WEEK 2: PHYSIOLOGY OF STRESS AND ANXIETY

Question 1

What is stress?

Answer 1

Any condition which disrupts homeostasis can be regarded as a form of stress, and most stresses are opposed by homeostatic responses

Question 2

Distinguish between eustress and distress.

Answer 2

Eustress:
* Typically considered to be positive stress
*Usually induces motivation and focus.
*Prepares one to face a challenge.
*Usually accompanied by excitement
*The energy provided by eustress is proportionate to what is needed in the situation.

Distress:
Typically considered to be negative stress
*It is pathologic and exceeds the bodies coping limit.
*It impairs performance.
*The energy provided by distress is excessive or unusable
*Cause physical and psychological symptoms like headaches, tension, insomnia, inattentiveness, irritability, and depression

Question 3

Name the term used for any stimulus that produces a stress response

Answer 3

Stressor

Question 4

List the types and examples of stressors.

Answer 4

1.physical – such as illness or injury
2.psychological – such as depression or anxiety
3.environmental – such as extreme heat or cold, poisons
and toxins
4.metabolic – such as acute starvation

Question 5

What is the general adaptation syndrome?

Answer 5

describes the body’s response to stress.

Question 6

Outline the stages of the general adaptation syndrome

Answer 6

1. Alarm phase
   2.Resistance phase
   3.exhaustion stage

Question 7

Describe the alarm phase of GAS

Answer 7

*Fight-or-flight response
*Short-term stress or acute stress
*Mediated by the sympathetic nervous system
*Mobilization of energy reserves
* Prepares the body for physical activity

Results in:
*Increase glucose metabolism
*High energy consumption by the cells
*Increased HR and RR
*Change in circulation

Question 8

Briefly state the summary on nerve fibers, neurotransmitters and receptors in the SNS

Answer 8

*The preganglionic fibers of the sympathetic system all secrete acetylcholine

*The postganglionic fibers mostly secrete noradrenaline and a sometimes adrenaline

*They bind to the same adrenergic receptors, with varying affinity

Question 9

A very few sympathetic postganglionic neurons release acetylcholine
Name all the structures that they innervate

Answer 9

These innervate sweat glands in the skin, and blood vessels of some skeletal muscles and the brain

Question 10

Where does the SNS originate?

Answer 10

The sympathetic component of the spinal cord. T1-L2/others say L3 thoracolumbar outflow.

Question 11

Hypothalamus sends descending fibers to the which part of the spinal cord?

Answer 11

Lateral grey horn

Question 12

Describe the innervation by the SNS

Answer 12

1.The sympathetic component of the spinal cord. T1-L2/others say L3 thoracolumbar outflow.

2.Hypothalamus sends descending fibres to the lateral grey horn of the spinal cord

3.The preganglionic fibres release ACh which stimulates the postganglionic fibres

5.Some preganglionic fibres are long and bypass the ganglia and go directly to the adrenal medulla

6.Release ACh activating chromaffin cells

7.This results in the secretion of adrenaline (80%) and noradrenaline (20%)

8.They bind to adrenergic receptors

Question 13

Name the cells activated by the releasee of acetylcholine in the adrenal medulla

Answer 13

chromaffin cells

Question 14

How are organs with no sympathetic innervation stimulated?

Answer 14

They are hormonally receive signal via adrenaline released from the adrenal medulla

Question 15

How is the adrenaline hormone released?

Answer 15

The preganglionic nerves enter the adrenal gland where they synapse on modified neurons which release adrenaline and some noradrenaline into surrounding cells

Question 16

Beta receptors respond better to which neurotransmitter?

Answer 16

Adrenaline

Question 17

Sympathetic chain and collateral ganglia mostly secrete which neurotransmitter?

Answer 17

Noradrenaline

Question 18

Name the types of adrenergic receptors

Answer 18

Four major types of noradrenaline/adrenaline (adrenergic) receptors are: α1, α 2, β1 and β2 and β3

Question 19

Why can the same neurotransmitter produce two different responses in different tissues?

