Catecholamines PDF

**Catecholamines.** Catecholamines are a group of **amine neurotransmitters** that are synthesized from the amino acid **tyrosine**. They include **dopamine**, **norepinephrine (noradrenaline)**, and **epinephrine (adrenaline)**. **Case story - "cheese effect"** The **tyramine connection** was di...

**Catecholamines.** Catecholamines are a group of **amine neurotransmitters** that are synthesized from the amino acid **tyrosine**. They include **dopamine**, **norepinephrine (noradrenaline)**, and **epinephrine (adrenaline)**. **Case story - "cheese effect"** The **tyramine connection** was discovered by a British pharmacist who observed that his wife experienced **severe headaches** after consuming **cheese** while taking **monoamine oxidase inhibitors (MAOIs)**. **Aged cheese** contains **high levels of tyramine**, which can trigger **hypertensive crises** in people on MAOIs. **Historical Reports**: **Hypertensive crises** due to MAOIs like **phenelzine** were first reported in 1962 by **Dally and Tailor**. These episodes were more common with **tranylcypromine**, as documented by **Barry Blackwell**, who studied **12 patients** (10 women). The main trigger was **cheese** (cooked or raw), causing blood pressure spikes from **160/90 to 220/115 mm Hg**. **Symptoms and Complications**: **Symptoms**: Severe **headaches**, **heart pounding**, and **palpitations** occurred **1--2 hours** after eating. **Complications**: Included **subarachnoid haemorrhage**, **hemiplegia**, **intracranial haemorrhage**, **cardiac arrhythmias**, **cardiac failure**, **pulmonary edema**, and even **death**. **Catecholamines transmitters get synthesised from tyrosine:** All **catecholamines** are synthesized from **L-phenylalanine**, which is converted to **L-tyrosine** as the first step in their biosynthetic pathway. **Catecholamines contain a catechol group and an amine group:** Catecholamines, including **dopamine (DA)**, **norepinephrine (NA)**, and **epinephrine (A)**, share a **catechol nucleus** and an **amine group**. Although they have distinct functions, they are synthesized through a **single biosynthetic pathway**. The synthesis of all catecholamines begins with the production of **dopamine**. **Making dopamine is a two-step process:** 1. **Tyrosine**, obtained from the diet, is actively transported into the brain. 2. The enzyme **tyrosine hydroxylase (TH)** converts tyrosine into **L-dopa** by adding a hydroxyl group. 3. **Dopa decarboxylase** removes a carboxyl group from **L-dopa**, converting it into **dopamine**. **The location of dopaminergic nuclei:** **Dopaminergic nuclei** are in the **substantia nigra** and the **ventral tegmental area (VTA)** of the midbrain. - **Substantia nigra**: Dopamine neurons here form the **nigrostriatal pathway**, crucial for **motor control**. - **VTA**: Dopamine neurons here form the **mesocorticolimbic pathway**, which is involved in **reward**, **reinforcement**, and **appetitive behaviour**. **Parkinson's disease is due to loss of DA neurons in SN:** **Healthy substantia nigra (SN) appears dark due to high neuromelanin content that forms from the L-DOPA precursor in\ dopamine synthesis. This characteristic is the source of the name of the region which means \"dark substance.\"** **Tyrosine hydroxylase is the rate-limiting enzyme in catecholamine synthesis:** 1. **Tyrosine Transport and Blood-Brain Barrier:** Tyrosine penetrates the blood-brain barrier via an active transport process. With normal dietary tyrosine levels, both active transport and tyrosine hydroxylase (TH) activity are fully saturated. 2. **Regulation of Tyrosine Hydroxylase (TH) Activity:** TH activity increases with catecholamine release through transcriptional, translational, and post-translational regulation. Stimuli that up-regulate TH expression: Chronic environmental stress, Drugs: caffeine, nicotine, morphine. Stimuli that down-regulate TH expression: Many antidepressants. 