The full catechol life cycle (in famine too)

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Catecholamines, including dopamine, norepinephrine, and epinephrine, have a fascinating life cycle that involves several stages:

• Synthesis:

• Tyrosine Hydroxylation: The amino acid tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase.

• Decarboxylation: L-DOPA is then converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC).

• Hydroxylation: Dopamine is converted into norepinephrine by dopamine β-hydroxylase (DBH).

• Methylation: Norepinephrine is converted into epinephrine by phenylethanolamine N-methyltransferase (PNMT) 1.

• Storage:
• Catecholamines are stored in vesicles within nerve terminals and adrenal medulla cells until they are needed.

• Release:
• In response to stress or other stimuli, catecholamines are released into the synaptic cleft or bloodstream.

• Receptor Binding:
• Once released, catecholamines bind to specific receptors on target cells, initiating various physiological responses such as increased heart rate, blood pressure, and glucose levels.

• Reuptake and Degradation:
• Catecholamines are taken back up into the nerve terminals by transporters.

• They are then degraded by enzymes such as monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) 1.

This cycle ensures that catecholamines are available when needed and are efficiently removed after their action is complete.

1. Synthesis in Detail:

• Tyrosine Hydroxylation: This is the rate-limiting step in catecholamine synthesis.

• Tyrosine is hydroxylated to L-DOPA by tyrosine hydroxylase, which requires tetrahydrobiopterin (BH4) as a cofactor.

• Decarboxylation: L-DOPA is decarboxylated to dopamine by aromatic L-amino acid decarboxylase (AADC), also known as DOPA decarboxylase.

• Hydroxylation: Dopamine is hydroxylated to norepinephrine by dopamine β-hydroxylase (DBH), which is located in the vesicles of noradrenergic neurons and requires ascorbate (vitamin C) as a cofactor.

• Methylation: Norepinephrine is methylated to epinephrine by phenylethanolamine N-methyltransferase (PNMT), which is primarily found in the adrenal medulla.

2. Storage:

• Catecholamines are stored in synaptic vesicles in nerve terminals and chromaffin cells of the adrenal medulla.

• These vesicles protect catecholamines from degradation and allow for rapid release upon stimulation.

3. Release:

• Upon stimulation (e.g., stress, exercise), catecholamines are released from vesicles into the synaptic cleft or bloodstream.

This process is calcium-dependent and involves the fusion of vesicles with the plasma membrane.

4. Receptor Binding:

• Catecholamines bind to adrenergic receptors (α and β receptors) on target cells. The binding triggers various physiological responses:

• Dopamine: Acts on D1-D5 receptors, influencing motor control, motivation, and reward.

• Norepinephrine: Acts on α1, α2, β1, and β2 receptors, affecting heart rate, blood pressure, and alertness.

• Epinephrine: Primarily acts on β1 and β2 receptors, influencing heart rate, muscle strength, and metabolism.

5. Reuptake and Degradation:

• Reuptake: Catecholamines are taken back into the presynaptic neuron by specific transporters (e.g., dopamine transporter (DAT), norepinephrine transporter (NET)).

• Degradation: Once inside the neuron, catecholamines are degraded by enzymes:

• Monoamine Oxidase (MAO): Deaminates catecholamines, producing aldehydes, which are further oxidized to carboxylic acids.

• Catechol-O-Methyltransferase (COMT): Methylates catecholamines, producing inactive metabolites.

6. Metabolite Excretion:

• The final metabolites, such as homovanillic acid (HVA) from dopamine and vanillylmandelic acid (VMA) from norepinephrine and epinephrine, are excreted in the urine.

Here’s a comprehensive list of enzymes involved in the lifecycle of catecholamines (synthesis, storage, release, and degradation):

● 1. Synthesis of Catecholamines:

The catecholamine synthesis pathway converts the amino acid tyrosine into dopamine, norepinephrine, and epinephrine through a series of enzymatic reactions:

1. Tyrosine hydroxylase (TH): Converts tyrosine to L-DOPA (rate-limiting step).

2. Aromatic L-amino acid decarboxylase (AADC): Converts L-DOPA to dopamine.

3. Dopamine β-hydroxylase (DBH): Converts dopamine to norepinephrine.

4. Phenylethanolamine N-methyltransferase (PNMT): Converts norepinephrine to epinephrine (mainly in the adrenal medulla).

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● 2. Storage of Catecholamines:

Catecholamines are stored in synaptic vesicles within nerve terminals:

1. Vesicular monoamine transporter (VMAT): Responsible for actively transporting dopamine, norepinephrine, and epinephrine into synaptic vesicles for storage.

