What is Epinephrine (also known as adrenaline) and what does it have to do with STRESS?

(R)-(–)-L-Epinephrine or (R)-(–)-L-adrenaline

Systematic (IUPAC) name
(R)-4-(1-hydroxy- 2-(methylamino)ethyl)benzene-1,2-diol
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a603002
Pregnancy cat.	A(AU) C(US)
Legal status	Prescription Only (S4) (AU) POM (UK) ℞-only (US)
Routes	IV, IM, endotracheal, IC
Pharmacokinetic data
Bioavailability	Nil (oral)
Metabolism	adrenergic synapse (MAO and COMT)
Half-life	2 minutes
Excretion	Urine
Identifiers
CAS number	51-43-4
ATC code	A01AD01 B02BC09 C01CA24 R01AA14 R03AA01 S01EA01
PubChem	CID 5816
IUPHAR ligand	509
DrugBank	DB00668
ChemSpider	5611
UNII	YKH834O4BH
KEGG	D00095
ChEBI	CHEBI:28918
ChEMBL	CHEMBL679
Chemical data
Formula	C9H13NO3
Mol. mass	183.204 g/mol
SMILES	eMolecules & PubChem
InChI[show]
(what is this?)  (verify)

Epinephrine (also known as adrenaline) is a hormone and a neurotransmitter.^[1] It increases heart rate, constricts blood vessels, dilates air passages, and participates in the fight-or-flight response of the sympathetic nervous system.^[2] In chemical terms, adrenaline is one of a group of monoamines called the catecholamines. It is produced in some neurons of the central nervous system and in the chromaffin cells of the adrenal medulla from the amino acids phenylalanine and tyrosine.^[3]

Extracts of the adrenal gland were first obtained by Polish physiologist Napoleon Cybulski in 1895. These extracts, which he called nadnerczyna, contained adrenaline and other catecholamines.^[4] Japanese chemist Jokichi Takamine and his assistant Keizo Uenaka independently discovered adrenaline in 1900.^[5][6] In 1901, Takamine successfully isolated and purified the hormone from the adrenal glands of sheep and oxen.^[7] Adrenaline was first synthesized in the laboratory by Friedrich Stolz and Henry Drysdale Dakin, independently, in 1904.^[6]

Contents [hide] 1 Medical uses 1.1 Cardiac arrest 1.2 Anaphylaxis 1.3 Croup 1.4 In local anesthetics 1.5 Autoinjectors 2 Adverse effects 3 Measurement in biological fluids 4 Mechanism of action 5 Biosynthesis and regulation 5.1 Regulation 6 Chemical synthesis 7 Adrenaline junkie 8 Adrenaline addiction 9 Terminology 10 Notes 11 References 12 External links

Medical uses

Adrenaline is used to treat a number of conditions including cardiac arrest, anaphylaxis, and superficial bleeding.^[8] It has been used historically for bronchospasm and hypoglycemia, but newer treatments for these, such as salbutamol, a synthetic epinephrine derivative, and dextrose, respectively, are currently preferred.^[8]

 Cardiac arrest

Adrenaline is used as a drug to treat cardiac arrest and other cardiac dysrhythmias resulting in diminished or absent cardiac output. Its actions are to increase peripheral resistance via α₁receptor-dependent vasoconstriction and to increase cardiac output via its binding to β₁ receptors.

Anaphylaxis

Due to its vasoconstrictive effects, adrenaline is the drug of choice for treating anaphylaxis. Allergy^[9] patients undergoing immunotherapy may receive an adrenaline rinse before the allergen extract is administered, thus reducing the immune response to the administered allergen. It is also used as a bronchodilator for asthma if specific β₂ agonists are unavailable or ineffective.^[10]

Because of various expressions of α₁ or β₂ receptors, depending on the patient, administration of adrenaline may raise or lower blood pressure, depending on whether or not the net increase or decrease in peripheral resistance can balance the positive inotropic and chronotropic effects of adrenaline on the heart, effects that increase the contractility and rate, respectively, of the heart.^{[citation needed]}

The usual concentration for SQ or IM injection is 0.3 – 0.5 mg 1:1,000.

Croup

Racemic epinephrine has historically been used for the treatment of croup.^[11][12] Racemic adrenaline is a 1:1 mixture of the dextrorotatory (d) and levorotatory (l) isomers of adrenaline.^[13] The l- form is the active component.^[13] Racemic adrenaline works by stimulation of the α-adrenergic receptors in the airway, with resultant mucosal vasoconstriction and decreased subglottic edema, and by stimulation of the β-adrenergic receptors, with resultant relaxation of the bronchial smooth muscle.^[12]

 In local anesthetics

Adrenaline is added to injectable forms of a number of local anesthetics, such as bupivacaine and lidocaine, as a vasoconstrictor to retard the absorption and, therefore, prolong the action of the anesthetic agent. Some of the adverse effects of local anesthetic use, such as apprehension, tachycardia, and tremor, may be caused by adrenaline.^[14]

 Autoinjectors

Adrenaline is available in an autoinjector delivery system. EpiPens, Anapens, and Twinjects all use adrenaline as their active ingredient. Twinjects contain a second dose of adrenaline in a separate syringe and needle delivery system contained within the body of the autoinjector.

Though both EpiPen and Twinject are trademark names, common usage of the terms is drifting toward the generic context of any adrenaline autoinjector.^{[citation needed]}

 Adverse effects

Adverse reactions to adrenaline include palpitations, tachycardia, arrhythmia, anxiety, headache, tremor, hypertension, and acute pulmonary edema.^[15]

Use is contraindicated in people on nonselective β-blockers, because severe hypertension and even cerebral hemorrhage may result.^[16] Although commonly believed that administration of adrenaline may cause heart failure by constricting coronary arteries, this is not the case. Coronary arteries have only β₂ receptors, which cause vasodilation in the presence of adrenaline.^[17] Even so, administering high-dose adrenaline has not been definitively proven to improve survival or neurologic outcomes in adult victims of cardiac arrest.^[18]

Measurement in biological fluids

Adrenaline may be quantitated in blood, plasma, or serum as a diagnostic aid, to monitor therapeutic administration, or to identify the causative agent in a potential poisoning victim. Endogenous plasma adrenaline concentrations in resting adults are normally less than 10 ng/L but may increase by 10-fold during exercise and by 50-fold or more during times of stress. Pheochromocytoma patients often have plasma adrenaline levels of 1000-10,000 ng/L. Parenteral administration of adrenaline to acute-care cardiac patients can produce plasma concentrations of 10,000 to 100,000 ng/L.^[19][20]

 Mechanism of action

As a hormone, adrenaline acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of adrenergic receptors. For example, adrenaline causes smooth muscle relaxation in the airways but causes contraction of the smooth muscle that lines most arterioles.

