Serotonin (5HT) PDF

**Serotonin (5HT).** **Serotonin** and the **catecholamine neurotransmitters** have closely related functions, closely related mechanisms of clearance from synapses, some shared pathways of metabolism, and, perhaps most importantly, are jointly targeted by several important classes of drugs, includ...

**Serotonin (5HT).** **Serotonin** and the **catecholamine neurotransmitters** have closely related functions, closely related mechanisms of clearance from synapses, some shared pathways of metabolism, and, perhaps most importantly, are jointly targeted by several important classes of drugs, including **psychostimulants** (DA, NA, and 5HT), **tricyclic antidepressants** (NA and 5HT), **monoamine oxidase inhibitors** (DA, NA, and 5HT), and **serotonin-noradrenaline selective reuptake inhibitors** (NA and 5HT). **Serotonin is synthesised from tryptophan:** Tryptophan is an amino acid that we get solely from our diet. 1. The **addition** of a **hydroxyl group** by **tryptophan** **hydroxylase** turns tryptophan into **5-HTP**. 2. 5-HTP is converted into serotonin when **5-HTP decarboxylase** removes a carboxyl group from 5-HTP. 3. Removal of serotonin from the synapse is by **reuptake** or degradation by **MAO**. **The location of serotonergic nuclei:** Cell bodies are in midline **raphe nuclei** throughout the brain stem. Caudal raphe nuclei project\ to the spinal cord and are important for the modulation of **afferent pain signals**. Rostral raphe nuclei project\ **just about everywhere else**! **THP is the rate-limiting enzyme in 5HT synthesis:** Tryptophan hydroxylase (**TPH**) is the **rate-limiting enzyme** in serotonin (**5HT**) biosynthesis. The process can be outlined in four main steps: 1. **Tryptophan Transport**: **Tryptophan** is actively transported across the **blood-brain barrier**, providing the precursor necessary for serotonin synthesis. 2. **Hydroxylation by TPH**: **TPH** hydroxylates tryptophan, converting it into **5-hydroxytryptophan (5HTP)**. This is the **critical rate-limiting step** in serotonin production. There are two **TPH genes**: **TPH1**, expressed predominantly in **peripheral tissues**, and **TPH2**, primarily found in the **brain**. **TPH activity** can be regulated by **neuronal activity**. 3. **Decarboxylation by AADC**: **Aromatic L-amino acid decarboxylase (AADC)** decarboxylates **5HTP** to produce **serotonin (5HT)**. This enzyme is also involved in the synthesis of other **catecholamines**. 4. **Vesicular Storage**: **Serotonin** is loaded into synaptic vesicles by the **vesicular monoamine transporter (VMAT)** for storage and release during neurotransmission. **Terminating the actions of 5HT:** Serotonin (**5HT**) is cleared from the synaptic cleft through two primary mechanisms: 1. **Reuptake**: **5HT** is taken back into the terminal by the **serotonin transporter (SERT)**, which is responsible for recycling the neurotransmitter. 2. **Enzymatic Breakdown**: **Monoamine oxidase (MAO)** metabolizes **5HT**. **MAO Properties**: **MAO** exists in both **intracellular** and **extracellular forms**. The **intracellular form** is associated with the **outer membrane of mitochondria**, while the **extracellular form** may metabolize **5HT** directly in the synapse. **MAO Isoforms**: **MAO A**: Expressed in **dopaminergic (DA)** and **noradrenergic (NA)** neurons. **MAO B**: Found in **5HT neurons**, with their axons containing **MAO A**. Affinity comparison: **MAO A = MAO B** for dopamine (**DA**), **MAO A \> MAO B** for **NA** and **5HT**. **MAO B** may play a role in maintaining **amine fidelity** by selectively processing certain amines. **MAO inhibitors (MAOI) and depression:** The first **MAOI**, **iproniazid**, was introduced in the 1950s for **tuberculosis** but was found to alleviate **depression** in patients. **Nonselective MAOIs** like **phenelzine**, **tranylcypromine**, and **isocarboxazid** effectively treat **depression** and **anxiety disorders**, particularly **atypical depression**, characterized by **hypersomnia** and **hyperphagia**. **Selegiline**, at **high doses**, also acts as a nonselective MAOI but requires **dietary precautions** due to the risk of **hypertensive crises**. **RIMAs (Reversible Inhibitors of MAO A)**, such as **meclobemide**, offer reduced dietary restrictions but may be less effective than other treatments. Today, **SSRIs** are favoured for their **better tolerability** and **fewer side effects**, making them the most common choice for treating **depression**. **There are many receptors for serotonin:** Serotonin (**5-HT**) receptors are the **targets of pharmacological treatments** for **mood disorders**. They are divided into different subtypes based on their location and function: - **5-HT1A, 5-HT1B, and 5-HT1D** are **presynaptic metabotropic receptors**, involved in regulating serotonin release. - **5-HT1E, 5-HT1F**, and **5-HT2A-5-HT2C** are **postsynaptic metabotropic