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Cell and Systems Biology
Francis Bambico

 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  How?  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  Happens in some patients, especially teenagers  5HT1A densities are much higher in teenagers  So you have to repeatedly expose the patient with SSRIs for one month before you see an effect because repeated activation of the autoreceptors will lead to desensitization of these receptors  Desensitization – prevent coupling of Gi; repeated stimulation -> get re uptaken to the cytoplasm; clathrin will cage the receptor that was recently activated and would recycle it; decrease in the functionality and number of 5HT1AR -> why you have to chronically treat them  Most anti-depressant have been shown to stimulate neurogenesis in the adult brain  Most neurogenesis begin to cease in adulthood but still happens in hippocampus, olfactory cortex and some ventricular regions  Hippocampus is important for emotional process and repeated treatment of anti-depressants have been shown to increase neurogenesis in the hippocampus  Birth of neurons is intrinsically a slow process o Differentiation, migration to the respective sides o Has to find its proper connections o Long process before you get new neurons that will integrate into the neuronal network  A few reasons why conventional anti depressants take a while   PET imaging/brain scan image of dorsal raphe of a depressed patient  These radio active substance bind to 5HT1AR  After treatment, 5HT1A decreased -> indicated by less gamma rays  Proves that long term treatment, in fact, lead to decrease in 5HT1AR   Experiment to measure 5HT neurons in lab animals 
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