stress and mood

The Stress Response

response to threats

• Some aspects of the response to many “stress-full” conditions are shared

• Being attacked

• Attacking somebody

• Hunger

• Cold

• Overheating

• Has effects throughout the body

ANY THREAT TO HOMEOSTASIS

Stress Stimulates the Sympathetic and Inhibits the Parasympathetic Nervous System

INCREASED sympathetic DECREASED parasympthetic on excited one suppressed

this causes symptoms associated ie less saliva dry mouth, inc hr, constricts blood, sweating ie cold clammy hands

Systems Stimulated during Stress: Adrenal Hormones

nordadrenaline is released as well as 2 hormones

Both released by the adrenal glands, the adrenal medulla and the adrenal cortex.

adrenaline medulla releases noradrenaline adrenaline and norephiphenine (stimulated by preganglionic stimulation release of acetylcholine that causes this release of hormone) SAME TIME AS ACTIATION OF SNS

The adrenal cortex releases the hormone cortisol which release energy from energy stores from glucose (released in response to adrenaocortotphic hormone to make cortisol into its final form from the HPA axis this release is caused by crh, which comes from the hypothalamus ) DUE TO ACTIVATION OF HPA AXIS

Paraventricular Nucleus (PVN)

Systems Stimulated during Stress: Adrenal Hormones

• The adrenal cortex

Systems Stimulated during Stress: Adrenal Hormones

• Pre-ganglionic neurons of the sympathetic nervous system stimulate the adrenal medulla to release adrenaline and noradrenaline into the blood stream. [adrenal medulla cells are modified post-ganglionic sympathetic neurons]

• The adrenal cortex – makes and releases cortisol (in humans). – This is stimulated by Adrenocorticotropic hormone (ACTH), released by the anterior pituitary gland into the blood. – ACTH release is in turn stimulated by corticotropin-releasing hormone (CRH), which is released by neurons in the paraventricular nucleus of the hypothalamus into the blood vessels in the stalk of the pituitary gland.

Systems Stimulated during Stress: Adrenal Hormones

• Pre-ganglionic neurons of the sympathetic nervous system stimulate the adrenal medulla

Activation of the Stress Response (how does the body trigger the body to prepare) 1) Amygdala (Telencephalon):

– Central Nucleus of the Amygdala (physical challneges ie blood loss)

• In response to homeostatic challenges

– Medial Nucleus of the Amygdala

• In response to psychogenic challenges (psychological ie danger from a predator)

– Amygdala activates the sympathetic nervous system (via lateral hypothalamus) and the HPA axis (via disinhibition)

-This will activate the stress response DIRECT ACTIVATION

Activation of the Stress Response 2) Subgenual Anterior Cingulate Cortex (sgACC - Telencephalon):

– Indirect activation

when active also activate the stress repsonse

both sympathetic nervous system and hpa axis (activated toegther but different onsets)

Activation of the Stress Response Activation of either brain area:

– activates the sympathetic nervous system – activates the HPA axis

regulation of the HPA axis to shut down the stress reponse

must shut down the stress response as body becomes ineffective during stressful situations

HPA axis is activated in stress and cortisol icnreases, when this stops cortisol will be cleared. for it to go down need the clearing and stop producing more of the cortisol, what stop this:

-HPA axis neg feedback

-hpa acis negative feedback in hippocampus

-hpa axis dorsal anteriro cingulzte cortex

HPA axis negative feedback

Direct negative feedback of Cortisol on the PVN via glucocorticoid receptors (GR)

when cortisol reaches a certain level its detected and the ACTH is released so less cortisol is made so cortisol goes down

this is how our body regulattes cortisol as we need it at all times

HPA axis: negative feedback (anterior) Hippocampus (Telencephalon)

– Indirect inhibition

– Contains many MR and GR (both cortisol receptor) (GR when really high MR regular maintenance)

– Intermediate-term feedback: returns psychogenic stress response back to baseline after a acute stress response

-Many receptors for cortisol

The hippocampus becomes active, and this suppresses the hpa axis

HPA axis: negative feedback Dorsal Anterior Cingulate Cortex (Telencephalon):

– Indirect inhibition

– GR receptors (cortisol receptor)

– Early and intermediate-term feedback

-shortens the peak and doesn’t let it go too high ie how high and how long it lasts not too strong or long

