
Which three areas do descending LC projections innervate?
Periaqueductal grey.
Other brainstem nuclei.
Spinal cord.