Answer 19

They work via a G-protein type receptor, the particular G-protein stimulated is different in each case, and the second messenger produced within the cell is also different

Question 20

Which neurotransmitter takes a long time to be removed from the postsynaptic neuron after use?

Answer 20

Adrenaline

Question 21

Describe the MOA of alpha 1 receptors

Answer 21

1.Activates a G-protein called Gq

2.Activation of a membrane bound phospholipase C enzyme

3.Splits the phosphatidyl inositol 4,5 bis phosphate (PIP2) to produce two second messenger molecules, inositol triphosphate, (IP3), and 1,2 diacylglycerol (DAG)

4.IP3: release of Ca2+ from the endoplasmic reticulum

5.Formation the Ca2+ calmodulin complex

6.DAG activates protein kinase C

7.Both Ca2+ calmodulin complex and protein kinase C can phosphorylate different proteins/ enzymes to either activate or inactivate them

8.Stimulation of α1 receptors on smooth muscle cells is responsible for constriction of peripheral blood vessels and closure of sphincters along the digestive tract and in the bladder

Question 22

State the role of DAG in the activation of alpha 1 adrenergic receptors

Answer 22

DAG activates protein kinase C

Question 23

What activates protein kinase C in alpha 1 receptors ?

Answer 23

The calcium ion calmodulin complex

Question 24

State the role of IP3 in alpha 1 receptors

Answer 24

Release calcium ions from the ER

Question 25

State the effects of the alarm phase

Answer 25

*Conversion of glycogen into glucose in liver

*Dilation of blood vessels of heart, lungs, brain and skeletal muscles

*Increased heart rate

*Dilation of airways

*Decrease in digestive, urinary and reproductive activities

*Constriction of blood vessels innervating most viscera and skin

*Water retention and elevated blood pressure
Sweating

*NA triggers release of glucose and fats from temporary storage

Question 26

Describe the MOA of alpha 2 adrenergic receptors

Answer 26

*Adrenaline has higher affinity than NA

*Activate a G inhibitory (Gi) protein

*Gi protein has three subunits (alpha, beta and gamma inhibitory)

*Alpha subunit binds to the membrane bound enzyme adenylate cyclase inhibiting it

*Resulting in the reduction of the second messenger molecule cyclic AMP (cAMP)

*cAMP activates protein kinase A which can phosphorylate different proteins and enzymes

*Beta and gamma subunits bind to channels which allows K+ to leave the cell

Question 27

State the role of alpha 2 adrenergic receptors

Answer 27

*Receptors inhibit the ‘rest and digest’ activity of the parasympathetic system in acute stress situations

Question 28

All β receptors follow a similar path.
Describe their MOA

Answer 28

*Activate a G stimulatory (Gs) protein

*Activates membrane bound adenylate cyclase stimulating the production of the second messenger cAMP

*cAMP activates protein kinase A which can phosphorylate different proteins and enzymes

*cAMP generally increases metabolic activity

Question 29

State the functions of beta 1 adrenergic receptors

Answer 29

1.Activate a G stimulatory (Gs) protein

2.Located in the cardiac muscles and the juxtaglomerular (JG) cells in the kidney

3.Increases heart rate and the force of contraction

4.Increases the rate of energy producing metabolic pathways, including glycogen breakdown and glycolysis

5.JG cells stimulates the release of renin, which causes the retention of water, hence increasing blood volume and blood pressure

Question 30

Describe the role of beta 2 adrenergic receptors

Answer 30

1.Activate a Gs protein producing cAMP

2.Located in the smooth muscles such as the bronchi and respiratory tract

3.cAMP inhibits the myosin light chain kinase enzyme which phosphorylates smooth muscle for contraction

4.Bronchial smooth muscles: Relaxation and widening of the airways hence more O2 in the blood

5.Skeletal muscle: increased muscle spindle firing causing increased muscle contraction, may also cause tremors

6.Increases the rate of energy producing metabolic pathways, including glycogen breakdown and glycolysis

