Anxiety

Serotonin

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter primarily found in the central nervous system (CNS) and the gastrointestinal tract. It plays a vital role in mood regulation, fear processing, and anxiety modulation.

Serotonin Pathways in Anxiety Regulation

• Serotonin is synthesized from L-tryptophan via the enzyme tryptophan hydroxylase (TPH).

• The raphe nuclei in the brainstem are the primary source of serotonin projections to various brain regions involved in anxiety:

Amygdala (fear and emotional processing)

Prefrontal cortex (cognitive control over emotions)

Prefrontal cortex (cognitive control over emotions)

Mechanism of Serotonin in Anxiety Control

• Serotonin exerts its effects through 14 different receptor subtypes (5-HT1–5-HT7).

• The 5-HT1A receptor is the most critical in anxiety regulation.

Agonism (activation) of 5-HT1A leads to reduced fear responses and anxiety (e.g., buspirone, a 5-HT1A agonist, is used as an anxiolytic).

Deficiency in 5-HT1A receptors has been linked to increased anxiety in animal models.

Evidence from Research

• Human and animal studies show that low serotonin levels or dysfunctional 5-HT receptors lead to exaggerated stress responses.

• Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, sertraline) enhance serotonergic neurotransmission, reducing anxiety symptoms by increasing serotonin availability in the synaptic cleft.

• Genetic studies: Variations in the serotonin transporter gene (5-HTTLPR) are associated with anxiety sensitivity and stress response.

Serotonin and the HPA Axis

• The hypothalamic-pituitary-adrenal (HPA) axis, which controls the body's stress response, is regulated by serotonin.

• Low serotonin levels are linked to increased cortisol release, contributing to heightened anxiety and stress sensitivity

Anxiety and Noradrenaline

Anxiety is more than just a mental state—it’s a neurochemical event, and noradrenaline plays a central role in how it feels in the body and brain. Understanding this link helps explain symptoms like a racing heart, restlessness, and constant worry.

Noradrenaline (norepinephrine) is both a neurotransmitter and a stress hormone. It’s produced in the locus coeruleus in the brainstem and the adrenal glands. It prepares your body for "fight or flight" by:

• Increasing heart rate and blood pressure

• Heightening alertness and focus

• Preparing muscles for quick response

• Suppressing digestion and rest functions

Adrenaline (Epinephrine) – “Fight or Flight” Hormone

• The adrenal glands release adrenaline during stress or danger. It increases heart rate, blood pressure, and energy.

• When you're anxious, your body may produce too much adrenaline, triggering physical symptoms like rapid heartbeat, sweating, and shakiness — classic "fight or flight" responses.

GABA (Gamma-aminobutyric acid) – “Calm Down” Neurotransmitter

• GABA is the brain’s main calming chemical. It inhibits excessive brain activity and helps relax the nervous system.

• Low levels of GABA are commonly linked to anxiety, racing thoughts, and restlessness. It’s like the brakes are failing in your brain.

DHEA (Dehydroepiandrosterone) – “Resilience” Hormone

• DHEA is a hormone produced by the adrenal glands, acting as a precursor to sex hormones and playing a role in mood, immunity, and stress resilience.

• Healthy DHEA levels can buffer the negative effects of cortisol (stress hormone). Low DHEA is often associated with poor stress tolerance and higher anxiety.

Cortisol – “Stress” Hormone

• Cortisol is released by the adrenal glands in response to stress. It helps regulate blood sugar, inflammation, metabolism, and memory.

• Chronically high cortisol keeps the body in a state of stress, leading to anxiety, sleep problems, and even panic attacks. Low cortisol (due to burnout/adrenal fatigue) can also affect emotional balance.

Glutamate

Glutamate is the brain’s primary excitatory neurotransmitter, essential for activating neurons, learning, and memory.

Glutamate is the brain’s primary excitatory neurotransmitter, essential for activating neurons, learning, and memory.

This hyperactivity especially affects the amygdala (the brain’s fear center) and the prefrontal cortex, contributing to:

• Heightened fear response

• Heightened fear response

• Racing thoughts

• Overreactions to stress

Chronic anxiety can create a feedback loop:

• Chronic anxiety can create a feedback loop:

• Elevated glutamate increases neural firing

• This amplifies anxiety symptoms, keeping the brain in a “threat” state

Research has shown:

• People with anxiety disorders often have elevated glutamate levels in specific brain regions (like the anterior cingulate cortex and insula).

• Overactivation of NMDA receptors (stimulated by glutamate) can worsen anxious thoughts and hyperarousal.

Glial cell dysfunction or inflammation can prevent proper glutamate clearance, prolonging excitatory signals and contributing to persistent anxiety.

Exhaustion Rapid fatiguing

Glutamate is a stimulating neurotransmitter, essential for cognitive function and alertness—but when it's out of balance, it can contribute to mental and physical exhaustion.

How It Works:

Under chronic stress or inflammation, glutamate levels can build up in the brain, especially if glial cells can’t clear it efficiently.

This overactivation of neurons leads to a state of constant neural firing, draining brain energy stores and overloading the nervous system.

Over time, this results in:

• Mental burnout

• Low resilience to stressors

• Rapid cognitive and physical fatigue even after minimal effort

Areas like the prefrontal cortex and hippocampus—key for focus, decision-making, and motivation—are especially vulnerable to glutamate-related fatigue.

Fast Fatigue? Here’s Why:

When neurons are overstimulated, they require more ATP (cellular energy) to recover.

This increased energy demand leads to:

• Quicker depletion of energy reserves

• Slower recovery between tasks

• Perception of “crashing” or hitting a wall quickly

This contributes to rapid fatiguing, even with basic tasks like reading, thinking, or walking.