Adrenaline acts by binding to a variety of adrenergic receptors. Adrenaline is a nonselective agonist of all adrenergic receptors, including α₁, α₂, β₁, β₂, and β₃ receptors.^[16] Epinephrine’s binding to these receptors triggers a number of metabolic changes. Binding to α-adrenergic receptors inhibits insulin secretion by the pancreas, stimulates glycogenolysis in the liver and muscle, and stimulates glycolysis in muscle.^[21] β-Adrenergic receptor binding triggers glucagon secretion in the pancreas, increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and increased lipolysis by adipose tissue. Together, these effects lead to increased blood glucose and fatty acids, providing substrates for energy production within cells throughout the body.^[21]

In addition to these metabolic changes, epinephrine also leads to broad alterations throughout all organ systems.

Physiologic responses to epinephrine by organ

Organ	Effects
Heart	Increases heart rate
Lungs	Increases respiratory rate
Nearly all tissues	Vasoconstriction or vasodilation
Liver	Stimulates glycogenolysis
N/A, systemic	Triggers lipolysis
N/A, systemic	Muscle contraction

 Biosynthesis and regulation

Adrenaline is synthesized in the medulla of the adrenal gland in an enzymatic pathway that converts the amino acid tyrosine into a series of intermediates and, ultimately, adrenaline. Tyrosine is first oxidized to L-DOPA, which is subsequently decarboxylated to give dopamine. Oxidation gives norepinephrine, which is methylated to give epinephrine.

Adrenaline is synthesized via methylation of the primary distal amine of noradrenaline by phenylethanolamine N-methyltransferase (PNMT) in the cytosol of adrenergic neurons and cells of the adrenal medulla (so-called chromaffin cells). PNMT is found in the cytosol of only cells of adrenal medullary cells. PNMT uses S-adenosylmethionine (SAMe) as a cofactor to donate the methyl group to noradrenaline, creating adrenaline.^{[citation needed]}

For noradrenaline to be acted upon by PNMT in the cytosol, it must first be shipped out of granules of the chromaffin cells. This may occur via the catecholamine-H⁺ exchanger VMAT1. VMAT1 is also responsible for transporting newly synthesized adrenaline from the cytosol back into chromaffin granules in preparation for release.^{[citation needed]}

In liver cells, adrenaline binds to the β-adrenergic receptor, which changes conformation and helps Gs, a G protein, exchange GDP to GTP. This trimeric G protein dissociates to Gs alpha and Gs beta/gamma subunits. Gs alpha binds to adenyl cyclase, thus converting ATP into cyclic AMP. Cyclic AMP binds to the regulatory subunit of protein kinase A: Protein kinase A phosphorylates phosphorylase kinase. Meanwhile, Gs beta/gamma binds to the calcium channel and allows calcium ions to enter the cytoplasm. Calcium ions bind to calmodulin proteins, a protein present in all eukaryotic cells, which then binds to phosphorylase kinase and finishes its activation. Phosphorylase kinase phosphorylates glycogen phosphorylase, which then phosphorylates glycogen and converts it to glucose-6-phosphate.^{[citation needed]}

Regulation

The major physiologic triggers of adrenaline release center upon stresses, such as physical threat, excitement, noise, bright lights, and high ambient temperature. All of these stimuli are processed in the central nervous system.^[22]

Adrenocorticotropic hormone (ACTH) and the sympathetic nervous system stimulate the synthesis of adrenaline precursors by enhancing the activity of tyrosine hydroxylase and dopamine-β-hydroxylase, two key enzymes involved in catecholamine synthesis.^{[citation needed]} ACTH also stimulates the adrenal cortex to release cortisol, which increases the expression of PNMT in chromaffin cells, enhancing adrenaline synthesis. This is most often done in response to stress.^{[citation needed]} The sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of adrenaline. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and, thus, the release of adrenaline (and noradrenaline) into the bloodstream.^{[citation needed]}

Adrenaline (as with noradrenaline) does exert negative feedback to down-regulate its own synthesis at the presynaptic alpha-2 adrenergic receptor.^{[citation needed]} Abnormally elevated levels of adrenaline can occur in a variety of conditions, such as surreptitious epinephrine administration, pheochromocytoma, and other tumors of the sympathetic ganglia.

Its action is terminated with reuptake into nerve terminal endings, some minute dilution, and metabolism by monoamine oxidase and catechol-O-methyl transferase.

Chemical synthesis

Epinephrine may be synthesized by the reaction of catechol with chloroacetyl chloride, followed by the reaction with methylamine to give the ketone, which is reduced to the desired hydroxy compound. The racemic mixture may be separated using tartaric acid.

 

Stress (physiology)

This article is an orphan, as few or no other articles link to it. Please introduce links to this page from related articles; suggestions may be available. (November 2010)

Physiological stress represents a wide range of physical responses that occur as a direct effect of a stressor causing an upset in the homeostasis of the body. Upon immediate disruption of either psychological or physical equilibrium, the body responds by stimulating the nervous, endocrine, and immune systems. The reaction of these systems causes a number of physical changes that have both short and long-term effects on the body.

Contents [hide] 1 Nervous system 1.1 Peripheral nervous system (PNS) 1.2 Central nervous system (CNS) 2 Endocrine system 3 Immune system 4 References

 Nervous system

 The peripheral nervous system (PNS)

The peripheral nervous system (PNS) consists of two subsystems: the sensory-somatic nervous system and the autonomic nervous system. When a physical stressor acts upon the body the sensory-somatic nervous system is triggered through stimulation of the body’s sensory nerves. The signal acts as a nerve impulse and travels through the body in a process of electrical cell-to-cell communication until it reaches the automatic nervous system. Activation of the automatic nervous system immediately triggers a series of involuntary chemical responses throughout the body. Preganglionic neurons release the neurotransmitter acetylcholine(ACh). This stimulates postganglionic neurons which release noradrenaline. The noradrenaline flows directly into the bloodstream ensuring that all cells in the body’s nervous and endocrine systems have been activated even in areas which the ganglionic neurons are unable to reach.

Central nervous system (CNS)

The central nervous system (CNS) is made up of the brain and the spinal cord. The brain is equipped to process stress in three main areas: the amygdala, the hippocampus, and the prefrontal cortex. Each of these areas is densely packed with stress corticosteroid receptors which process the intensity of physical and psychological stressors acting upon the body through a process of hormone reception. The mineralocorticoid receptors (MR) make up the majority of stress corticosteroid receptors and have an extremely high affinity for cortisol. This means that they are at least partially stimulated at all times and therefore are entirely activated almost immediately when a true stressor is disrupting the homeostasis of the body. The second type of receptor, glucocorticoid receptors (GR), have a low affinity for cortisol and only begin to become activated as the sensation of stress reaches its peak intensity on the brain.

Stress dramatically reduces the ability of the blood-brain barrier (BBB) to block the transfer of chemicals including hormones from entering the brain from the bloodstream. Therefore when corticosteroids are released into the bloodstream – they are immediately able to penetrate the brain and bind to first the MR and then the GR. As the GR begins to become activated, neurons in the amygdala, hippocampus, and prefrontal cortex become overstimulated. This stimulation of the neurons triggers a fight-or-flight response which allows the brain to quickly process information and therefore deal with life-threatening situations. If the stress response continues and becomes chronic, the hyperactivity of the neurons begins to physically change the brain and have severely damaging effects on one’s mental health. As the neurons begin to become stimulated, calcium is released through channels in their cell membranes. Although initially, this allows the cell’s chemical signals to continue to fire, allowing nerve cells to remain stimulated if this continues the cells will become overloaded with calcium leading to over-firing of neuron signals. The over-firing of the neurons is seen in the brain as a dangerous malfunction; therefore, triggering the cells to shut down to avoid death due to over stimulation.

