Serotonin

Structure of serotonin

Serotonin is a monoamine neurotransmitter. It is one of the key chemicals and hormones in the body and is affected by a large range of substances. Establishing a good understanding of how serotonin and its receptors function is key to understanding how psychoactive substances, along with a variety of other drugs, produce their effects. There is a wide variety of different substances that impact serotonin and its receptors: full/partial/inverse agonists, releasing agents, reuptake inhibitors, and antagonists. All of these interact with the serotonin system in different ways. Although there is too much research about serotonin to summarize here, the general structure, function, biosynthesis and receptors can be looked at. I do want to make it known however, that I am in no way a biochemist or an expert in this area. I have summarized the research I have found to the best of my ability.

Serotonin (C10H12N2O) or ‘5-hydroxytryptamine’ (5-HT) is a chemical that carries ‘messages’ between nerve cells in the brain and the rest of the body.[30] It has a pivotal role in basic physiology and is found in all bilateral animals, as well as in fungi and plants.[32][36] Chemically, it is classified as a monoamine neurotransmitter, [17] which is a type of neurotransmitter that contains one amino group connected to an aromatic ring followed by a two carbon chain.[31] Its biological function is complex: modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vasoconstriction.[32] Serotonin is able to achieve all of these functions because it is found throughout the body, although most of it is found in the intestines (about 95% is found in the cells lining the gastrointestinal tract).[30][36] It is produced in the central nervous system (CNS), specifically in the raphe nuclei located in the brainstem, Merkel cells located in the skin, pulmonary neuroendocrine cells and in the pineal gland as an intermediate in the synthesis of melatonin.[32][36]

Serotonin was first discovered by Vittorio Erspamer in the enterochromaffin cells (intestinal cells) during the 1930s. He originally did not know what it was and called the amine “enteramine’.[33] Serotonin was further researched and was the first of the monoamine neurotransmitters to be discovered, as a consequence of LSD research in the 1950s and was only demonstrated in the mammalian brain a decade after the discovery of LSD.[17][43] The discovery of serotonin led to the elucidation of receptors and their fundamental role in neurological function.[17]

The biosynthesis of serotonin is fairly simple and is achieved in two steps. It is formed from L-tryptophan which is a chemical found in foods such as chocolate, meat, and nuts. The general steps are: 1) serotonin derives from the amino acid L-Tryptophan, via the (rate-limiting) hydroxylation of the 5 position on the ring (forming the intermediate 5-Hydroxy-L-tryptophan (5-HTP)). This means that an OH group is added to L-tryptophan. Then 2) decarboxylation to produce serotonin. This step basically removes the carboxyl group (COOH) on the molecule.

In more detail however serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes, L-tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase (DDC), along with the coenzyme pyridoxal phosphate.[17][32] The TPH-mediated reaction is the rate-limiting step in the pathway.[36] This means that the speed at which this reaction can take place is dependent on the concentration of L-tryptophan and TPH. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a neuron-specific isoform.[36] The overall process involves the conversion of L-tryptophan to 5-hydroxy-L-tryptophan by TPH.[36] The second metabolic step involves the decarboxylation of 5-hydroxy-L-tryptophan by the action of the cytosolic enzyme L-aromatic amino acid decarboxylase (AADC).[17]

The metabolism of serotonin can take two pathways; however, one is generally considered insignificant. I will not go into detail about this pathway since it does not play an important role in how substances interact with the serotonin system. I am also not confident enough in my biochem knowledge to properly explain these steps. Serotonin signaling is the same as other neurotransmitters. In neurons, neurotransmitters travel from the presynaptic bouton across the synaptic cleft to act on postsynaptic receptors. In the case of serotonin, it is stored in vesicles at the bouton of the presynaptic neuron (1).[17] In response to an action potential transmitted within the presynaptic neuron (signal), serotonin is released from the storage vesicles into the synaptic cleft.[17] Serotonin molecules diffuse across to bind to serotonin (5-HT) receptors on the surface of the postsynaptic neuron (2).[17] Simply put, one neuron gets a signal to release serotonin across the space between two neurons. Then, serotonin binds to its orthosteric binding site on the extracellular domain of the membrane-bound 5-HT receptor molecule, which elicits a characteristic conformational change resulting in a cascade of events related to G-protein cleavage and downstream interactions and catalysis involving second-messenger molecules such as inositol phosphate and cyclic AMP, and proteins such as β-arrestin (3).[17] The exact molecules involved in this process can get complicated; however, the important part is that there are receptors on the outside of a cell that can bind with serotonin (or agonists) to cause a chemical cascade.

Different substances impact the serotonin system differently based on chemical structure and type. Classes of substances react with various receptors and therefore create different reactions. There are six different ways a chemical can interact with serotonin receptors (along with example substances):

• Full Agonist: A few psychedelic drugs are full agonists of the 5-HT2A receptor; among them are 25I-NBOMe and Bromo-DragonFLY
• Partial Agonist: Most classical psychedelic drugs are partial agonists of the 5-HT2A receptor; among them are LSD, psilocin and mescaline
  • Many antidepressants, anxiolytics/anti-anxiety drugs, and cluster headache medicines are also partial serotonin receptor agonists
• Inverse Agonist: Some antipsychotics such as Pimavanserin, Risperidone and Olanzapine are 5-HT2A inverse agonists
• Releasing Agents: Many recreational drugs are serotonin releasing agents; among them are MDMA, MDA and mephedrone.
  • Many analgesics/pain-relievers and appetite suppressants are also serotonin releasing agents
• Reuptake Inhibitor: Many antidepressants such as: venlafaxine (Effexor), an SNRI, citalopram (Celexa), a SSRI and amitriptyline (Elavil)
  • Many recreational drugs like cocaine and tramadol are also serotonin reuptake inhibitors
• Antagonist: Many antipsychotics such as haloperidol or quetiapine and anti-emetics are serotonin receptor antagonists
  • One example is galanolactone, a chemical found in ginger, that acts as an antiemetic via its action as a 5-HT3 antagonist