Anxiety (Physiology 2)

A feeling of unease, such as worry or fear.

Can range from mild to severe.

Anxiety serves as a learned response to avoid harmful experiences (e.g., not touching a hot stove).

Acts as an innate response to threatening stimuli, enhancing alertness and defensive behaviours.

Defensive behaviours.

Autonomic reflexes.

Increased alertness.

Innate and species-specific fears.

Yes, fear can be anticipatory.

Fear responses are not always appropriate to the situation.

Anxiety becomes a problem when it is:

Chronic and irrational.

Linked to social disturbances.

Causes avoidance behaviours.

Accompanied by incessant worry.

Leads to concentration or memory problems.

Intense and disproportionate to its source.

Psychological: Anxiety involves feelings of unease, worry, or fear.

Physiological: Symptoms include:

Tachycardia

Shortness of breath

Excessive sweating

Trembling or shaking

Headache and dizziness

Pins and needles

Gastrointestinal disturbances

Nausea

Fatigue

Insomnia

Sugar

Caffeine

Physical health problems, such as chronic conditions, can trigger or exacerbate anxiety.

Mental health conditions, such as depression, can also trigger or worsen anxiety.

Difficult experiences in childhood, adolescence, or adulthood are common triggers for anxiety.

Current issues or problems in daily life can lead to anxiety.

Recreational drugs of abuse (e.g. psychostimulants) can trigger anxiety symptoms via mechanisms specific to each drug or class of drugs.

Alcohol, as a CNS depressant, increases GABAergic neurotransmission and blocks glutamatergic neurotransmission, disrupting the balance between GABA and glutamate in the brain.

Alcohol disrupts the balance between GABA and glutamate, which is crucial for optimal brain function.

The brain adapts to counteract this imbalance, leading to low levels of GABA and high levels of glutamate, which can trigger anxiety symptoms.

Research has linked genetic factors to several anxiety disorders (e.g. panic disorder) (Na et al., 2011).

Anxiety disorders are not based on a single gene but likely have a complex genetic basis, which can be affected by environmental factors.

The hallmark of anxiety disorders is an inappropriate stress response, either when a stressor is not present or not immediately threatening.

The stress response is the coordinated reaction to threatening stimuli and is regulated by the hypothalamus-pituitary-adrenal (HPA) axis.

The HPA axis regulates the release of cortisol (a glucocorticoid), which contributes to the body’s physiological response to stress.

The activation of CRH (corticotropin releasing hormone) in the hypothalamus plays a key role in regulating the stress response:

Overexpressing CRH in rodent models leads to increased anxiety-like behaviors.

Knocking out CRH receptors in rodent models leads to fewer anxiety-like behaviors.

Amygdala:

Plays a key role in emotion and the fear response.

Stimulates the HPA axis to promote cortisol release.

Amygdala hyperactivity is linked to anxiety disorders.

Hippocampus:

Plays a key role in learning and memory.

Suppresses the HPA axis to prevent excessive cortisol release.

Hippocampus underactivity is linked to anxiety disorders.

Anxiety disorders

Obsessive-compulsive disorders

Trauma and stressor-related disorders

Generalized anxiety disorder (GAD)

Specific phobias

Social phobias

Panic disorder

Substance/medication-induced anxiety disorder

Anxiety disorder due to a medical condition

Obsessive-compulsive disorder (OCD)

Body dysmorphic disorder

Hoarding disorder

Trichotillomania (hair-pulling disorder)

Post-traumatic stress disorder (PTSD)

Excessive anxiety and worry occurring for at least six months, which is difficult to control and impairs activities of daily living.

Associated with three or more of six symptoms (unspecified in the prompt).

Symptoms are not attributable to a substance or medical condition.

Symptoms are not better explained by another type of anxiety disorder.

GAD sufferers' symptoms are likely to differ from one person's experience to another.

Extreme fears or anxieties provoked by exposure to a particular situation or object, often leading to avoidance behaviors.

The phobic object or situation almost always provokes immediate fear or anxiety, out of proportion to the actual danger.

Phobia is persistent, typically lasting at least six months, impairing activities of daily living.

Symptoms are not attributable to a substance or medical condition and are not better explained by another type of anxiety disorder.