The decline in both neuroplasticity and long term potentiation (LTP) occurs in humans after experiencing levels of high continual stress. To maintain homeostasis the brain is continuously forming new neural connections, reorganizing its neural pathways, and working to fix damages caused by injury and disease. This keeps the brain vital and able to perform cognitive complex thinking. When the brain receives a distress signal it immediately begins to go into overdrive. Neural pathways begin to fire and rewire at hyper-speed to help the brain understand how to handle the task at hand. Often, the brain becomes so intently focused on this one task that it is unable to comprehend, learn, or cognitively understand any other sensory information that is being thrown at it during this time. This over stimulation in specific areas and extreme lack of use in others causes several physiological changes in the brain to take place which overall reduce or even destroy the neuroplasticity of the brain. Dendritic spines found of the dendrite of neurons begin to disappear and many dendrites become shorter and even less complex in structure. Glia cells begin to atrophy and neurogenesis often ceases completely. Without neuroplasticity, the brain loses the ability to form new connections and process new sensory information. Connections between neurons become so weak that it becomes nearly impossible for the brain to effectively encode long-term memories; therefore, the LTP of the hippocampus declines dramatically.

 Endocrine system

When a stressor acts upon the body, the endocrine system is triggered by the release of the neurotransmitter, noradrenaline, by the automatic nervous system. Noradrenaline stimulates the Hypothalamo-Pituitary-Adrenal (HPA) axis which processes the information about the stressor in the hypothalamus. This quickly signals the pituitary gland and finally triggers the adrenal cortex. The adrenal cortex responds by signaling the release of the corticosteroids cortisol and corticotropin-releasing hormone (CRH) directly into the bloodstream.

 Immune system

The most important aspect of the immune system are T-cells found in the form of T-helper and T-suppressor cells. Cortisol, once released into the bloodstream, immediately begins to cause division of T-Suppressor cells. This rapid cell division increases the number of T-Suppressor cells while at the same time suppressing T-helper cells. This reduces immune protection and leaves the body vulnerable to disease and infection.

 

Stress (biology)

Stress is a term that is commonly used today but has become increasingly difficult to define. It shares, to some extent, common meanings in both the biological and psychological sciences. Stress typically describes a negative concept that can have an impact on one’s mental and physical well-being, but it is unclear what exactly defines stress and whether or not stress is a cause, an effect, or the process connecting the two. With organisms as complex as humans, stress can take on entirely concrete or abstract meanings with highly subjective qualities, satisfying definitions of both cause and effect in ways that can be both tangible and intangible.

The term stress had none of its contemporary connotations before the 1920s. It is a form of the Middle English destresse, derived via Old French from the Latin stringere, “to draw tight.”^[1] It had long been in use in physics to refer to the internal distribution of a force exerted on a material body, resulting in strain. In the 1920s and 1930s, the term was occasionally being used in biological and psychological circles to refer to a mental strain, unwelcome happening, or, more medically, a harmful environmental agent that could cause illness. Walter Cannon used it in 1926 to refer to external factors that disrupted what he called homeostasis. ^[2]

Homeostasis is a concept central to the idea of stress. In biology, most biochemical processes strive to maintain equilibrium, a steady state that exists more as an ideal and less as an achievable condition. Environmental factors, internal or external stimuli, continually disrupt homeostasis; an organism’s present condition is a state in constant flux wavering about a homeostatic point that is that organism’s optimal condition for living. Factors causing an organism’s condition to waver away from homeostasis can be interpreted as stress. A life-threatening situation such as a physical insult or prolonged starvation can greatly disrupt homeostasis. On the other hand, an organism’s effortful attempt at restoring conditions back to or near homeostasis, oftentimes consuming energy and natural resources, can also be interpreted as stress. In such instances, an organism’s fight-or-flight response recruits the body’s energy stores and focuses attention to overcome the challenge at hand. The ambiguity in defining this phenomenon was first recognized by Hans Selye in 1926 who loosely described stress as something that “…in addition to being itself, was also the cause of itself, and the result of itself.”^[3] First to use the term in a biological context, Selye continued to define stress as “the non-specific response of the body to any demand placed upon it.” Present-day neuroscientists including Bruce McEwen and Jaap Koolhaas believe that stress, based on years of empirical research, “should be restricted to conditions where an environmental demand exceeds the natural regulatory capacity of an organism.”^[4] Despite the numerous definitions given to stress, homeostasis appears to lie at its core.

Biology has progressed in this field greatly, elucidating complex biochemical mechanisms that appear to underlie diverse aspects of stress, shining a necessary light on its clinical relevance and significance. Despite this, science still runs into the problem of not being able to settle or agree on the conceptual and operational definitions of stress. Because stress is ultimately perceived as a subjective experience, it follows that its definition perhaps ought to remain fluid. For a concept so ambiguous and difficult to define, stress nevertheless plays an obvious and predominant role in the everyday lives of humans and nature alike.

Contents [hide] 1 Biological background 1.1 Neuroanatomy 1.1.1 Brain 1.1.1.1 Hypothalamus 1.1.1.2 Amygdala 1.1.1.3 Hippocampus 1.1.1.4 Locus coeruleus 1.1.1.5 Raphe nucleus 1.1.2 Spinal cord 1.1.3 Pituitary gland 1.1.4 Adrenal gland 1.2 Neurochemistry 1.2.1 Corticotropin-releasing hormone 1.2.2 Adrenocorticotropic hormone 1.2.3 Cortisol 1.2.4 Norepinephrine 1.2.5 Serotonin 1.2.6 Neuropeptide Y 2 Biological mechanisms 2.1 Hypothalamic-pituitary-adrenal (HPA) axis 2.2 Immune response 2.2.1 Effect of stress on the immune system 3 Psychological concepts 3.1 Eustress 3.2 Coping 3.3 Cognitive appraisal 4 Clinical symptoms and disorders 4.1 DSM-IV TR 4.1.1 Health risk factors 4.2 Generalized anxiety syndrome 4.3 Panic disorder 4.4 General adaptive syndrome 4.5 Phobia 4.6 Post-traumatic stress disorder (PTSD) 4.7 Depression 5 History in research 6 See also 7 References 7.1 Notes 7.2 External links 7.2.1 Introductory 7.3 Bibliography

[edit] Biological background

Biology primarily attempts to explain major concepts of stress in a stimulus-response manner, much like a how a psychobiological sensory system operates. The central nervous system (brain and spinal cord) plays a crucial role in the body’s stress-related mechanisms. Whether these mechanisms ought to be interpreted as the body’s response to a stressor or embody the act of stress itself is part of the ambiguity in defining what exactly stress is. Nevertheless, the central nervous system works closely with the body’s endocrine system to regulate these mechanisms. One branch of the central nervous system, the sympathetic nervous system, becomes primarily active during a stress response, regulating many of the body’s physiological functions in ways that ought to make an organism more adaptive to its environment. Below is a brief biological background of the neuroanatomy and neurochemistry and how they relate to stress.