Question 31

Outline the role of beta 3 adrenergic receptors

Answer 31

1.Found in adipose tissue and activate lipolysis

2.Increased detrusor relaxation in the bladder, causing urinary retention

3.The β3-AR agonist mirabegron used as a therapy for overactive bladder syndrome (OAB)

Question 32

Describe how adrenergic receptors affect the salivary glands and eyes

Answer 32

1.Salivary glands have both α1 and β2 adrenergic receptors

2.Activation of α1 adrenergic receptors in smooth muscle supplying the salivary glands reduces blood flow

3.Activation of β2 adrenergic receptors: reduction of water and electrolytes in saliva; and increases the mucin proteins and salivary enzymes

1.The eye has both α1 and β2 adrenergic receptors

2.β2 adrenergic receptor activation causes relaxation of the ciliary muscle relaxes causing the lens to flatten

3.α1 adrenergic receptors activation causes contraction of dilator pupillae causing pupil dilation

Question 33

State where the adrenergic receptors are found

Answer 33

alpha 1: blood vessels, GIT sphincters, Urinary tract, eyes
Alpha 2: GIT

Beta 1:JG cells, heart
beta 2:respiratory, blood vessels, GIT, bladder, uterus, liver
Beta 3: adipose tissue, bladder

Question 34

Describe what happens in the resistance phase

Answer 34

*Involves HPA axis
*Long term stress
*More energy consumption
*Mobilization of long term energy reserves

Question 35

Describe the mechanism of HPA axis

Answer 35

1.The resistance reaction is initiated in large part by hypothalamic releasing hormones and is a longer-lasting response

2.Stressors activate the hypothalamic paraventricular neurons (PVN) which secrete CRH into the portal circulation

3.These capillaries unite to form the short hypophyseal portal vein which carries blood down the pituitary stalk to the capillary bed of the anterior pituitary.

4.CRH stimulates corticotropes in the anterior pituitary which secrete ACTH

5.ACTH stimulates adrenal cortex to release glucocorticoid hormones into the blood circulation

Question 36

State the roles of cortisol in the resistance phase

Answer 36

1.Cortisol stimulates hepatic gluconeogenesis

2.Facilitates lipolysis hence releasing fatty acids into the blood stream as an alternative metabolic fuel

3.Catabolism of proteins into amino acids

4.Tissues throughout the body can use the resulting glucose, fatty acids, and amino acids to produce ATP or to repair damaged cells

5.Cortisol must be present in large amounts to allow catecholamines to induce vasoconstriction

6.Cortisol also reduces inflammation by partially blocking the production of inflammatory chemical mediators e.g. prostaglandins

7.Inhibits immune responses by interfering with antibody production by lymphocytes.

Question 37

State the role of other hormones in the resistance phase

Answer 37

1.Growth hormone releasing hormone (GHRH): secretion of human growth hormone (hGH).
*hGH stimulates lipolysis and glycogenolysis in the liver

2.Thyrotrophin releasing hormone (TRH): secretion of thyroid-stimulating hormone (TSH).
*TSH promotes secretion of thyroid hormones, which stimulate the increased use of glucose for ATP production

3.Endorphins and enkephalins are produced particularly under stress conditions

4.Adrenaline: Mobilising energy reserves

5.Glucagon: Mobilises energy reserves and stimulates gluconeogenesis in the liver

Question 38

State the role of glycogen as an energy reserve

Answer 38

Glycogen: Important in the ‘fight or flight’ response for rapid supply of energy.

Question 39

What mobilizes muscle glycogen?

Answer 39

Muscle glycogen is mobilised by sympathetic stimulation and adrenaline

Question 40

what mobilizes liver glycogen?

Answer 40

Liver glycogen is mobilised in response to glucagon stimulation

Question 41

They can maintain the resistance phase for weeks or months.

What energy reserve is this?

Answer 41

Triacyglycerol

Question 42

Fatty acids can be metabolized by any tissue with mitochondria, except the CNS.
WHY?

Answer 42

The tissues of the central nervous system cannot use fatty acids, despite containing mitochondria, because long-chain fatty acids (as opposed to medium-chain fatty acids) cannot cross the blood-brain barrier into the interstitial fluids that bathe these cells.

