Serotonin

• Serotonin (5-HT) is an indolamine compound derived from the dietary amino acid L-Tryptophan, which crosses the blood brain barrier via a neutral amino acid transporter. Tryptophan hydroxylase, an enzyme found in serotonin-producing neurons, is the rate limiting step in serotonin synthesis.
• Serotonin naturally constricts blood vessels and promotes peristalsis in the gastrointestinal (GI) tract, hence its name "sero-tonin." In fact, there is more serotonin in our gastrointestinal tract than our brains. 
• Serotonin was first characterized as a neurotransmitter in the 1950s and later it was discovered to be one of the major modulatory neurotransmitters in the brain. 
• Cell bodies of serotonin neurons are primarily located in the Raphe Nuclei of the brainstem and project to most areas of the brain and spinal cord.

• Let's briefly discuss serotonin receptors.
• There are fourteen (14) different serotonin receptors identified to date. Serotonin receptors are classified into 7 classes, 5HT1-7, with additional subtypes within each numeric class. All serotonin receptors are metabotropic G-protein coupled receptors (GPCRs) with the exception of 5HT3 receptors which are ionotropic. 

• Some receptors are located almost exclusively on postsynaptic neurons or presynaptic neurons whereas others are located on both presynaptic and postsynaptic neurons. 
• We will review each serotonin receptor as we move through each class of antidepressant.
• Let's take a closer look at 5HT1A receptors. 
• 5HT1A receptors can be both presynaptic and postsynaptic. When presynaptic, 5HT1A receptors are auto receptors that provide a "braking system" for serotonin neurons. 
• 5HT1A auto receptors located at the cell body region (i.e., somatodenritic region) of serotonin neurons decrease their impulse flow, or firing rate. They act as the police for serotonin neurotransmission by slowing down the impulse flow of serotonin neurons.
• 5HT1A auto receptors located at the nerve terminal region of serotonin neurons decrease the amount of serotonin released into the synapse with each action potential. See the figure below.

• Selective serotonin reuptake inhibitors (SSRIs) selectively block serotonin transporters (SERTs) which are located at both the cell body (i.e., somatodendritic) region and the nerve terminal region of serotonin producing neurons. Blocking these transporters increases extracellular serotonin in those areas. 
• Oddly, the immediate increase in serotonin after administering an SSRI does not correlate with improvement in mood. In fact, it may take a few weeks to appreciate a therapeutic response. 
• So why does it take so long for SSRIs to work? Let's review the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) to better understand why this happens.

Selective Serotonin Reuptake Inhibitors (SSRIs)

• As stated previously, SSRIs inhibit serotonin reuptake into the nerve terminal by blocking the serotonin transporter (SERT).  

• Initially, serotonin levels increase faster at the cell body (i.e., somatodendritic) region of serotonin neurons than they do at the nerve terminal regions. The reason for this remains unclear. 

• The rapid accumulation of serotonin at the somatodendritic region causes repeated stimulation of presynaptic somatodendritic 5HT1A auto receptors. 

• Repeated stimulation of 5HT1A auto receptors causes them to downregulate. The downregulation of 5HT1A receptors removes the braking system and therefore increases the firing rate of serotonin neurons (fewer police officers mean the serotonin neuron can fire faster). As a result, more serotonin is released at the nerve terminal region. 

• The problem with increasing serotonin levels abruptly is that more postsynaptic serotonin receptors will be stimulated--and this correlates with unwanted side effects such as anxiety, jitteriness, nausea, and sexual dysfunction.

• Over time (usually weeks), the postsynaptic serotonin receptors down-regulate, which correlates with the therapeutic effects and the disappearance of side effects.