[edit] Neuroanatomy

[edit] Brain

The brain plays a critical role in the body’s perception of and response to stress. However, pinpointing exactly which regions of the brain are responsible for particular aspects of a stress response is difficult and often unclear. Understanding that the brain works in more of a network-like fashion carrying information about a stressful situation across regions of the brain (from cortical sensory areas to more basal structures and vice versa) can help explain how stress and its negative consequences are heavily rooted in neural communication dysfunction. In spite of this, several important brain structures implicated in playing key roles in stress response pathways are described below.

[edit] Hypothalamus

The hypothalamus is a small portion of the brain located “below the thalamus” and above the brainstem. One of its most important functions is to help link together the body’s nervous and endocrine systems. This structure has many bidirectional neural inputs and outputs from and to various other brain regions. These connections help regulate the hypothalamus’ ability to secrete hormones into the body’s bloodstream, having far-reaching and long-lasting effects on physiological processes such as metabolism. During a stress response, the hypothalamus secretes various hormones, namely corticotropin-releasing hormone, which stimulates the body’s pituitary gland and initiates a heavily regulated stress response pathway.

[edit] Amygdala

The amygdala is a small, “almond”-shaped structure located bilaterally, deep within the medial temporal lobes of the brain and is a part of the brain’s limbic system, with projections to and from the hypothalamus, hippocampus, and locus coeruleus, among other areas. Thought to play a role in the processing of emotions, the amygdala has been implicated in modulating stress response mechanisms, particularly when feelings of anxiety or fear is involved.

[edit] Hippocampus

The hippocampus is a structure located bilaterally, deep within the medial temporal lobes of the brain, just lateral to each amygdala, and is a part of the brain’s limbic system. The hippocampus is thought to play an important role in memory formation. There are numerous connections to the hippocampus from the cerebral cortex, hypothalamus, and amygdala, among other regions. During stress, the hippocampus is particularly important, in that cognitive processes such as prior memories can have a great influence on enhancing, suppressing, or even independently generating a stress response. The hippocampus is also an area in the brain that is susceptible to damage brought upon by chronic stress.

[edit] Locus coeruleus

The locus coeruleus is an area located in the pons of the brainstem that is the principal site of the synthesis of the neurotransmitter norepinephrine, which plays an important role in the sympathetic nervous system’s fight-or-flight response to stress. This area receives input from the hypothalamus, amygdala, and raphe nucleus among other regions, and projects widely across the brain as well as to the spinal cord.

[edit] Raphe nucleus

The raphe nucleus is an area located in the pons of the brainstem that is the principal site of the synthesis of the neurotransmitter serotonin, which plays an important role in mood regulation, particularly when stress is associated with depression and anxiety. Projections extend from this region to widespread areas across the brain, namely the hypothalamus, and are thought to modulate an organism’s circadian rhythm and sensation of pain among other processes.

[edit] Spinal cord

The spinal cord plays a critical role in transferring stress response neural impulses from the brain to the rest of the body. In addition to the neuroendocrine blood hormone signaling system initiated by the hypothalamus, the spinal cord communicates with the rest of the body by innervating the peripheral nervous system. Certain nerves that belong to the sympathetic branch of the central nervous system exit the spinal cord and stimulate peripheral nerves, which in turn engage the body’s major organs and muscles in a fight-or-flight manner.

[edit] Pituitary gland

The pituitary gland is a small organ that is located at the base of the brain just under the hypothalamus. This gland releases various hormones that play significant roles in regulating homeostasis. During a stress response, the pituitary gland releases hormones into the bloodstream, namely adrenocorticotropic hormone, which modulates a heavily regulated stress response system

[edit] Adrenal gland

The adrenal gland is a major organ of the endocrine system that is located directly on top of the kidneys and is chiefly responsible for the synthesis of stress hormones that are released into the bloodstream during a stress response. Cortisol is the major stress hormone released by the adrenal gland.

In addition to the locus coeruleus existing as a source of the neurotransmitter norepinephrine within the central nervous system, the adrenal gland can also release norepinephrine during a stress response into the body’s bloodstream, at which point norepinephrine acts as a hormone in the endocrine system.

[edit] Neurochemistry

[edit] Corticotropin-releasing hormone

Corticotropin-releasing hormone is the neurohormone secreted by the hypothalamus during a stress response that stimulates the anterior lobe of the pituitary gland by binding to its corticotropin-releasing hormone-receptors, causing the anterior pituitary to release adrenocorticotropic hormone.

[edit] Adrenocorticotropic hormone

Adrenocorticotropic hormone is the hormone secreted by the anterior lobe of the pituitary gland into the body’s blood stream that stimulates the cortex of the adrenal gland by binding to its adrenocorticotropic hormone-receptors, causing the adrenal gland to release cortisol.

[edit] Cortisol

Cortisol is a steroid hormone, belonging to a broader class of steroids called glucocorticoids, produced by the adrenal gland and secreted during a stress response. Its primary function is to redistribute energy (glucose) to regions of the body that need it most (i.e., the brain and major muscles during a fight-or-flight situation). As a part of the body’s fight-or-flight response, cortisol also acts to suppress the body’s immune system.

[edit] Norepinephrine

Norepinephrine is a neurotransmitter released from locus coeruleus when stimulated by the hypothalamus during a stress response. Norepinephrine serves as the primary chemical messenger of the central nervous system’s sympathetic branch that prepares the body for fight-or-flight response.

[edit] Serotonin

Serotonin is a neurotransmitter synthesized in the raphe nucleus of the pons of the brainstem and projects to most brain areas. Serotonin is thought to play an important role in mood regulation. Stress-induced serotonin dysfunctions have been associated with anxiety, fear, and depression-like symptoms.

[edit] Neuropeptide Y

Neuropeptide Y is a protein that is synthesized in the hypothalamus and acts as a chemical messenger in the brain. Traditionally, it has been thought to play an important role in appetite, feeding behavior, and satiety, but more recent findings have implicated Neuropeptide Y in stress, specifically, stress resiliency.^[5]

[edit] Biological mechanisms

[edit] Hypothalamic-pituitary-adrenal (HPA) axis

The HPA axis is a multi-step biochemical pathway where information is transmitted from one area of the body to the next via chemical messengers^{[disambiguation needed ]}. Each step in this pathway, as in many biochemical pathways, not only passes information along to stimulate the next region but also receives feedback from messengers produced later in the pathway to either enhance or suppress earlier steps in the pathway – this is one way a biochemical pathway can regulate itself, via a feedback mechanism.

