Lecture 3

• Stress


  A combination of physical and psychological features, normal adaptive responses if they subside
• Different kinds of stress

  • Eustress
  • Anxiety
  • Distress
• Eustress


  • Acute stress
  • Physical = tachycardia, hypertension, sweating, GI activity
  • Psychological = alertness, anxiety
  • Fight or flight - normal stress response to acute pressure
• Anxiety


  • Fearful anticipation of a perceived threat
• Distress


  • Chronic stress
  • Unrelenting pressure for long periods with usually psychological stressors but can be physical
  • Lead to pathological stress response
  • Physical symptoms = tachycardia, hypertension, shortness of breath, sweating, generalised muscle ache and tension headache, GI problems
  • Psychological = memory impairment, insomnia + tiredness, irritability, depression and anxiety
  • Anxiety doesn't subside/out of proportion to threat
• Generalised anxiety disorder


  • Persistent anxiety >6 months
  • Fear of future events/personal safety
  • Often present with somatic complaints
• Obsessive compulsive disorder

  • Obsessive repetitive thoughts often negative
  • Counteracted by compulsive behaviours providing temporary relief
• Panic disorder


  • Sudden unexpected panic attacks
  • Intense, recurrent fear might die/be ill
  • Palpitations, tremor, dizzy, chest pains
  • Fear of a certain place result in phobic avoidance = agoraphobia
• Phobic disorders

  • Excessive fear disproportionate to specific situation
  • Generally predictable thus phobic avoidance
  • Social phobia = excessive fear of social situations, fear of being negatively scrutinised, humiliated
• PTSD


  • Onset delayed weeks to months following intense traumatic experience
  • Re-experience of trauma (flashbacks)
  • Triggered by sensory cues so develop avoidance symptoms
  • Hyperarousal with hypervigilence
• Factors increasing likelihood of developing anxiety disorders


  • General genetic predisposition
  • Behavioural inhibition temperament (BI) - low threshold for amygdala arousal due to unfamiliar situation
  • Early experiences with lack of control situations (neglect)
  • Active avoidance of anxiety-provoking situations can reinforce anxiety
• Pathways involved in stress responses

  • CNS (behavioural)
  • HPA axis (endocrine)
  • Autonomic NS
• CNS role in stress response

  • Threat is perceived as sensory stimuli and signals are sent to the thalamus, which sends signals to the basolateral side of the amygdala
  • Amygdala = threat is appraised, integrated and response is co-ordinated
  • Fear learning (conditioning) - amygdala associates stimuli with consequences of experience (fear) = acquisition
• Circuits of behavioural stress response

  1. Signals from basolateral to central nucleus of the amygdala

  2. Central nucleus releases CRF (corticotrophin releasing factor/hormone), peptidergic neurotransmitter

  3. Signals to striatum, locus coeruleus and hypothalamus (paraventricular nucleus)
• CRF's role in stress response

  • Activates locus coeruleus to produce NA, stimulating vagal nuclei to activate parasympathetic effects
  • Activates the hypothalamus (paraventricular nucleus), activating sympathetic effects
  • Behavioural activation - psychomotor activity, arousal/agitation
• The psychological stress of 15 min exposure to the sight and sound of rats on a foot-shock floor increases CRF mRNA in the amygdala
• Effect of CRF on behaviour

  • CRF in locus coeruleus (LC) and cerebral aqueduct increased spontaneous activity indicating arousal and agitation
  • CRF in cerebral aqueduct increased locomotor activity slightly
  • High levels of CRF in cerebral aqueduct inhibits spontaneous activity and locomotor activity indicating freezing
• Circuits involved in autonomic stress responses

  1. BL amygdala → CN amygdala → striatum, LC and hypothalamus (CRF)

  2. LC → NA → vagal nuclei → PS effects (urination, GI activity)

  3. PV nucleus → symp effects (cardio function in anticipation of threat)
• Circuits involved in endocrine stress responses

  1. Amygdala → CRF → hypothalamus PV nucleus → Symp NS

  2. PV nucleus → CRF → pituitary → ACTH → adrenal cortex + medulla → cortisol + adrenaline

  3. -ve feedback - glucocorticoid receptors + mineralocorticoid receptors
• Functional MRI showing increased activity of the left amygdala in PTSD subjects exposed to fearful images
• Combat-related PTSD have elevated levels of CRF in cerebral spinal fluid (CSF)
• Some PTSD studies have decreased urinary cortisol levels
• Some PTSD studies have no changes in urinary cortisol in women = related to age, sex
• PTSD hypothesis


  • ↑glucocorticoid receptor feedback sensitivity
  • Enhanced response to low dose dexamethasone suppression test
  • ↑ glucocorticoid receptor density (lymphocytes)
  • CRH levels in CSF increase in PTSD
  • Cortisol levels decrease/no difference in PTSD
  • Dexamethasone response↑in PTSD
• Panic disorder ↑/— cortisol levels
• Panic response ↑/— ACTH response to stressor
• Subtle dysfunction on HPA axis may be a result of comorbidity with depression
• Phobic disorders/panic disorders/PTSD all show increase in sympathetic NS activation
• Plasma NA in response increases in GAD, panic disorder + PTSD
• Evidence of α2-adrenoceptor dysfunction

  • Injection of a α2-adrenoceptor antagonist raises NA levels in controls = inhibitory autoreceptor is blocked
  • Injection of a α2-adrenoceptor antagonist has no effect on NA levels in corticosterone = inhibitory autoreceptor is desensitised
  • Rats — repeated cold stress: ↑NA released in response to novel stressor, ↓α2-adrenoceptor expression in brain, Normal ↓ NA release in response to α2-adrenoceptor agonist clonidine is blunted
  • Humans - social anxiety disorder: Normal ↑ growth hormone levels in response to clonidine is blunted
• Decreased 5-HT1A receptor binding in anxiety disorders
• Elevated plus maze + elevated T maze - 5-HT1A k/o mice show increase time in closed arm and decreased time in open arm, meaning increased anxiety due to ^ 5-HT levels
• Chronic stress v 5-HT1A receptor expression