Question 43

Describe the % of fatty acids to glycerol in triacylglycerol

Answer 43

fatty acids (90%) and glycerol (10%).

Question 44

How are fatty acids and glycerol used as energy reserves in the resistance phase?

Answer 44

Glycerol can be converted to glucose in the liver by gluconeogenesis.

Fatty acids can be converted to ketones which can be used in CNS metabolism

Question 45

How are proteins used in the resistance phase?

Answer 45

Protein – can be broken down and used to synthesise glucose during fasting. Muscle depletion caused this way may be the major limitation of the length of the resistance phase

Question 46

What is the role of AMYGDALA in regulation of HPA axis?

Answer 46

The amygdala implicated in processing of fearful stimuli. It sends distress signals to the hypothalamus

The amygdala attenuates the negative feedback exerted by glucocorticoids

probably by reducing hippocampal glucocorticoid receptors and thus facilitating the activation of the HPA axis

Question 47

What is the role of hippocampus in the regulation of the HPA axis?

Answer 47

The hippocampus exerts a trans-synaptic influence on the PVN that is primarily inhibitory in nature.

Hippocampal lesions elevate basal glucocorticoid levels.

Ablation of the dorsal hippocampus disrupts the diurnal corticosteroid rhythm and elevates resting corticosteroids

Question 48

What does HPA axis stand for?

Answer 48

The hypothalamic-pituitary-adrenal (HPA) axis

Question 49

What is the role of the HPA axis?

Answer 49

involves the central nervous system and the endocrine system adjusting the balance of hormones in response to stress.

Question 50

Between the amygdala and hippocampus, which one is inhibitory to the HPA axis?

Answer 50

hippocampus

Question 51

State the roles of the hypothalamus

Answer 51

Subconscious control of skeletal muscle, via its effect on other areas of the brain.

Control of autonomic function, via centres in the brain stem that regulate heart rate, blood pressure, respiration and digestion

Co-ordination of activities of the nervous and endocrine systems, via its effects on the pituitary gland. This is vital to the resistance phase of the stress response

The regulation of body temperature, particularly by regulating blood flow through peripheral blood vessels

The hypothalamus is thus a co-ordination centre where conscious and sensory inputs, including ones with emotional content, produce responses which influence output of the autonomic nervous system and the endocrine system.

The control of circadian rhythms. It receives inputs from the retina of the eye and its output adjusts the activities of other parts of the brain concerned with maintenance of daily rhythms

production of behavioural drives. The hypothalamus contains the feeding satiety, and thirst centres, which stimulate or inhibit feeding behaviour. These are examples of ‘drives’which also influence emotional states

the secretion of hormones, oxytocin and vasopressin (ADH)

Question 52

State the limitations of resistance phase

Answer 52

The body’s fat reserves can maintain the resistance phase for weeks or months, but not indefinitely

If starvation is the stress factor the resistance phase ends when the lipid reserves run out and the body starts to metabolise structural protein

The resistance phase ends due to complications caused by side effects of the stress hormones.

The anti-inflammatory action of glucocorticoids slows wound healing and increases susceptibility to infection.

Conservation of fluids under the influence of ADH and aldosterone stresses the cardiovascular system by producing elevated blood volumes and increased blood pressure.

The adrenal cortex may become unable to continue glucocorticoid production, causing failure to maintain blood glucose concentrations

Question 53

Outline causes of exhaustion phase

Answer 53

exhaustion of lipid reserves

inability to produce glucocorticoids

Failure of electrolyte balance

Damage of vital organs

Question 54

Describe what happens in the exhaustion phase

Answer 54

The resources of the body may eventually become so depleted that they cannot sustain the resistance stage, and exhaustion ensues

1.Prolonged exposure to high levels of cortisol and other hormones involved in the resistance reaction causes:

*wasting of muscle, suppression of the immune system, ulceration of the gastrointestinal tract, and failure of pancreatic beta cells.