When the hypothalamus receives signals from one of its many inputs (e.g., cerebral cortex, limbic system, visceral organs) about conditions that deviate from an ideal homeostatic state (e.g., alarming sensory stimulus, emotionally charged event, energy deficiency), this can be interpreted as the initiation step of the stress-response cascade. The hypothalamus is stimulated by its inputs and then proceeds to secrete corticotropin-releasing hormones. This hormone is transported to its target, the pituitary gland, via the hypophyseal portal system (short blood vessels system), to which it binds and causes the pituitary gland to, in turn, secrete its own messenger, adrenocorticotropic hormone, systemically into the body’s bloodstream. When adrenocorticotropic hormone reaches and binds to its target, the adrenal gland, the adrenal gland in turn releases the final key messenger in the cascade, cortisol. Cortisol, once released, has widespread effects in the body. During an alarming situation in which a threat is detected and signaled to the hypothalamus from primary sensory and limbic structures, cortisol is one way the brain instructs the body to attempt to regain homeostasis – by redistributing energy (glucose) to areas of the body that need it most, that is, toward critical organs (the heart, the brain) and away from digestive and reproductive organs, during a potentially harmful situation in an attempt to overcome the challenge at hand.

After enough cortisol has been secreted to best restore homeostasis and the body’s stressor is no longer present or the threat is no longer perceived, the heightened levels of cortisol in the body’s bloodstream eventually circulate to the pituitary gland and hypothalamus to which cortisol can bind and inhibit, essentially turning off the HPA-axis’ stress-response cascade via feedback inhibition. This prevents additional cortisol from being released. This is biologically identified as a normal, healthy stress mechanism in response to a situation or stressor – a biological coping mechanism for a threat to homeostasis.

It is when the body’s HPA-axis cannot overcome a challenge and/or is chronically exposed to a threat that this system becomes overtaxed and can be harmful to the body and brain. A second major effect of cortisol is to suppress the body’s immune system during a stressful situation, again, for the purpose of redistributing metabolic resources primarily to fight-or-flight organs. While not a major risk to the body if only for a short period of time if under chronic stress, the body becomes exceptionally vulnerable to immune system attacks. This is a biologically negative consequence of an exposure to a severe stressor and can be interpreted as stress in and of itself – a detrimental inability of biological mechanisms to effectively adapt to changes in homeostasis.

On December 13th, 2011, an online news release from  – Tufts University in Boston, Massachusetts (specifically, the Tufts University School of Medicine and Sackler School of Graduate Biomedical Sciences at Tufts University)  – author Jamie Maguire, PhD, assistant professor in the department of neuroscience says … “Neuroscience researchers have demonstrated, for the first time, that the physiological response to stress depends on neurosteroids acting on specific receptors in the brain, and they have been able to block that response in mice. This breakthrough suggests that these critical receptors may be drug therapy targets for control of the stress-response pathway. This finding may pave the way for new approaches to managing a wide range of neurological disorders involving stress. The stress-control pathway, more technically known as the Hypothalamus-Pituitary-Adrenal (HPA) axis, determines the levels of cortisol and other stress hormones in the human body. In addition to being implicated in the types of emotional and psychological stress that can lead to major depression, disorders of the stress-control pathway are also associated with obesity, premenstrual syndrome, postpartum depression, hypercortisolism (Cushing’s syndrome), and diseases including epilepsy and osteoporosis.” … “We have identified a novel mechanism regulating the body’s response to stress by determining that neurosteroids are required to mount the physiological response to stress. Moreover, we were able to completely block the physiological response to stress as well as prevent stress-induced anxiety,” … “Using the brain tissues of adult mice, the research team identified mechanisms controlling the activity of Corticotropin-releasing hormone (CRH) neurons involved in the control of the stress pathway. By monitoring the activity of CRH neurons following stress and measuring levels of corticosterone in the blood, they found that the production of stress hormones required the action of neurosteroids on specific receptors on CRH neurons. Apart from the finding that stress causes a neurosteroid-induced increase in blood corticosterone levels, the researchers also found that blocking the synthesis of neurosteroids is sufficient to block the stress-induced elevations in corticosterone and prevent stress-induced, anxiety-like behavior in mice. Previous research had identified the presence of specialized CRH-nerve-cell receptors in the HPA axis, but the findings had been controversial because of limited studies showing any connection between these receptors and the regulation of the CRH nerve cells.” … “We have found a definite role of neurosteroids on the receptors regulating CRH nerve cells and the stress response. The data suggest that these receptors may be novel targets for control of the stress-control pathway. Our next work will focus on modulating these receptors to treat disorders associated with stress, including epilepsy and depression-like behaviors,” ^[6]

[edit] Immune response

Cortisol can weaken the activity of the immune system. Cortisol prevents the proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1 (IL-1), and unable to produce the T-cell growth factor.[35]Cortisol also has a negative-feedback effect on interleukin-1.[36] IL-1 must be especially useful in combating some diseases; however, endotoxic bacteria have gained an advantage by forcing the hypothalamus to increase cortisol levels (forcing the secretion of CRH hormone, thus antagonizing IL-1). The suppressor cells are not affected by glucosteroid response-modifying factor (GRMF),[37] so the effective setpoint for the immune cells may be even higher than the setpoint for physiological processes (reflecting leukocyte redistribution to lymph nodes, bone marrow, and skin). Rapid administration of corticosterone (the endogenous Type I and Type II receptor agonist) orRU28362 (a specific Type II receptor agonist) to adrenalectomized animals induced changes in leukocyte distribution. Natural killer cells are not affected by cortisol.[38]

[edit] Effect of stress on the immune system

Stress is the body’s reaction to any stimuli that disturb its equilibrium. When the equilibrium of various hormones has altered the effect of these changes can be detrimental to the immune system. ^[7] Much research has shown a negative effect stress has on the immune system, mostly through studies where participants were subjected to a variety of viruses. In one study, individuals caring for a spouse with dementia, representing the stress group, saw a significant decrease in immune response when given an influenza-virus vaccine compared to a non-stressed control group. ^{[8] [9]} A similar study was conducted using a respiratory virus. Participants were infected with the virus and given a stress index. Results showed that an increase in score on the stress index correlated with greater severity of cold symptoms. ^[10] Studies with HIV have also shown stress to speed up viral progression. Men with HIV were 2-3 times more likely to develop AIDS when under above-average stress. ^[11]

Chronic stress

Chronic stress is defined as a “state of prolonged tension from internal or external stressors, which may cause various physical manifestations–eg, asthma, back pain, arrhythmias, fatigue, headaches, HTN, irritable bowel syndrome, ulcers, and suppress the immune system”. Chronic stress takes a more significant toll on your body than acute stress does. It can raise blood pressure, increase the risk of heart attack and stroke, increase vulnerability to anxiety and depression, contribute to infertility, and hasten the aging process. For example, results of one study demonstrated that individuals who reported relationship conflict lasting one month or longer have a greater risk of developing illness and show slower wound healing. Similarly, the effects that acute stressors have on the immune system may be increased when there is perceived stress and/or anxiety due to other events. For example, students who are taking exams show weaker immune responses if they also report stress due to daily hassles. ^[12]

