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Lecture 14

CSB332H1 Lecture Notes - Lecture 14: Raphe Nuclei, 5-Ht1A Receptor, Autoreceptor

Cell and Systems Biology
Course Code
Francis Bambico

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Suppose you’re a member of a clinical team composed of psychologists, psychiatrists, and social workers
And a patient is suffering from major depression and is not responding to any anti depressant treatments
Team is testing 2 drugs
Drug x has a very slow onset of action (regular treatment for a month/two months before improvement occurs)
Drug y is very fast and kicks in 1 hour after 1 injection but some serious side effects such as sleep walking with
strange behavior (possibly violent during the sleep walk)
So which experimental drug would you give?
Consider risk of suicide of the patient
Dangerous to use both because of drug interactions; possible but studies must be done first
Problem with treating depression: really slow; a month to kick in
There are very fast acting anti depressant the first one that was used;
o Take only a few mins
o Amphetamine very effective
o Side effects: very addictive
o Could lead to psychosis and other emotional stresses
Examine the brain of a depressed individuals
SSRIs act on serotonin in the brain
Some act on dopa and noradrenergic system
Wide acceptance that dopaminergic and noradrenergic system funnel down into one common pathway on the
sertonergic system
SSRIs primarily act on this
In depressed people, serotonin system is hypoactive
Serotonin neurons are located in raphe nuclei in the midbrain of the brain stem and project to almost all parts of
the cerebral cortex
In depression, these neurons are hypoactive less serotonin
Indication that serotonin levels are lower than normal
Firing of brains recorded for dorsal raphe nuclei
Significantly low compared to control
Firing rate/s in normal indiv is 1 Hz
Stress -> dramatically decreased to about 0.6-0.75 Hz
Prozac increases the synaptic content of serotonin
They block the reuptake transporters located in cell bodies and axons and prevents recycling of serotonin
Allowing serotonin in synaptic cleft to stay longer
One single injection of Prozac won’t lead into a maintained increase of serotonin because if you increase the
synaptic content of serotonin
Serotonin molecules around the neurons will activate one type of receptor located in the cell body
Acute SSRI addition increase in the content of serotonin around the cell body and synapse but this will increase
5-HT1A autoreceptors (inhibitory) in the postsynaptic membrane
5-HT regulate the activity of serotonin neurons’ firing activity
Coupled to Gi proteins -> decrease in the conductance K and Ca -> hyperpolarization of the cell
Therefore one dose is not effective
The decrease of 5HT eventually -> but firing activity of serotonin can be suppressed -> make it worse
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