Acrophobia (fear of heights)

Ornithophobia (fear of birds)

Trypanophobia (fear of needles)

Nomophobia (fear of being without a mobile phone)

Triskaidekaphobia (fear of the number 13)

Significant anxiety provoked by exposure to certain types of social or performance situations.

Social situations almost always provoke immediate fear or anxiety, out of proportion to the actual danger.

The phobia is persistent, typically lasting at least six months, impairing activities of daily living.

Symptoms are not attributable to a substance or medical condition and are not better explained by another type of anxiety disorder.

Social interactions

Performing in front of others

Being observed

Recurring panic attacks without a clear cause or trigger.

A panic attack is an abrupt surge of intense fear or discomfort, reaching a peak within minutes.

Associated with four or more of thirteen symptoms as per the DSM-5, including:

Increased heart rate

Sweating

Trembling/shaking

Shortness of breath

Fear of dying

Anxiety

Panic attack

Fear of another panic attack

More anxiety leading to another panic attack, and so on, continuing the cycle.

Panic attacks can occur spontaneously.

Panic attacks can also be a feature of other anxiety disorders.

OCD is characterized by compulsive, ritualistic behavior driven by irrational anxiety.

Obsessions and compulsions are time-consuming, typically taking over an hour per day, impairing activities of daily living.

OCD is not attributable to a substance or medical condition and is not better explained by another type of anxiety disorder.

Recurrent, intrusive thoughts, images, ideas, or impulses are typical of obsessions.

Recurrent, intrusive thoughts, images, ideas, or impulses.

Repetitive behaviors or mental acts performed to reduce anxiety associated with the obsessions.

PTSD is characterized by distress triggered by the recall of past traumatic experiences.

Disturbances persist for at least one month, impairing activities of daily living.

PTSD is not attributable to a substance or medical condition.

Triggered by exposure to certain situations, such as actual or threatened death, serious injury, or sexual violence. Exposure may be direct, as a witness, or by learning that a close family member or friend experienced the traumatic event.

Recurrent intrusive memories

Nightmares

Dissociative reactions (e.g., flashbacks)

Psychological and physiological distress at exposure to cues resembling the traumatic event.

Psychological: Cognitive behavioural therapy (CBT)

Pharmacological: Anxiolytics

Benzodiazepines

5-HT1A receptor agonists

b -noradrenergic receptor antagonists

Benzodiazepines act as GABAA receptor modulators, enhancing the effects of the neurotransmitter GABA to reduce anxiety.

5-HT1A receptor agonists target serotonin receptors, helping to regulate mood and anxiety.

b -noradrenergic receptor antagonists work by blocking certain noradrenergic receptors, helping to reduce the physiological symptoms of anxiety.

GABAA receptor is a ligand-gated chloride (Cl-) channel, and it is a key target for anxiolytic drugs, which modulate its activity to reduce anxiety.

The receptor has a pentameric structure with six ᵷ subtypes (ᵷ 1-6).

It typically includes two α subunits, two β subunits, and one γ subunit, which is the most common configuration.

Other subunits include δ, ε, π, and θ.

Agonist/antagonist binding site, e.g., GABA.

Benzodiazepine binding site.

Channel blockers binding site, e.g., picrotoxin.

Channel modulators binding site, e.g., GA.

Allosteric modulators binding site, e.g., barbiturates.

GABA activity is terminated upon reuptake by the GABA reuptake transporter (GAT).

Benzodiazepines are a class of positive allosteric modulators of the GABAA receptor.

Benzodiazepines bind to a distinct regulatory site on GABAA receptors.

They stabilize the GABAA receptor in the open configuration, increasing GABA affinity.

Benzodiazepines increase GABA affinity for its binding site.

This results in the potentiation of GABA responses, enhancing its neuroinhibitory actions.

Benzodiazepines are considered "cleaner" because they do not activate other receptors, such as glycine or glutamate receptors, unlike barbiturates.

Duration of action: Ultrashort (< 6 hours).

Main use(s): Anaesthetic.

Duration of action: Short (12-18 hours).

Main use(s): Anxiolytic, hypnotic, anti-convulsant.

Duration of action: Medium (24 hours).

Main use(s): Anxiolytic.

Duration of action: Long (24-48 hours).

Main use(s): Anxiolytic, anti-convulsant.