Mechanisms of Chronic Stress

Studies revealing the relationship between the immune system and the central nervous system indicate that stress can alter the function of white blood cells involved in immune function, known as lymphocytes and macrophages. People undergoing stressful life events, such as marital turmoil or bereavement, have a weaker lymphoproliferative response. After antigens initiate an immune response, these white blood cells send signals, composed of cytokines and other hormonal proteins, to the brain and neuroendocrine system. ^[13] Cytokines are molecules involved with cell signaling. Cortisol, a hormone released during stressful situations, affects the immune system greatly by preventing the production of cytokines. During chronic stress, cortisol is overproduced, causing fewer receptors to be produced on immune cells so that inflammation cannot be ended. A study involving cancer patient’s parents confirmed this finding. Blood samples were taken from the participants. Researchers treated the samples of the parents of cancer patients with a cortisol-like substance and stimulated cytokine production. Cancer patient parents’ blood was significantly less effective at stopping cytokine from being produced. ^[14]

Stress and Wound Healing

The immune system also plays a role in stress and the early stages of wound healing. It is responsible for preparing tissue for repair and promoting recruitment of certain cells to the wound area. ^[15] Consistent with the fact that stress alters the production of cytokines, Graham et al. found that chronic stress associated with caregiving for a person with Alzheimer’s Disease leads to delayed wound healing. Results indicated that biopsy wounds healed 25% more slowly in the chronically stressed group, or those caring for a person with Alzheimer’s disease. ^[16]

Chronic stress has also been shown to impair developmental growth in children by lowering the pituitary gland‘s production of growth hormone, as in children associated with a home environment involving serious marital discord, alcoholism, or child abuse.^[17]

Chronic stress is seen to affect parts of the brain where memories are processed through and stored. When people feel stressed, stress hormones get over-secreted, which affects the brain. This secretion is made up of glucocorticoids, including cortisol, which are steroid hormones that the adrenal gland releases.^[18]

Studies of female monkeys at Wake Forest University (2009) discovered that individuals suffering from higher stress have higher levels of visceral fat in their bodies. This suggests a possible cause-and-effect link between the two, wherein stress promotes the accumulation of visceral fat, which in turn causes hormonal and metabolic changes that contribute to heart disease and other health problems.^[19]

[edit] Psychological concepts

[edit] Eustress

Selye published in 1975 a model dividing stress into eustress and distress.^[20] Where stress enhances function (physical or mental, such as through strength training or challenging work), it may be considered eustress. Persistent stress that is not resolved through coping or adaptation, deemed distress, may lead to anxiety or withdrawal (depression) behavior.

The difference between experiences that result in eustress and those that result in distress is determined by the disparity between an experience (real or imagined) and personal expectations, and resources to cope with the stress. Alarming experiences, either real or imagined, can trigger a stress response.^[21]

[edit] Coping

Responses to stress include adaptation, psychological coping such as stress management, anxiety, and depression. Over the long term, distress can lead to diminished health and/or increased propensity to illness; to avoid this, stress must be managed.

Stress management encompasses techniques intended to equip a person with effective coping mechanisms for dealing with psychological stress, with stress defined as a person’s physiological response to an internal or external stimulus that triggers the fight-or-flight response. Stress management is effective when a person uses strategies to cope with or alter stressful situations.

There are several ways of coping with stress,^{[citation needed]} such as controlling the source of stress or learning to set limits and to say “No” to some demands that bosses or family members may make.

A person’s capacity to tolerate the source of stress may be increased by thinking about another topic such as a hobby, listening to music, or spending time in a wilderness.

[edit] Cognitive appraisal

Lazarus^[22] argued that, in order for a psychosocial situation to be stressful, it must be appraised as such. He argued that cognitive processes of appraisal are central in determining whether a situation is potentially threatening, constitutes a harm/loss or a challenge, or is benign.

Both personal and environmental factors influence this primary appraisal, which then triggers the selection of coping processes. Problem-focused coping is directed at managing the problem, whereas emotion-focused coping processes are directed at managing the negative emotions. Secondary appraisal refers to the evaluation of the resources available to cope with the problem, and may alter the primary appraisal.

In other words, primary appraisal includes the perception of how stressful the problem is and the secondary appraisal of estimating whether one has more than or less than adequate resources to deal with the problem that affects the overall appraisal of stressfulness. Further, coping is flexible in that, in general, the individual examines the effectiveness of the coping on the situation; if it is not having the desired effect, s/he will, in general, try different strategies.^[23]

[edit] Clinical symptoms and disorders

Symptoms Signs of stress may be cognitive, emotional, physical, or behavioral.

Cognitive symptoms

• Memory problems
• Inability to concentrate
• Poor judgment
• Pessimistic approach or thoughts
• Anxious or racing thoughts
• Constant worrying

Emotional symptoms

• Moodiness
• Irritability or short temper
• Agitation, inability to relax
• Feeling overwhelmed
• Sense of loneliness and isolation
• Depression or general unhappiness

Physical symptoms

• Aches and pains
• Diarrhea or constipation
• Nausea, dizziness
• Chest pain, rapid heartbeat
• Loss of sex drive
• Frequent colds

Behavioral symptoms

• Eating more or less
• Sleeping too much or too little
• Isolating oneself from others
• Procrastinating or neglecting responsibilities
• Using alcohol, cigarettes, or drugs to relax
• Nervous habits (e.g. nail biting, pacing)

[edit] DSM-IV TR

Diagnosis

A renewed interest in salivary alpha-amylase as a marker for stress has surfaced. Yamaguchi M, Yoshida H (2005) have analyzed a newly introduced hand-held device called the Cocorometer developed by Nipro Corp., Japan. They state that this can be reliably used to analyze the amylase levels and is definitely a cheaper alternative as compared to the more expensive ELISA kits. The working consists of a meter and a saliva collecting chip, which can be inserted into the meter to give the readings. The levels of amylase obtained have been calibrated according to standard population, and can be categorized into four levels of severity.^[24]

Measuring stress level independent of differences in people’s personalities has been inherently difficult: Some people are able to process many stressors simultaneously, while others can barely address a few. Such tests as the Trier Social Stress Test attempted to isolate the effects of personalities on ability to handle stress in a laboratory environment. Other psychologists, however, proposed measuring stress indirectly, through self-tests.

Because the amount of stressors in a person’s life often (although not always) correlates with the amount of stress that person experiences, researchers combine the results of stress and burnout self-tests. Stress tests help determine the number of stressors in a person’s life, while burnout tests determine the degree to which the person is close to the state of burnout. Combining both helps researchers gauge how likely additional stressors will make him or her experience mental exhaustion.^[25]

[edit] Health risk factors

Both negative and positive stressors can lead to stress. The intensity and duration of stress changes depending on the circumstances and emotional condition of the person suffering from it (Arnold. E and Boggs. K. 2007). Some common categories and examples of stressors include:

• Sensory input such as pain, bright light, noise, temperatures, or environmental issues such as a lack of control over environmental circumstances, such as food, air and/or water quality, housing, health, freedom, or mobility.
• Social issues can also cause stress, such as struggles with conspecific or difficult individuals and social defeat, or relationship conflict, deception, or breakups, and major events such as birth and deaths, marriage, and divorce.
• Life experiences such as poverty, unemployment, clinical depression, obsessive-compulsive disorder, heavy drinking,^[26] or insufficient sleep can also cause stress. Students and workers may face performance pressure stress from exams and project deadlines.
• Adverse experiences during development (e.g. prenatal exposure to maternal stress,^[27][28] poor attachment histories,^[29] sexual abuse^[30]) are thought to contribute to deficits in the maturity of an individual’s stress response systems. One evaluation of the different stresses in people’s lives is the Holmes and Rahe stress scale.