Major (Unipolar) Depression

• Some Symptoms:

• depressed mood

• change in appetite

• sleeping problems

• lethargy

• fatigue

• feelings of worthlessness

• This has to be persistent and debilitating, and not easily explained by outside factors

• Twice as common in women as in men

Depression and the HPA axis

• Dysregulated HPA axis is common in affective disorders -constantly high cprtisol rather than the normal carcadian rythym that animals have. most have the peak but no trough, flattens up stress response

• Both pathological increases and decreases in cortisol (due to other causes) can lead to depressive symptoms. ie cushings disease can be linked to depression and addison’s disorder. link between coritols hpa and depression

dysregulated some high some low cortisol

Chronic Stress: Positive Feedback

• Amygdala stimulates the HPA axis hpa releases cortiosl

• Glucocorticoids activate the Locus Coeruleus

• Locus Coeruleus has noradrenergic projections which activate (among other brain areas) the Amygdala

short-term stress will cut this short, but if there isnt, it's self-stimulating and can spiral out of control

Chronic stress is a risk factor, inducing chronic stress leads to depression

Chronic Stress: Reduced Negative Feedback

• Repeated stimulation by glucocorticoids reduces the sensitivity of receptors in the hippocampus

• Chronically high glucocorticoids also damage hippocampal neurons, leading to a further reduction of negative feedback (in the long term)

chronic stress damages the mecahnisms that are there to control the negative feedback so its easier for it to sprial out of control not clear why the damge doesnt effect everyone like this

Reduction of the stress response is a common theme among effective treatments

Major Depressive Disorder and Sleep

key elements of REM sleep differences in depressed people

REM sleep is entered too early

REM deprivation as a treatment

• REM sleep deprivation has long-term effects

• Many anti-depressants (but not all) suppress REM sleep

Monoamine Effects of Chronic Stress

• Depletion of noradrenaline from Locus Coeruleus • Depletion of serotonin from Raphe Nuclei • Depletion of dopamine from Ventral Tegmental Area to n. Accumbens and prefrontal Cortex

Major Depressive Disorder: Pharmacological Treatments

• Targeting mono-amines • Ketamine

Role of Mono-amines in depression

• Reserpine (Mono-Amine antagonist) induces depression

• Lower levels of 5-Hydroxyindoleacetic Acid (5-HIAA) in Cerebrospinal Fluid

• Tryptophan depletion experiments

Targeting Monoamines: SSRIs

• Usually ingested (pills) • All very lipophilic • Different pharmacokinetics for different drugs: – Fluoxetine (Prozac): slow uptake, half-life 1-4 days – Fluvoxamine (Faverin): bit faster, half-life 8-28 h – Citalopram (Cipramil): bit faster, half-life ~36 h

SSRIS DONT WORK FOR A FEW WEEKS why in the first 2 weeks

adaption of autoreceptors

how do ssris work

how do autoreceptors adapt

Adaptation of autoreceptors Summary

• Initially, SSRIs increase 5HT levels in the synapse (by blocking reuptake channels)

• Autoreceptors respond to this and reduce 5HT release through negative feedback

• This leads to no change in 5HT levels at the target cells (lower release, but stays in synapse for longer, cancelling each other out)

• It takes about 2 weeks for the autoreceptors to adapt (tolerance) to the higher levels of 5HT

• This adaptation dials down the negative feedback, leading to a gradual increase in release of 5HT

• Since 5HT reuptake is still blocked, now levels of 5HT at the synapse do go up above original levels, leading to more 5HT binding to post-synaptic receptors

SSRIs BUT: • SSRIs only work after several weeks why?

– First two weeks: adaptation of auto-receptors – Further weeks: • Could they have the opposite effect? • Could be normalization of HPA axis feedback? • Maybe the effect is a healing process?