2.In addition, pathological changes may occur because resistance reactions persist after the stressor has been removed

3.Exhaustion of lipid reserves, inability to produce glucocorticoids, failure of electrolyte balance
Cumulative structural or functional damage to vital organs

Question 55

An effective treatment for individuals who have posttraumatic stress disorder (PTSD), panic disorder, obsessive-compulsive disorder (OCD), and other anxiety disorders e.g. phobias

Patients are often taught relaxation techniques and exposed to their fears in a controlled environment

The body cannot maintain the stress response indefinitely, the person will be forced into relaxation state and cured of the disorder.

WHAT TECHNIQUE IS THIS?

Answer 55

Flooding technique

Question 56

Describe the effects of stress on the immune system

Answer 56

The major effect of corticosteroids on the immune system is the production of I-kB.

This protein is the inhibitor of a major immune system controller, the transcription factor NF-kB.

I-kB complexes the transcription factor, preventing its movement from its site of synthesis in the cytoplasm to the nucleus.

NF-kB is responsible for the transcription of genes involved in the inflammatory response, particularly in T-cell activation and cytokine production.

Question 57

State the effects of NF-κB inhibition

Answer 57

Reduces phagocytic and killing abilities of macrophages and neutrophils.

Reduces chemotaxis, so that fewer inflammatory cells are recruited.

Reduces expression of class 2 MHC antigens and IL -1 by macrophages

Stabilizes lysosomal membranes so that killing enzymes and radicals are not released.

Reduces numbers of circulating lymphocytes

Increases apoptosis of lymphocytes

Shrinks size of lymph nodes and thymus

Question 58

State the effects and MOA of Interleukin-1(IL-1) inhibition.

Answer 58

Interleukin-1, a substance secreted by macrophages of the immune system

A link between stress and immunity

It stimulates the secretion of ACTH, which in turn stimulates the production of cortisol

Cortisol also suppresses further production of interleukin-1

Thus, the immune system is involved in activation of the stress response, and the resulting cortisol then turns off the IL-1 an immune system mediator

This negative feedback system suppresses immune function once HPA axis has been activated.

Because of this activity, cortisol and other glucocorticoids are used as immunosuppressive drugs for organ transplant recipients

Question 59

WHY is cortisol and other glucocorticoids are used as immunosuppressive drugs for organ transplant recipients?

Answer 59

The immune system is involved in activation of the stress response, and the resulting cortisol then turns off the IL-1 an immune system mediator.

Question 60

Describe the Treatments For Stress &Anxiety

Answer 60

Anxiety disorders can be effectively treated with psychopharmacological and cognitive–behavioral interventions

CBT has received the greatest amount of empirical support for the psychological treatment of anxiety disorders

CBT stands with the SSRIs as a first-line treatment

Combining drug therapy and CBT would be the ideal treatment

Question 61

Describe pharmacological Treatments for Anxiety

Answer 61

The drug of choice is probably a selective serotonin re-uptake inhibitor (SSRIs), such as Prozac, which has fewer side effects and is less dangerous in overdose

Benzodiazepines (e.g. valium) they are very effective, though continued use can lead to dependence

β-receptor antagonists (β-blockers, such as propranolol) may be used to control somatic symptoms.

Tricyclic antidepressants are re-uptake inhibitors of serotonin and noradrenalin. These non-specific drugs have side effects and are dangerous in overdose

Mono-amine oxidase inhibitors also prevent the breakdown of adrenergic neurotransmitters. They have serious side effects and interact with certain foods and other drugs.

Moclobemide is a selective and reversible mono-amine oxidase inhibitor which does not have the dangerous interactions of less selective types

Question 62

Name the enzyme inhibited by cAMP which phosphorylates smooth muscle for contraction.

Answer 62

myosin light chain kinase enzyme

Question 63

Used as a therapy for overactive bladder syndrome (OAB).
Name this drug

Answer 63

The β3-AR agonist mirabegron

Question 64

Name the nucleus in the hypothalamus which secrete CRH into the portal circulation when activated by stressors.

Answer 64

Paraventricular neurons (PVN)