[edit] Generalized anxiety syndrome

The areas of the brain affected by a generalized anxiety disorder

During passive activity, patients with generalised anxiety disorder (GAD) exhibit increased metabolic rates in the occipital, temporal and frontal lobes and in the cerebellum and thalamus compared with healthy controls. Increased metabolic activity in the basal ganglia has also been reported in patients with GAD during vigilance tasks. These findings suggest that there may be hyperactive brain circuits in GAD.^[31]

The areas of the brain affected in generalized anxiety disorder (advanced)

Patients with generalised anxiety disorder (GAD) exhibit increased metabolic rates in several brain regions compared with healthy controls. Hyperactive neurotransmitter circuits between the cortex, thalamus, amygdala and hypothalamus have been implicated in the disorder. Hypofunction of serotonergic neurones arising from the dorsal raphe nucleus and GABAergic neurones that are widely distributed in the brain may result in a lack of inhibitory effect on the putative GAD pathway. Furthermore, overactivity of noradrenergic neurones arising from the locus coeruleus may produce excessive excitation in the brain areas implicated in GAD.^[32]

The septohippocampal circuit

Based on early neuroanatomical observations and studies with psychoactive drugs, the septohippocampal circuit has been proposed as a model for anxiety disorders. The circuit that links the septum, amygdala, hippocampus and fornix is thought to process external stimuli and regulate the behavioural response through wider projections in the brain. Hyperstimulation of this putative ‘behavioural inhibition’ circuit, through dysfunctional noradrenergic and serotonergic neurotransmission, has been implicated in producing anxiety, and increased arousal and attention.^[33]

The noradrenaline pathways in generalized anxiety disorder

In generalised anxiety disorder (GAD) there is increased noradrenaline transmission from both the locus coeruleus and the caudal raphe nuclei. The locus coeruleus-noradrenaline system is associated with anxiety and may mediate the autonomic symptoms associated with stress such as increased heart rate, dilated pupils, tremors, and sweating.^[34]

Serotonergic pathways showing the effects of generalized anxiety disorder

Serotonergic nuclei are found in the rostral and caudal raphe nuclei. Neurones ascend from the rostral raphe nuclei to the cerebral cortex, limbic regions and basal ganglia. The activity of neurones innervating the pre-frontal cortex, basal ganglia and limbic region is decreased in generalised anxiety disorder (GAD). The activity of descending neurons from serotonergic nuclei in the brainstem is unaffected in GAD. This altered neurotransmitter balance contributes to the feeling of anxiety associated with GAD.^[35]

GABAergic pathways showing the effects of generalized anxiety disorder

GABA is the main inhibitory neurotransmitter in the central nervous system (CNS). GABAergic inhibition is seen at all levels of the CNS, including the hypothalamus, hippocampus, cerebral cortex and cerebellar cortex. The activity of GABAergic neurons is decreased in generalized anxiety disorder.^[36]

[edit] Panic disorder

The areas of the brain affected in panic disorder

There are a number of areas of the brain affected by panic disorder. Decreased serotonin activity in the amygdala and frontal cortex induces symptoms of anxiety, whereas decreased activity in the periaqueductal grey results in defensive behaviours and postural freezing. The locus coeruleus increases norepinephrine release mediating physiological and behavioural arousal, while the hypothalamus mediates the sympathetic nervous system.^{[37] [38] [39]}
The areas of the brain affected in panic disorder (advanced)

Hyperactive neurotransmitter circuits between the cortex, thalamus, hippocampus, amygdala, hypothalamus, and peri-aqueductal grey matter have been implicated in panic disorder. Hypofunction of serotonergic neurons arising from the rostral raphe nucleus may result in a lack of inhibitory effect on the putative panic pathways in the brain. While, overactivity of norepinephrine neurons arising from the locus coeruleus may produce excessive excitation in the regions implicated in panic disorder. Physiological symptoms of the panic response are mediated by the autonomic nervous system through connections with the locus coeruleus and hypothalamus.^{[40] [41] [42] [43] [44]}

 

The serotonin pathways in panic disorder

The principal serotonin centers in the brain are the caudal and rostral raphe nuclei. Transmission of serotonin from the rostral raphe nuclei to the pre-aqueductal grey, amygdala, temporal lobe, and limbic cortex is decreased in panic disorder compared with normal. Serotonin transmission to other target regions of the brain remains unchanged.^[45]
The norepinephrine pathways in panic disorder

In panic disorder there is increased norepinephrine transmission from both the locus coeruleus and the caudal raphe nuclei. The locus coeruleus-norepinephrine system may have a significant role in processing fear-related stimuli or it may affect fear-related processing by stimulating other regions of the brain implicated in anxiety and fear behaviours ie amygdala, hippocampus, hypothalamus, cortex and spinal cord. ^[46]

[edit] General adaptive syndrome

Physiologists define stress as how the body reacts to a stressor, real or imagined, a stimulus that causes stress. Acute stressors affect an organism in the short term; chronic stressors over the longer term.

The alarm is the first stage. When the threat or stressor is identified or realized, the body’s stress response is a state of alarm. During this stage, adrenaline will be produced in order to bring about the fight-or-flight response. There is also some activation of the HPA axis, producing cortisol

Resistance is the second stage. If the stressor persists, it becomes necessary to attempt some means of coping with the stress. Although the body begins to try to adapt to the strains or demands of the environment, the body cannot keep this up indefinitely, so its resources are gradually depleted.

Exhaustion is the third and final stage in the GAS model. At this point, all of the body’s resources are eventually depleted and the body is unable to maintain normal function. The initial autonomic nervous system symptoms may reappear (sweating, raised heart rate, etc.). If stage three is extended, long-term damage may result, as the body’s immune system becomes exhausted, and bodily functions become impaired, resulting in decompensation.

The result can manifest itself in obvious illnesses such as ulcers, depression, diabetes, trouble with the digestive system, or even cardiovascular problems, along with other mental illnesses.

