Anxiety

Question 1

Define pathological anxiety

Answer 1

when stress responses are excessive and have direct impact on an individuals ability to lead a normal life

Question 2

Prevalence of anxiety?

Answer 2

21% NIMH

2:1 female:male ratio

often co-mordid with other disorders such as depression

Question 3

Animal models used in anxiety research?

Answer 3

1. elevated plus maze

2. open field test

Question 4

What is aetiology of anxiety disorders?

Answer 4

Multifactorial - environmental, genetic, psychological, developmental

Genetic factors have been implicated in twin studies and family studies but in lots of anxieties clear that stress plays a major role. For instance, PTSD follows a traumatic event but arguably these individuals are more predisposed to PTSD.

Question 5

What does stress activate?

Answer 5

The paraventricular nucleus of the hypothalamus

Question 6

Describe the HPA axis

Answer 6

The hypothalamic pituitary adrenal axis.

Activation of the paraventricular nucleus of the hypothalamus leads to the release of corticotrophin releasing hormone (CRH) that acts on the pituitary gland to release adrenocorticotrophic hormone (ACTH). This in turn acts on the adrenal gland to release cortisol which has both metabolic and regulatory actions.

Question 7

Why is cortisol feedback essential for HPA axis function?

Answer 7

Cortisol concentration acts as a negative feedback system and shuts of the activation of the HPA axis. Steriod feedback works at different levels of the HPA -

1. In the hippocampus + other limbic areas it increases the inhibitory input into the paraventricular nucleus of the hypothalamus.
2. in PVN it switches off the release and synthesis of CRH
3. It pituitary it switches off the synthesis of adrenocorticotropic hormone (ACTH)

SUSTAINED ACTIVATION OR REDUCED FEEDBACK WILL LEAD TO LONG-TERM HIGH STEROID LEVELS WHICH IN TURN WILL ALTER BRAIN NEUROCHEMISTRY.

Question 8

Give some experimental data that demonstrates that the HPA axis is altered in anxiety patients

Answer 8

Implicated both in patients and animal models

1. In PTSD patients they have elevated CSF levels of CRH demonstrating that the -ve feedback isn’t working as it should be and corticosteriods are just being continually released.
2. When rat given CRH, the rats exhibit more anxious behaviour such as less time in the centre that indicates they are more anxious. This demonstrates that increase CRH levels leads to increased anxiety.

Question 9

What are the types of corticotrophin releasing hormone (CRH) receptor

Answer 9

CRF-R1 and CRF-R2

CRF-R1 mediates the anxiolytic effects of stress –> arousal, anxiety like behaviour, disruption of sleep

Question 10

What does CRH stand for?

Answer 10

corticotrophin releasing hormone

Question 11

What does ACTH stand for?

Answer 11

adrenocorticotrophic hormone

Question 12

What neurotransmitters are indicated in anxiety?

Answer 12

5-HT, NA, GABAa

Question 13

What is NA proposed involvement in anxiety? What is the evidence for this proposed involvement (3 different things)?

Answer 13

Exact nature of NA dysfunction in clinical anxiety remains unclear. In general anxiety disorder it is preposed that chronic, hyper secretion of NA.

> Defective alpha2-adrenoceptors (inhibits pre-synaptic NA release - also on terminals of 5-HT neurones) result in increased NA release and thus increased cortical excitation.

> PTSD patients have elevated urinary concentrations of NA in the CSF and urine.

> The clonidine challenge is used as a means of assessing alpha2-adrenoreceptor function and with this challenge patients with anxiety disorders show defective alpha2-adrenoreceptor function. Something that can’t be confirmed with imaging yet.

> Yohimidine is a alpha2-adrenoreceptor antagonists and increases DA concentrations and this is ANXIOGENIC.

Question 14

What is 5-HT preposed role in anxiety? What experimental data supports its role?

Answer 14

> Decreased 5-HT1a receptors (inhibit excitability) and therefore decreased inhibition leads to increased excitation.

Decreased 5-HT1A binding (same as depression) and this decreased binding is all over the brain - not just in one specific brain region.

5-HT1A NO mice show increased anxiety in the elevated plus maze task –> spend lots of time in the open and less time in the closed regions.

Question 15

What is the role of GABA in anxiety?

Answer 15

GABAergic dysfunction are causally related to the symptoms of anxiety –> enhancing GABAa transmission (benzodiazepines) is a powerful mechanism to inhibit the experience of anxiety (anxiolysis). Neuroimaging has given a new insight into GABAa involvement in anxiety.

> decreased GABAa receptors = decreased inhibiton and increased excitation.

> In PET scan using a GABA-A binding ligand, a reduction of GABAa receptors across all regions of the brain was shown in patients with panic disorder. Greatest decrease in areas that had previously been associated with anxiety such as the temporal cortex and orbitofrontal cortex.

> Localised reduction in benzodiazepine binding also observed (acts on GABAa receptors) throughout the brain in generalised anxiety disorder.

Question 16

In general, what are the 4 main causes of anxiety?

Answer 16

1. increase in stress/ increased CRH in CSF -> sustained activation or reduced inhibition leads to chronic high-levels of cortisol/ steroid and leads to altered neurochemistry.
2. Defective alpha2 adrenoceptors
3. Decrease in 5-HT1a receptors
4. Decrease in GABAa receptors.

All lead to an INCREASED EXCITATION in the cortex, hippocampus and amygdala –> anxiety but remember that much of the aetiology of anxiety is unknown and revealing the aetiology could lead to successful treatments!