Flashcards in 3 - NA, DA, 5-HT and HA Deck (53):
What does NA stand for?
What does DA stand for?
What does HA stand for?
What is a catecholamine?
A catecholamine (CA) is a monoamine, an organic compound that has a catechol (benzene with two hydroxyl side groups) and a side-chain amine.
What amino acid do all catecholamines derive from?
What are the three most common catecholamines in the body?
What are the three types of adrenergic receptors and what G proteins are they coupled to?
- α1 (Gq)
- α2 (Gi)
- β(1,2,3) (Gs)
Write the synthesis paths of the catecholamines from tyrosine to epinephrine and the enzymes involved (4 steps/enzymes)
1. Tyrosine to L-DOPA (tyrosine hydroxylase)
2. L-DOPA to dopamine (AADC - aromatic L-amino acid decarboxylase)
3. Dopamine to norepinephrine (dopamine β-hydroxylase DβH)
4. Norepinephrine to adrenaline (PNMT - phenylathanolamine-N-methyltransferase)
Name the transporters involved in the synthesis of catecholamines from L-DOPA to degradation by monoamine oxidase.
1. L-DOPA is transported into a vesicle by VMAT (vesicular monoamine transporter)
2. norepinephrine in a synapse is reuptaken by NET (norepinephrine transmembrane transporter). It is then either shuttled into a vesicle by VMAT or degraded by monoamine oxidase
Where do norepinephrine containing neurons arise in the brain?
The locus coeruleus in the brainstem
Where can norepinephrine be found in the brain?
Where can norepinephrine by found in the PNS?
Most postganglionic neurons of the sympathetic system
What type of feedback mechanism prevents over stimulation of β-adrenergic receptors?
A negative feedback loop
1. G protein-coupled receptor kinase (GPK) phosphorylates the receptor that then becomes a target for arrestins
2. β-arrestin (βARR) promotes receptor internalization of the receptor by binding to clathrin
3. Clathrin starts endocytosis of the receptors (the receptor can then be recycled or degraded)
This is a negative feedback loop because agonists of the β-adrenergic receptor cause this
What happens to mice lacking dopamine β-hydroxylase (DβH)?
They are unable to synthesize norepinephrine and epinephrine, and so lack response to serotonergic antidepressents
Where do the two most important dopamine tracts originate?
What is the nigrostriatal tract?
A dopamine tract that connects the substantia nigra in the midbrain with the basal ganglia below the cortex.
Damage causes Parkinson's disease
What is the mesolimbic tract?
A dopaminergic tract that arises from the ventral tegmental area (VTA) and projects to limbic structures such as the ventral striatum, nucleus accumbens, amygdala and the cortex
True or false? All known dopaminergic receptors are metabotropic.
How can alternative splicing create different variants of dopamine receptors?
D1-like receptors: No introns
D2-like receptors: Introns present
What are the two dopamine receptor subtypes and the receptors within these subtypes?
D1-like: D1, D5
D2-like: D2, D3, D4
What G proteins are coupled to D1-like dopamine receptors?
What G proteins are coupled to D2-like dopamine receptors?
True or false? Dopaminergic activity increases with age.
False. Dopaminergic activity decreases with age.
What happens to mice with the D1 dopamine receptor gene knocked out?
- Growth retarded
- Not interested in drinking and feeding
- Lack of locomotor activation after cocaine.
- Abnormal development of the striatum
What happens to mice with the D5 dopamine receptor gene knocked out?
Higher than normal locomotor activity, response to cocaine not altered
What happens to mice with the D2 dopamine receptor gene knocked out?
Decreased locomotor activity, response to cocaine not altered.
What happens to mice with the D3 dopamine receptor gene knocked out?
Increased locomotion in novel environments. Supersensitive to cocaine and amphetamines
What happens to mice with the D4 dopamine receptor gene knocked out?
Reduced locomotor behaviour. Supersensitive to the locomotor stimulating effect of cocaine and emphetamine
What happens to mice with the D1, D3 and D5 dopamine receptor genes knocked out?
Mice develop hypertension, indicating a role for these dopamine receptors in blood pressure control
How do neuroleptics treat psychosis in schizophrenia as well as Huntingtons and Alzheimers? What is a common side effect?
These block the activity (antagonists) of D2-like dopamine receptors
This can cause Parkinson's like effects by acting on the nigrostriatal pathway
L-DOPA is commonly used to treat Parkinson's Disease. What are some ways to boost treatment effectivity?
- Blocking peripheral aromatic amino acid decarboxylases so that dopamine is synthesized in the brain and L-DOPA is not used up in the periphery
- Selective MAO inhibitors
- Selective COMT (Catechol-O-methyl transferase) inhibitors (inhibits degradation of catecholamines)
Where do serotonin containing neurons arise from in the brain?
The raphe nuclei, part of the reticular formation in the upper brainstem. These distribute widely throughout the brain
Describe the serotonin synthesis pathway (2 steps and enzymes)
- Tryptophan to 5-hydroxytryptophan (5-HTP) (by tryptophan hydroxylase)
- 5-HTP to serotonin (by L-aromatic amino acid decarboxylase)
What enzyme degrades serotonin and what is the resulting metabolite?
MAO and aldehyde dehydrogenases
Result is 5-hydroxyindoleacetic acid (5-HIAA )
There are 7 serotonergic receptors, which one is inhibitory? Which one is ionotropic?
5-HT1 (5-HT2-7 are all excitatory)
5-HT3 is ionotropic (rest are metabotropic)
What is often a symptom associated with decreased serotonin 5-HT1a receptors?
What are 5-HT1b receptor agonists being used for?
- Migraine treatment
LSD and other hallucinogens produce hallucinations by activating ____?
5-HT2a serotonin receptors
What happens in mice with the 5-HT2c serotonin receptor knocked out?
Spontaneous convulsions, cognitive impairment, increased food intake and obesity.
What are 5-HT3 receptor antagonists used for?
Treatment of hemotherapy and radiotherapy induced nausea and vomiting
What are selective 5-HT6 serotonin receptor antagonists and agonists commonly used for?
Treating memory impairment and cognition (antagonists)
Treating anxiety and depression (agonists)
What are SSRIs?
selective serotonin reuptake inhibitors, inhibit 5-HT transporters`
Serotonin 2C agonists or antagonists may be used to treat obesity?
What transporter shuttles histidine into neurons?
L-amino acid transporter
What must happen to histamine before it is available for secretion into a neural synapse?
- Histidine is transported into the neuron with L-amino acid transporter
- Histidine is converted to histamine by histidine carboxylase
- Histamine is packaged into vesicles with vesicular monoamine transporter
What enzyme breaks down secreted histamine?
What are the 2 most common non-neuronal actions of histamine?
- Stimulation of immune response (H1 receptor)
- Gastric acid secretion (H2 receptor)
Where do histaminergic neurons in the brain originate from?
- Tuberomamillary nuclei in the hypothalamus
- Mast cells in thalamus
What are two types of drugs affecting histaminergic receptors?
Antagonists against H1 (asthma) and H2 (gastric ulcers)
What histaminergic receptor knockout produced lower day to night locomotion ratio?
H1 and H3
What histaminergic receptor knockout produced obesity?
What transmitter is often present in food and metabolized by diamine oxidase (DAO)?