3. **L-Dopa for Parkinson's Disease (PD) Treatment:** Increased dopamine synthesis for PD treatment is achieved through peripheral L-dopa administration. L-dopa bypasses the rate-limiting TH step and crosses the blood-brain barrier, provided its peripheral metabolism is blocked. 4. **Vesicular Monoamine Transporter (VMAT):** Dopamine and other monoamines are loaded into vesicles by VMAT. **Terminating the actions of dopamine:** 1. **Reuptake:** Dopamine is taken back into the terminal via the Dopamine Transporter (DAT). 2. **Enzymatic Degradation:** Dopamine is broken down by enzymes Monoamine Oxidase (MAO) and Catechol-O-Methyltransferase (COMT). **MAO** metabolizes all catecholamines (dopamine, norepinephrine) and serotonin (5HT). It exists in two forms: intracellular (associated with the mitochondrial outer membrane) and extracellular (active in the synapse). There are two isoforms of MAO: - **MAO-A** is found in dopamine and norepinephrine neurons. - **MAO-B** is present in serotonin neurons, with axons containing MAO-A. **MAO-A and MAO-B** have similar affinities for dopamine. However, MAO-A has higher affinity for norepinephrine and serotonin. MAO-B may help maintain neurotransmitter fidelity. **COMT** works alongside MAO to further break down dopamine and other catecholamines. **MAOIs (Monoamine Oxidase Inhibitors)** are used to treat **Parkinson's disease (PD)**. This treatment strategy was explored after it was discovered that the neurotoxin **MPTP**---a byproduct of illicit drug synthesis---causes PD by being converted to its toxic form, **MPP+**, by **MAO-B**. MPTP contamination in synthetic **meperidine** led to severe Parkinsonian symptoms in individuals who injected it, as their **substantia nigra (SN) dopamine neurons** were destroyed by **extreme oxidative damage**. To mitigate this oxidative stress, the **selective MAO-B inhibitor selegiline (deprenyl)** was used effectively. **Expression of DA receptors:** **Clozapine** is a relatively unselective antagonist. **DA receptors can be both inhibitory and excitatory:** Dopamine (**DA**) can have **excitatory** or **inhibitory effects** depending on the **type of receptor** it binds to. The five dopamine receptors (**D1 to D5**) are classified into two categories: 1. **D1-like Receptors (D1 and D5)**: Typically **stimulate adenylyl cyclase (AC)** activity, leading to increased production of **cAMP**. Generally **excitatory** in their effects. 2. **D2-like Receptors (D2, D3, and D4)**: Typically **inhibit adenylyl cyclase (AC)** activity, reducing **cAMP** levels. Generally **inhibitory** in their effects. The specific effect of dopamine depends on the receptor subtype expressed in the target cells and their associated signalling pathways. **DA receptors are targets in many diseases:** Dopamine plays a critical role in the **cognitive control of behaviour**, **attention**, and **working memory**. For conditions like **ADHD**, psychostimulants such as **methylphenidate** and **amphetamines** are commonly used treatments. These drugs act as **indirect dopamine agonists** by blocking the **dopamine transporter (DAT)** or reversing dopamine transport, thereby increasing dopamine levels in the synapse. In **psychosis**, **antipsychotic drugs** produce their therapeutic effects by **blocking D2 receptors** in subcortical structures of the **limbic forebrain**, reducing symptoms like **delusions** and **hallucinations**. The exact mechanism by which excessive dopamine contributes to psychotic symptoms is not fully understood. However, **D2 receptor inhibition** in the **striatum** can lead to side effects that resemble **Parkinson's disease** symptoms, often managed with **anticholinergic medications**. **Clozapine**, an atypical antipsychotic, has a lower tendency to produce these side effects due to its unique receptor binding properties, including a **lower affinity for D2 receptors**, **antagonism of 5HT2A receptors**, and **antagonism of muscarinic cholinergic receptors**. In **Parkinson's disease (PD)**, **D2 agonists** like **bromocriptine** are used to alleviate symptoms by compensating for dopamine deficiency. Additionally, **D3-preferring agonists** such as **pramipexole** and **ropinirole** show promise as effective treatments, offering targeted therapeutic benefits. **Drugs affecting DA transmission:** **Noradrenaline is made from dopamine****:** **Noradrenaline** is synthesized from **dopamine** through the addition of a hydroxyl group, a reaction catalysed by the enzyme **dopamine β-hydroxylase (DBH)**. This process converts dopamine into noradrenaline. The mechanisms for **terminating the actions of noradrenaline** are the same as those for dopamine, involving **reuptake** via transporters and **enzymatic degradation** by **MAO (Monoamine Oxidase)** and **COMT (Catechol-O-Methyltransferase)**. Noradrenaline plays a key role in **regulating attention and impulsivity**, as well as being central to **autonomic functions**, including the control of heart rate, blood pressure, and stress responses. **The location of noradrenergic nuclei:** The cell bodies of about **50% of noradrenaline (NA) neurons** are located in the **locus coeruleus**, with roughly **12,000 neurons** per hemisphere. These neurons have **diffused projections** throughout the **cortex**, **diencephalon**, and **cerebellum**, with each neuron making around **250,000 synapses**. The rest of the NA neurons are found in small clusters in the **brainstem**. **Adrenaline is made from noradrenaline:** **Adrenaline** is synthesized from **noradrenaline** by the addition of a **methyl group** to noradrenaline, a process catalysed by the enzyme **phenylethanolamine N-methyltransferase (PNMT)**. The mechanisms for **terminating the actions of adrenaline** are the same as for **dopamine** and **noradrenaline**, involving **reuptake** via transporters and **enzymatic degradation** by **MAO (Monoamine Oxidase)** and **COMT (Catechol-O-Methyltransferase)**.  **Production of noradrenaline and adrenaline:** 1. **Tyrosine** is converted to **Dopa**, which is then converted to **dopamine**. Dopamine is transported into synaptic vesicles by **VMAT (Vesicular Monoamine Transporter)**. 2. **Noradrenaline (NA)** is synthesized in the synaptic vesicles. In **NA neurons**, **dopamine-β-hydroxylase (DBH)** catalyses the conversion of dopamine to noradrenaline. 3. In neurons that produce **adrenaline**, **noradrenaline** is released from the vesicles. 4. **Phenylethanolamine-N-methyltransferase (PNMT)** converts **noradrenaline** into **adrenaline**. 5. Finally, **adrenaline** is packed into vesicles by **VMAT**. **Terminating the actions of NA (and adrenaline, A):** The actions of **noradrenaline (NA)** and **adrenaline (A)** are terminated in similar ways to dopamine (DA): 1. **Reuptake**: Both **NA** and **A** are taken back up into the presynaptic terminal. **NA** is specifically transported via the **norepinephrine transporter (NAT)**. 2. **Enzymatic Breakdown**: The enzymes **MAO (Monoamine Oxidase)** and **COMT (Catechol-O-Methyltransferase)** break down both **NA** and **A** (as well as **DA**). - **MAO** exists in both **intracellular** and **extracellular** forms and metabolizes all **catecholamines** (including **NA**, **A**, and **5HT**). - There are two isoforms of **MAO**: - **MAO-A** is expressed in **DA** and **NA neurons** and has a higher affinity for **NA** and **5HT** than for **DA**. - **MAO-B** might be important for maintaining **amine fidelity**, particularly in **dopamine**. 3. **COMT Inhibitors** (e.g., **entacapone**, **tolcapone**, **tropolone**) increase the levels of **DA** and **NA** in synapses, prolonging receptor activation. However, **COMT** plays a smaller role in terminating the synaptic action of catecholamines compared to their specific **membrane transporters** like **DAT** (dopamine transporter) and **NET** (norepinephrine transporter). **All adrenoreceptors are metabotropic:** The **expression of adrenoreceptors** for **noradrenaline (NA)** and **adrenaline (A)** is the same, as both use the same receptor subtypes. - **Postsynaptic receptors** like **β1**, **β2**, **β3**, and **α1** are generally **excitatory**, while the **presynaptic α2 auto receptor** is **inhibitory**. - The effects of activation depend on the **second messenger systems** in the postsynaptic cells, which can lead to either **excitatory** or **inhibitory** effects. - Both **NA** and **A** activate the same receptors, with varying affinities, and adrenergic drugs mainly target the **autonomic nervous system**. **Auto receptors typically function to inhibit activity:** **Auto receptors** typically function to **inhibit activity**. When **α-adrenergic receptors (α-ARs)** on a **noradrenergic cell body** are activated (e.g., through the release of **noradrenaline (NA)**), they cause a **decrease in the firing rate** of the cell, which can be measured experimentally using an **extracellular electrode**. In the **synaptic terminal**, the release of **NA** into the synaptic cleft activates **presynaptic α-ARs**, leading to inhibition of further **NA synthesis** and blocking the release of more transmitter. This creates a **negative feedback loop** that modulates **signalling** between neurons, ensuring that the release of **NA** is appropriately regulated. **Adrenergic functions in health and disease:** **Noradrenaline (NA)**, along with other signalling molecules like **serotonin (5HT)** and **acetylcholine (ACh)**, plays a critical role in regulating the **sleep--wake cycle** and levels of **arousal**. The **locus coeruleus (LC)**, which produces **NA**, receives input from systems involved in sleep and arousal regulation. 1. **Increased Arousal**: The LC influences attention and vigilance, and in response to **threat**, **LC firing** may increase anxiety by releasing **NA** in regions like the **amygdala** and other parts of the **limbic forebrain**. 2. **Memory Enhancement**: **Stimulation of β-adrenergic receptors** in the **amygdala** enhances memory for stimuli encoded under strong **negative emotions**, aiding the recall of **danger-predicting stimuli**. This process may contribute to conditions like **post-traumatic stress disorder (PTSD)**. - **β-adrenergic receptor antagonists** (e.g., **propranolol**) are being studied to reduce the intensity of traumatic memories in **PTSD**. 3. **ADHD Treatment**: **Drugs** like **desipramine** or **atomoxetine**, which block the **norepinephrine transporter (NAT)** and increase synaptic **NA**, show some efficacy in treating **ADHD**. However, **psychostimulants** (which increase both **dopamine (DA)** and **NA**) are more effective, as they also act on the **dopamine transporter (DAT)** and the **serotonin transporter (SERT)**. 4. **Opiate Dependence**: Chronic use of **opiates** leads to adaptations in **LC neurons**, resulting in **tolerance** and **dependence**. Upon cessation, this can lead to the **physical withdrawal syndrome**. The **cheese effect** refers to a dangerous **hypertensive crisis** that can occur when people taking **monoamine oxidase inhibitors (MAOIs)** consume foods rich in **tyramine**, such as aged cheese, cured meats, or fermented foods. Here's why it happens: 1. **Tyramine** is a naturally occurring compound found in certain foods, especially aged cheeses, cured meats, and fermented products. Under normal conditions, **monoamine oxidase (MAO)**, an enzyme responsible for breaking down monoamines (including tyramine), deactivates tyramine in the body. 2. **MAOIs** (e.g., **phenelzine** or **tranylcypromine**), which are used as antidepressants, inhibit the action of MAO. This means that **tyramine** isn't broken down as it normally would be. 3. When **high amounts of tyramine** enter the bloodstream, it can cause a **dramatic increase in blood pressure**, leading to a **hypertensive crisis**. This is because tyramine stimulates the release of **norepinephrine** (NA) and **adrenaline (A)**, causing vasoconstriction (narrowing of blood vessels) and an increase in heart rate and blood pressure. 4. Symptoms of a hypertensive crisis include **headache**, **nausea**, **vomiting**, **stiff neck**, and **vision problems**, and it can be life-threatening if not treated promptly. To avoid this, people taking **MAOIs** are advised to avoid tyramine-rich foods, a precaution known as the **cheese effect**.