Serotonergic Transmission Flashcards
What type and subtype of NT is 5-HT?
Amine –> indolamine.
What is an indolamine?
Tryptophan-derived specialised metabolites belonging to the huge and ubiquitous indole alkaloids group.
What are the four similarities between 5-HT and catecholamines?
Closely related functions.
Shared mechanisms of clearance from synapses.
Shared metabolic pathways.
Jointly targeted by psychomotor stimulants, tricyclic antidepressants, MAOIs, and SSRIs.
How do we obtain the amino acid tryptophan?
Solely from our diet.
How is tryptophan converted into 5-HTP?
Tryptophan hydroxylase removes a hydroxyl group from tryptophan.
How is 5-HTP converted into 5-HT?
5-HTP decarboxylase removes a carboxyl group from 5-HTP.
Describe the process of 5-HT removal from the synapse.
Reuptake into terminal via SERT (serotonin transporter).
Enzymatic degradation by MAO.
How is tryptophan transported into the brain?
Actively transported across the BBB.
What is the rate-limiting enzyme for 5-HT biosynthesis?
Tryptophan hydroxylase.
Which transporter loads 5-HT into vesicles?
VMAT (vesicular monoamine transporter).
How can drugs alter levels of 5-HT in the brain?
Drugs, e.g. PCPA, can irreversibly inhibit TPH to produce a long-lasting depletion of 5-HT in the brain.
How can diet alter levels of 5-HT in the brain?
A low-tryptophan diet can lead to a dramatic reduction in blood tryptophan levels and a substantial reduction of 5-HT in the brain.
How many families of 5-HT receptors are there?
Seven.
5-HT(1-7).
What are the subtypes of 5-HT(1) receptors?
5-HT(1A-1F).
What are the subtypes of 5-HT(2) receptors?
5-HT(2A-2C).
What are the subtypes of 5-HT(5) receptors?
5-HT(5A-5B).
Which 5-HT receptors are postsynaptic metabotropic receptors?
5-HT(1E-1F) and 5-HT(2A-2C).
Which 5-HT receptors are presynaptic metabotropic receptors?
5-HT(1A), 5-HT(1B) and 5-HT(1D).
Which 5-HT receptors are postsynaptic ionotropic receptors?
5-HT(3).
What specific type of receptor is 5-HT(1A)?
Somatodendritic autoreceptor.
Where in a neuron is 5-HT(1A) found?
Soma and dendrites.
Which two 5-HT receptors regulate the synthesis and release of 5-HT?
5-HT(1A).
5-HT(1D).
In which six regions of the brain is 5-HT receptor expression high?
Cortex.
Nucleus accumbens,
Striatum.
Hippocampus.
Substantia nigra.
VTA.
Where is the majority of the body’s 5-HT produced?
In the intestines.
What is the role of intestinal 5-HT?
Mediates hormonal, autocrine, paracrine and endocrine functions.
What is the peristaltic reflex?
Mechanical stimulation of the sensory neurons results in the simultaneous activation of both excitatory and inhibitory motor neurons.
What is the role of excitatory motor neurons in the peristaltic reflex?
Cause contraction of the circular muscles behind the bolus, propelling it along the GI tract.
What is the role of inhibitory motor neurons in the peristaltic reflex?
Cause relaxation of the circular muscles in front of the bolus, allowing it to pass unimpeded.
Why are drugs targeting 5-HT transmission often used to treat IBS?
IBS has been linked to dysfunctional SERTs in the gut.
Where is 5-HT synthesised in the brain?
Group of brainstem nuclei called the raphe nuclei.
Where do caudal raphe nuclei project to?
The spinal cord.
Where do rostral raphe nuclei project to?
Almost everywhere.
What is unipolar depression?
Individuals experience episodes of depression only.
What is bipolar disorder?
Individuals experience at least one episode of mania as well as depression.
What are the symptoms of mania?
Feelings of happiness and creativity.
Experiencing loss of appetite, insomnia, rapid speech and irritability.
Name three examples of unipolar depression.
Major depression.
Postnatal depression.
Seasonal effective disorder.
What are affective disorders?
Characterised by disturbances in mood rather than disturbances in thought or cognition.
What is the neurological basis of sleep disturbances?
Alterations in brainstem monoamine or cholinergic nuclei.
Disruptions in the suprachiasmatic nucleus (SCN) of the hypothalamus.
What is the neurological basis of changes in appetite and energy?
Abnormalities in various hypothalamic nuclei.
What is the neurological basis of depressed mood, anhedonia or mania?
Opposing abnormalities in the nucleus accumbens, medial prefrontal cortex, or amygdala.
What is the neurological basis of anxiety?
Abnormalities in the functioning of the amygdala and bed nucleus of the stria terminalis (BNST).
What is the neurological basis of the release of stress hormones?
Hyperfunctioning of the paraventricular nucleus (PVN).
Hyperfunctioning of the amygdala, which activates the PVN.
What is the neurological basis of alterations in thought content?
Abnormal functioning of the cerebral cortex.
Why is it so difficult to treat affective disorders?
An overwhelming number of brain structures are involved.
What predicts responsiveness to treatment with antidepressant drugs?
Increased activity in the anterior cingulate cortex.
When is DBS used for depression?
When patients do not respond to drugs, psychotherapy or electroconvulsive therapy.
What is the monoamine hypothesis of depression?
Most drug treatments for depression act on targets within monoaminergic synapses, enhancing transmission by NA, 5-HT or both.
Why are monoaminergic systems thought to play an important role in the pathophysiology of affective disorders?
There have widespread projections and a role in antidepressant action.
Define antidepressant drugs.
A heterogeneous group of compounds that are effective in the treatment of depression.
Name the five categories of antidepressant drugs.
Tricyclic.
Selective serotonin reuptake inhibitors (SSRIs).
Selective noradrenaline reuptake inhibitors (NRIs).
Serotonin and noradrenaline reuptake inhibitors (SNRIs).
Monoamine oxidase inhibitors (MAOIs).
Which monoaminergic system has the most massive and diffuse projections?
Serotonergic system.
Where in the brain is noradrenaline synthesised?
In several brainstem nuclei, mainly the locus coeruleus.
What is the requirement for effective antidepressants?
They enhance release and/or availability, or prevent the degradation of monoamines.
How do SRIs act on monoamines?
High selectivity for the 5-HT transporter.
Weak affinity for the NA transporter.
How do SNRIs act on monoamines?
Moderate affinity for both NA and 5-HT transporters.
How do MAOIs act on monoamines?
Prevent the degradation of all monoamines.