[edit] Phobia

The areas of the brain affected in phobia

There are a number of areas of the brain affected by phobia. Activation of the amygdala causes anticipatory anxiety or avoidance (conditioned fear) while activation of the hypothalamus activates the sympathetic nervous system. Other regions of the brain involved in phobia include the thalamus and the cortical structures, which may form a key neural network along with the amygdala. Stimulation of the locus coeruleus increases noradrenaline release mediating physiological and behavioral arousal.^[47]

The noradrenaline pathways in phobia

One hypothesis about the biological basis of phobia suggests that there is an excess of noradrenaline in the principal noradrenergic pathways in the brain and that this causes a down-regulation of postsynaptic adrenergic receptors. Transmission of noradrenaline from the caudal raphe nuclei and the locus coeruleus is increased in phobia. ^[48]

The serotonin pathways in phobia

The principal serotonin centers in the brain are the caudal and rostral raphe nuclei. Transmission of serotonin from the rostral raphe nuclei to the thalamus, limbic cortex, and cerebral cortex is decreased in phobia compared with normal. The other major pathways for serotonin transmission which involve the basal ganglia and cerebellum, and project down the spinal cord, remain unchanged.^[49]

[edit] Post-traumatic stress disorder (PTSD)

Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that can develop after exposure to any event that results in psychological trauma. This event may involve the threat of death to oneself or to someone else, or to one’s own or someone else’s physical, sexual, or psychological integrity, overwhelming the individual’s ability to cope. As an effect of psychological trauma, PTSD is less frequent and more enduring than the more commonly seen acute stress response. Diagnostic symptoms for PTSD include re-experiencing the original trauma(s) through flashbacks or nightmares, avoidance of stimuli associated with the trauma, and increased arousals – such as difficulty falling or staying asleep, anger, and hypervigilance. Formal diagnostic criteria (both DSM-IV-TR and ICD-10) require that the symptoms last more than one month and cause significant impairment in social, occupational, or other important areas of functioning.

The areas of the brain affected in post-traumatic stress disorder

Sensory input, memory formation and stress response mechanisms are affected in patients with post-traumatic stress disorder (PTSD). The regions of the brain involved in memory processing that is implicated in PTSD include the hippocampus, amygdala and frontal cortex. While the heightened stress response is likely to involve the thalamus, hypothalamus, and locus coeruleus.^{[50] [51]}

Memory

Cortisol works with epinephrine (adrenaline) to create memories of short-term emotional events; this is the proposed mechanism for the storage of flashbulb memories and may originate as a means to remember what to avoid in the future. However, long-term exposure to cortisol damages cells in the hippocampus; this damage results in impaired learning. Furthermore, it has been shown that cortisol inhibits memory retrieval of already stored information.

Atrophy of the hippocampus in posttraumatic stress disorder

There is consistent evidence from MRI volumetric studies that hippocampal volume is reduced in posttraumatic stress disorder (PTSD). This atrophy of the hippocampus is thought to represent decreased neuronal density. However, other studies suggest that hippocampal changes are explained by whole-brain atrophy and generalized white matter atrophy is exhibited by people with PTSD.^{[52] [53]}

[edit] Depression

The areas of the brain affected in depression

Many areas of the brain appear to be involved in depression including the frontal and temporal lobes and parts of the limbic system including the cingulate gyrus. However, it is not clear if the changes in these areas cause depression or if the disturbance occurs as a result of the etiology of psychiatric disorders.^[54]

The hypothalamic-pituitary-adrenal (HPA) axis in depression

In depression, the hypothalamic-pituitary-adrenal (HPA) axis is upregulated with a down-regulation of its negative feedback controls. Corticotropin-releasing factor (CRF) is hypersecretion from the hypothalamus and induces the release of adrenocorticotropin hormone (ACTH) from the pituitary. ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands; adrenal hypertrophy can also occur. The release of cortisol into the circulation has a number of effects, including elevation of blood glucose. The negative feedback of cortisol to the hypothalamus, pituitary, and immune system is impaired. This leads to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized leading to increased activity of the pro-inflammatory immune mediators and disturbances in neurotransmitter transmission.^{[55] [56] [57] [58]}

The serotonin pathways in depression

Serotonin transmission from both the caudal raphe nuclei and rostral raphe nuclei is reduced in patients with depression compared with non-depressed controls. Increasing the levels of serotonin in these pathways, by reducing serotonin reuptake and hence increasing serotonin function, is one of the therapeutic approaches to treating depression.^[59]

The noradrenaline pathways in depression

In depression the transmission of noradrenaline is reduced from both of the principal noradrenergic centres – the locus coeruleus and the caudal raphe nuclei. An increase in noradrenaline in the frontal/prefrontal cortex modulates the action of selective noradrenaline reuptake inhibition and improves mood. Increasing noradrenaline transmission to other areas of the frontal cortex modulates attention.^[60]

[edit] History in research

However, the novel usage arose out of Selye‘s 1930s experiments. He started to use the term to refer not just to the agent but to the state of the organism as it responded and adapted to the environment. His theories of a universal non-specific stress response attracted great interest and contention in academic physiology and he undertook extensive research programs and publication efforts.^[61]

While the work attracted continued support from advocates of psychosomatic medicine, many in experimental physiology concluded that his concepts were too vague and unmeasurable. During the 1950s, Selye turned away from the laboratory to promote his concept through popular books and lecture tours. He wrote for both non-academic physicians and, in an international bestseller entitled Stress of Life, for the general public.

A broad biopsychosocial concept of stress and adaptation offered the promise of helping everyone achieve health and happiness by successfully responding to changing global challenges and the problems of modern civilization. Selye coined the term “eustress” for positive stress, by contrast to distress. He argued that all people have a natural urge and need to work for their own benefit, a message that found favor with industrialists and governments.^[61] He also coined the term stressor to refer to the causative event or stimulus, as opposed to the resulting state of stress.

From the late 1960s, academic psychologists started to adopt Selye‘s concept; they sought to quantify “life stress” by scoring “significant life events,” and a large amount of research was undertaken to examine links between stress and disease of all kinds. By the late 1970s, stress had become the medical area of greatest concern to the general population, and more basic research was called for to better address the issue. There was also renewed laboratory research into the neuroendocrine, molecular, and immunological bases of stress, conceived as a useful heuristic not necessarily tied to Selye‘s original hypotheses. The US military became a key center of stress research, attempting to understand and reduce combat neurosis and psychiatric casualties.^[61]

The psychiatric diagnosis post-traumatic stress disorder (PTSD) was coined in the mid 1970s, in part through the efforts of anti-Vietnam War activists and the anti-war group Vietnam Veterans Against the War and Chaim F. Shatan. The condition was added to the Diagnostic and Statistical Manual of Mental Disorders as posttraumatic stress disorder in 1980.^[62] PTSD was considered a severe and ongoing emotional reaction to an extreme psychological trauma, and as such often associated with soldiers, police officers, and other emergency personnel. The stressor may involve threat to life (or viewing the actual death of someone else), serious physical injury, or threat to physical or psychological integrity. In some cases, it can also be from profound psychological and emotional trauma, apart from any actual physical harm or threat. Often, however, the two are combined.

By the 1990s, “stress” had become an integral part of modern scientific understanding in all areas of physiology and human functioning, and one of the great metaphors of Western life. Focus grew on stress in certain settings, such as workplace stress, and stress management techniques were developed. The term also became a euphemism, a way of referring to problems and eliciting sympathy without being explicitly confessional, just “stressed out.” It came to cover a huge range of phenomena from mild irritation to the kind of severe problems that might result in a real breakdown of health. In popular usage, almost any event or situation between these extremes could be described as stressful.^[1][61

 

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