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● 3. Release of Catecholamines:

Catecholamines are released via vesicular exocytosis, a process that doesn’t directly involve enzymes but depends on proteins like SNARE complexes for vesicle fusion with the plasma membrane.
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● 4. Degradation of Catecholamines:

Enzymes involved in the breakdown and removal of catecholamines include:

1. Monoamine oxidase (MAO):

MAO-A: Preferentially degrades norepinephrine, epinephrine, and serotonin.

MAO-B: More selective for dopamine.

Converts catecholamines to their respective aldehydes.

2. Catechol-O-methyltransferase (COMT):

Adds a methyl group to catecholamines, forming methylated metabolites like metanephrine and normetanephrine.

3. Aldehyde dehydrogenase (ALDH): Converts aldehyde intermediates from MAO activity to carboxylic acids.

4. Aldehyde reductase: Converts aldehydes to alcohol derivatives.

5. Sulfotransferases (SULTs): Conjugate catecholamines or their metabolites with sulfate to increase solubility for excretion.

6. Glucuronosyltransferases (UGTs): Conjugate catecholamine metabolites with glucuronic acid for excretion.

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● Summary:

Key enzymes in synthesis:

Tyrosine hydroxylase (TH)

Aromatic L-amino acid decarboxylase (AADC)

Dopamine β-hydroxylase (DBH)

Phenylethanolamine N-methyltransferase (PNMT)

Key enzymes in degradation:

Monoamine oxidase (MAO-A and MAO-B)

Catechol-O-methyltransferase (COMT)

Aldehyde dehydrogenase (ALDH)

Aldehyde reductase

Sulfotransferases (SULTs)

Glucuronosyltransferases (UGTs)


What happens during a famine to the reward circuit ?

During famine, the reward circuit in the brain, primarily governed by the mesolimbic dopamine system (including the ventral tegmental area (VTA) and nucleus accumbens), undergoes several adaptations to prioritize survival. These changes reflect the body's effort to regulate motivation, pleasure, and goal-directed behavior in response to severe food scarcity.


1. Dopaminergic Activity and Reward Sensitivity

Baseline Dopamine Levels Decrease: Starvation reduces dopamine production and release, lowering overall reward sensitivity. This results in less motivation for non-essential activities and anhedonia (reduced ability to experience pleasure).

Enhanced Sensitivity to Food Cues: Despite low dopamine levels, food-related stimuli (e.g., smell, sight, or thought of food) become hyper-salient, amplifying the drive to seek food. This is an adaptive survival mechanism.


2. Hormonal Regulation of the Reward Circuit

Ghrelin Increases: The hunger hormone ghrelin rises during starvation and acts on the VTA to stimulate dopaminergic neurons. This enhances motivation and reinforces food-seeking behaviors.

Leptin Decreases: Low energy stores reduce leptin levels, disinhibiting the reward circuit and increasing the brain's drive to seek high-calorie foods.

Cortisol Increases: Starvation-induced stress raises cortisol levels, which dysregulates the reward system and may promote compulsive or risky behaviors to obtain food.


3. Prioritization of Food Rewards

Heightened Food Motivation: The reward system becomes laser-focused on obtaining food, diverting attention and energy from other reward-seeking behaviors like social interaction or reproduction.

Suppression of Non-Essential Rewards: Activities unrelated to survival become less rewarding due to diminished dopaminergic signaling in non-food-related circuits.


4. Behavioral and Cognitive Changes

Obsessive Thoughts About Food: Starvation drives obsessive focus on food-related ideas, often manifesting as preoccupation or fantasizing about eating.

Increased Risk-Taking: To secure food, the brain promotes exploration and risk-taking behaviors, which are critical for survival during famine.


5. Long-Term Neuroadaptations

Downregulation of Dopamine Receptors: Prolonged famine can reduce dopamine receptor density, making the reward system less responsive to rewards over time.

Post-Famine Dysregulation: After food becomes available, the reward circuit may overcompensate, leading to behaviors like binge eating or heightened sensitivity to caloric rewards.


6. Emotional and Psychological Effects

Anhedonia and Depression: Reduced dopamine activity can result in low mood and diminished interest in previously pleasurable activities.

Stress and Anxiety: Chronic hunger-associated stress can alter reward-related behaviors, potentially leading to maladaptive coping mechanisms.


Summary

During famine, the reward circuit adapts by amplifying food-seeking behaviors while suppressing non-essential rewards. These changes, driven by hormonal shifts and dopaminergic regulation, are geared toward survival but can lead to long-term dysregulation of the reward system, influencing behavior even after the famine ends.