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Re: Serotonin

Posted by Sunnely on August 27, 2000, at 21:45:53

In reply to Serotonin, posted by RobinN58 on August 27, 2000, at 10:53:43

> I had been taking an antidepressant medication that was supposed to affect serotonin levels. Could you help me understand a little better how serotonin works? Is it manufactured in the neuron and released at the receptor? I understand about the SSRI drug that it occupies the receptor site after serotonin leaves to prevent reuptake. What happens then? Is serotonin taken up by a different type of neuron at its receptor site? Is that how it gets used? Also, if no SSRI is present, does serotonin keep reattaching to the original receptor site, and then keeps getting spit out again until it eventually gets captured by the right neuron? Thanks for any light you can shed on this.

Hi Robin,

There are several proposed hypotheses to explain the cause of depression. Looking at the biological basis, the "monoamine hypothesis of depression" appears to be the leading theory. This theory proposes that depression is due to a deficiency in one or another of three biogenic monoamines, namely serotonin, norepinephrine (noradrenaline) and/or dopamine.

The following discusses only the serotonin neurotransmitter (brain chemical) and its role in depression.

Serotonin (aka 5HT; 5-hydroxytryptamine) is produced from enzymes after the amino acid precursor tryptophan is transported into the serotonin neuron (nerve cell). Once transported into the serotonin neuron, tryptophan is converted into 5-hydroxytryptophan (5HTP) by the enzyme tryptophan hydroxylase. 5HTP is then converted into 5HT by the enzyme aromatic amino acid decarboxylase (AAADC) Serotonin is then stored in synaptic vesicles (storage) where it stays until released by a neuronal impulse. Serotonin is destroyed by the enzyme monoamine oxidase (MAO), and converted into an inactive metabolite.

During a neuronal impulse, serotonin is released from its presynaptic storage into the synapse (canal) then subsequently attaches itself to the serotonin postsynaptic receptors. The presynaptic serotonin reuptake pump terminates the action of unused serotonin out of the synapse. In this case, serotonin is released at a normal rate, so there is no depression. During this state, all the regulatory elements of the neuron are also normal: namely, the enzyme monoamine oxidase (MAO) which destroys the neurotransmitter; the serotonin reuptake pump which terminates the action of serotonin by sweeping it out of the synapse; and the postsynaptic receptors which react to the release of serotonin.

In the case of depression, serotonin is depleted, causing neurotransmitter (serotonin) deficiency. Such state of depletion in serotonin further leads to the upregulation (increased in number) of both presynaptic and postsynaptic serotonin receptors. This upregulation correlates with the production of depressive illness, and is hypothetically linked to the cause of depression.

There are several subtypes of serotonin receptors. It appears that the 5HT1A receptor contributes in a major way to the overall antidepressant effect of the SSRIs. Other subtypes of serotonin receptors play major roles in the side effects of the SSRIs. These receptors include 5HT2 and 5HT3.

Based on the above explanation, during depressed state, serotonin is deficient, the number of serotonin receptors is upregulated (increased), and there are low amount of signals in the neuron to release serotonin. The following explains the proposed antidepressant action of SSRIs (a bit technical). When an SSRI is administered, it immediately blocks the serotonin reuptake pump. This causes serotonin to increase initially only in the somatodendritic area. This in turn, leads to the downregulation (decreased in number) of 5HT1A autoreceptors or presynaptic receptors. Once these receptors are downregulated, there is no longer inhibition of impulse flow in the serotonin neuron. Thus, neuronal impulse flow is turned on. The consequence of this is for serotonin to be released in the axon terminal (into the synapse). However, this increase is delayed compared to the increase of serotonin in the somatodendritic areas of the serotonin neuron described earlier. This delay is the result of the time it takes for somatodendritic serotonin to downregulate the 5HT1A autoreceptors, and turn on neuronal impulse flow in the serotonin neuron. This delay may account for why antidepressants do not relieve depression immediately (antidepressant lag time, usually 2-3 weeks). It is also the reason why the mechanism of action of antidepressants may be linked to increasing neuronal impulse flow in serotonin neurons with serotonin levels increasing in the axon terminals before an SSRI can exert its antidepressant effects. Finally, increased serotonin availability leads to the downregulation (decreased) of the postsynaptic serotonin receptors.

It has been proposed that the SSRI effect on 5HT1A receptors not only lead to its antidepressant action but also anti-obssesive compulsive disorder properties, anti-panic effects, anti-social phobia properties (social anxiety disorder), and anti-bulimic properties.

Unfortunately, SSRIs also affect other serotonin receptors which account for their unwanted side effects. Stimulating the serotonin receptor called 5HT2 could lead to agitation, akathisia (motor restlessness), anxiety, panic attacks, insomnia, sexual dysfunction. Stimulating the serotonin receptor called 5HT3 could lead to nausea, gastrointestinal distress, diarrhea, and headache.

Hope this helps.

Reference: Psychopharmacology of Antidepressants by Stephen M. Stahl, M.D., Martin Dunitz, Ltd., London, UK, 1997.


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