Adult hippocampal neurogenesis

• In animal models of depression, adult hippocampal neurogenesis is suppressed • Anti-depressants increase neurogenesis • Time course of increase = time course of effectiveness • Destroying adult neurogenesis prevents anti-depressant effects • Exercise increases adult neurogenesis and improves depression symptoms

ketamine

• Dissociative anaesthetic and analgesic • Taken through different routes: – Snorted as a powder – In pills – Injected IV (including clinical use) • Initial biological half-life 10-15 minutes (overall on average about 45 minutes)

ketamine short term effects

• Low doses: – Lightness & euphoria – Disconnection of thoughts and from the world – Strange perceptions • Higher doses – Mind-body disconnect – K-holing (unresponsive to the world, hallucinations)

Ketamine physiological action

• NMDA-R Antagonist • Responsible for – Anaesthesia – Dissociation & Hallucinations – Amnesia – Analgesia (in the spinal cord)

Ketamine as an antidepressant

• Sub-anaesthetic dose can have a profound effect within hours of injection

• Typically a course of several doses per week for a few weeks

• Does not last more than a few months

• Seems to work through new synapse formation in anterior cingulate cortex

Ketamine long-term effects

• Memory/cognitive problems (possibly reversible)

• Bladder and kidney damage (irreversible)

• Abdominal cramps (k-cramps)

Ketamine addictiveness

• Physical addictiveness: – tolerance does build up – withdrawal symptoms include psychotic features

• Psychological addictiveness: – Less known about it – NMDA-R antagonists can influence dopamine release in nAcc

Ketamine Legal Status

• CLASS B: – Illegal to possess – Illegal to sell – Illegal to give away – Possession: up to 5 years + unlimited fine – Dealing: up to 14 years + unlimited fine

Anxiety disorders

• A range of disorders, characterized by extreme worry, fear, and chronic stress

• Often comorbid with depression and other disorders

• To be a disorder, it has to last more than 6 months, be inappropriate to the situation, and be debilitating

• Twice as common in women than in men

Treatments for anxiety

• Talking therapies (e.g. CBT) • Exposure therapies • Drug treatments – SSRIs – Beta-blockers – Benzodiazepines

Benzodiazepines: Sedatives and Anxiolytics

• Usually ingested (pills) – Valium, Xanax, Librium, Klonopin, Rohypnol,...

• Reach max. blood concentration in about 60 minutes (different drugs, different kinetics) • Lipid solubility varies from drug to drug

• Depending on the exact chemical, half-life can be 90 min - 6 days (including active metabolites)

Benzodiazepines Short Term effects

• Effects: – Sleepiness (sedative) – Reduction of anxiety – Anterograde amnesia – Muscle relaxation – Mental confusion

Benzodiazepines Clinical use:

– Sleeping pills (against insomnia) – Anxiolytic (against anxiety and panic disorders) – Recovery from alcohol withdrawal – Anticonvulsant (in combination with other drugs)

Benzodiazepines Physiological Action

• Facilitation of GABA-A receptors (increases inhibitory processes)

• GABA-A receptors exist throughout the brain

– Cerebral cortex (amnesia & confusion) – Hippocampus (amnesia and anti-epileptic) – Spinal cord, brain stem (muscle relaxant) – Cerebellum (muscle relaxant, anti-epileptic) – Amygdala, orbitofrontal cortex, insula (anxiolytic) – Tuberomammillary nucleus, etc. (hypnotic)

Benzodiazepine Long-term effects

• Mental confusion

• Induction or extension of dementia

• Learning problems

can improve after cessation of the medication

Benzodiazepine Addictiveness • Physical dependence

– Will develop even with therapeutic doses – Withdrawal symptoms include: • Anxiety (possibly higher than before) • Insomnia • Restlessness • Agitation • Irritability

Benzodiazepine Addictiveness • Psychological dependence:

– Alcoholics can be sensitive to benzodiazepine addiction as well

– There are GABA-A receptors in the Ventral Tegmental area and the N. Accumbens as well

Benzodiazepines Legal Status

• CLASS C: – Illegal to possess (except by prescription) – Illegal to sell (except by pharmacists) – Illegal to give away (except by prescription) – Possession: up to 2 years + unlimited fine – Dealing: up to 14 years + unlimited fine – Driving under influence: heavy consequences

Summary

• Chronically activated stress response can lead to mood disorders in susceptible people • SSRIs and other drugs targeting monoamines are prescribed for depression • Ketamine and psychedelics are possible new treatments for depression • Benzodiazepines are prescribed for anxiety and insomnia

which is the neurotransmitter used by the post-ganglionic neurons of the sympathetic nervous system?

nordarenaline

ie heart beat faster etc

which stress hormone peaks first

The adrenaline as cortisol must be stimulated by hormones, whereas the other is electrical activation ie neurone response, which is quicker then 2 hormones