receptors**, mediating various downstream signalling pathways. - **5-HT3 receptors** are unique as they are **ionotropic receptors**, allowing for direct ion flow across membranes. **Hallucinogens and 5HT2A Receptors:** Hallucinogens, often called **psychedelic drugs**, act as **partial agonists** at **5HT2A receptors**, leading to changes in perception and consciousness. One well-known example is **LSD (d-lysergic acid diethylamide)**, first synthesized in **1943** by **Albert Hofmann**. Hofmann\'s accidental ingestion of LSD revealed its ability to induce **sensory distortions**, including **visual illusions**, **hallucinations** (mostly visual), and **emotional shifts** ranging from elevated moods to severe **anxiety**. Although initially tested for use in treating **schizophrenia** and **alcoholism**, LSD showed limited benefits and became popular as a **recreational drug** during the **1960s** and **1970s**. LSD, while a **nonselective serotonin receptor agonist**, primarily produces its **perceptual distortions** through its partial agonist activity at **5HT2A receptors**. Other hallucinogens, including **DMT**, **psilocybin**, **mescaline**, and **DOM**, share this mechanism. Studies show that **selective 5HT2A receptor antagonists** can block the **hallucinatory effects** of these substances in **animal models**. The sensory disruptions caused by these drugs are believed to stem from the **dense serotonin innervation** of the **cerebral cortex**, which affects perception and cognition. **Drugs affecting serotonergic transmission:** **DA, NA, and 5HT Transporter Reuptake Inhibitors:** **DAT**, **NAT**, and **SERT** are **transmembrane proteins** responsible for **neurotransmitter reuptake** from the **synapse** into the **presynaptic terminal**. Once inside the terminal, neurotransmitters are either **reloaded into vesicles** by **VMAT** or broken down by **MAO**. These transporters are the key targets for two main classes of **psychotropic drugs**: **antidepressants** and **psychostimulants**. **Tricyclic antidepressants (TCAs)** and **serotonin-noradrenaline reuptake inhibitors (SNRIs)** block **NAT**, **SERT**, or both, but with varying selectivity. **Noradrenaline reuptake inhibitors (NRIs)** selectively block **NAT**, while **selective serotonin reuptake inhibitors (SSRIs)** specifically target **SERT**. Less commonly, drugs like **bupropion** can also inhibit **DAT**. A key difference between newer antidepressants (SSRIs, SNRIs, NRIs) and **TCAs** is that **TCAs** also block **α1 adrenergic receptors**, **H1 histamine receptors**, and **muscarinic cholinergic receptors**. This results in side effects like **postural hypotension** (from α1 receptor blockade), **sedation** (due to histamine, α1, and muscarinic receptor antagonism), and **anticholinergic symptoms** (e.g., **dry mouth**, **constipation**, **urinary retention**, **failure of pupillary accommodation**). While newer antidepressants have side effects like **sexual dysfunction**, they are generally better tolerated by most people. **Psychostimulants interact with NAT, DAT and SERT:** **Cocaine** blocks **NAT**, **DAT**, and **SERT**, thereby inhibiting the reuptake of **noradrenaline (NA)**, **dopamine (DA)**, and **serotonin (5HT)** after their normal vesicular release into the synapse. This leads to an increase in the concentration of these neurotransmitters in the synaptic cleft, enhancing their effects. **Amphetamines** have a more complex mode of action. They enter **monoaminergic nerve terminals** via **DAT**, **NAT**, and **SERT**, and disrupt the function of **VMAT** (vesicular monoamine transporter), causing neurotransmitters to leak out of synaptic vesicles. This leads to a rise in **cytoplasmic levels** of the neurotransmitters, which then triggers **reverse transport** through the transporters (**DAT**, **NAT**, **SERT**), releasing neurotransmitters back into the synapse. **MDMA (3,4-Methylenedioxymethamphetamine)**, commonly known as **ecstasy**, is an **amphetamine derivative** that produces both **psychostimulant-like** and weak **LSD-like effects** at low doses. Unlike **LSD**, **MDMA** is reinforcing, likely due to its interactions with **dopamine systems**, which contribute to its potential for **compulsive abuse**. The weak **psychedelic effects** of MDMA are linked to its actions on the **serotonin reuptake transporter**, leading to **serotonin efflux**. However, MDMA has been shown to cause **lesions in serotonin neurons** in both animal models and humans, indicating potential long-term harm to serotonin systems. **Prucalopride** selectively binds to the 5-HT4 receptor with high affinity (high pKi), as indicated by the green and red dots. It demonstrates significantly weaker binding to other receptors (black dots), highlighting its specificity. This selectivity ensures prucalopride effectively treats constipation through 5-HT4 activation while minimizing off-target side effects.