Benzodiazepines act quickly and are useful for acute treatment that can be taken “as needed”, unlike 5-HT1A agonists and anti-depressants, which take longer to take effect.

Unwanted side-effects: Amnesia and other cognitive impairments.

Addiction-related issues: Tolerance and withdrawal symptoms can develop with prolonged use.

Neurotransmitter: Found in the peripheral nervous system (PNS) and central nervous system (CNS).

Receptor activation: Activates G-protein coupled receptor sub-types (5-HT1 - 5-HT7), except for 5-HT3, which is a ligand-gated ion channel.

Drug target: Plays a key role in treating depression (e.g. SSRIs) and anxiety disorders (e.g. 5-HT1A agonists), with roles in mood, sleep, and emotional behaviors.

Buspirone is an example of a 5-HT1A receptor agonist, primarily used to treat generalised anxiety disorder (GAD).

Side effects: Less troublesome than benzodiazepines, but may include dizziness, nausea, and headache.

Delayed effect: Anxiolytic effects take several days to be seen.

Mechanism:

Activates 5-HT1A auto-receptors, inhibiting serotonin (5-HT) release.

Inhibits noradrenergic neurons, decreasing arousal reactions.

Buspirone activates 5-HT1A auto-receptors, which decreases serotonin (5-HT) release. It is used for generalised anxiety disorder (GAD) and has delayed effects.

Selective serotonin re-uptake inhibitors (SSRIs) work by blocking the serotonin re-uptake transporter (SERT), leading to more serotonin (5-HT) being available in the brain.

SSRIs are more commonly used for long-term treatment of anxiety and depression.

Both medications affect serotonin but in different ways to manage anxiety disorders.

Buspirone is a 5-HT1A receptor agonist, meaning it binds to and activates 5-HT1A receptors in the brain.

Initially, the 5-HT1A receptors are auto-inhibitory, so when buspirone activates them, it inhibits serotonin (5-HT) release from serotonergic neurons.

With prolonged use, the brain desensitizes these auto-inhibitory receptors and downregulates the 5-HT1A receptors, meaning they become less sensitive to the effects of serotonin.

This process leads to heightened excitation of serotonergic neurons, resulting in increased serotonin release over time.

This mechanism helps reduce anxiety and alleviate symptoms of generalized anxiety disorder (GAD). However, buspirone is not effective for phobias.

Noradrenaline is the major neurotransmitter of the sympathetic nervous system, influencing cardiovascular tone.

It also plays a role in attention, arousal, and sleep-wake cycles.

Noradrenaline activates G-protein coupled receptor subtypes, including α- and β-noradrenergic receptors.

As a drug target, α-noradrenergic receptor antagonists can be used to treat the peripheral manifestations of anxiety.

β-noradrenergic receptor antagonists (e.g. propranolol) are used to treat some anxiety forms.

Propranolol is non-selective between β1 and β2 receptors.

Effects of receptor activation: Increased heart rate, force, bronchodilation, vasodilation, and muscle tremor.

They reduce peripheral anxiety symptoms like tachycardia, sweating, and tremors.

Effectiveness is due to blocking peripheral sympathetic responses rather than central effects, aiding in sports (reduces tremor) and performing arts (reduces stage fright).

Anxiety disorders involve significant feelings of anxiety (worry about future events) and fear (reaction to current events).

These feelings can cause physical symptoms, such as fast heart rate and shakiness.

Panic disorder is characterized by recurring panic attacks.

A panic attack involves sudden intense fear with symptoms like palpitations, sweating, shaking, and shortness of breath.

These attacks often occur unexpectedly.

Agoraphobia is an extreme or irrational fear of places where escape may be difficult.

This condition can limit one's ability to be in certain environments.

Obsessive-compulsive disorder (OCD) involves excessive orderliness, perfectionism, and attention to details.

Individuals with OCD may feel a need for control in their relationships and daily activities.

This can impair functioning and cause distress.

Post-traumatic stress disorder (PTSD) occurs due to severe psychological shock or injury.

It leads to persistent mental and emotional stress, including vivid memories and sleep disturbances.

Individuals may experience dulled responses to others and the outside world.

Benzodiazepines are a class of drugs used as short-term anxiolytics.

They are commonly prescribed for anxiety relief but can be habit-forming if used long-term.