Anxiety Flashcards
What is the link between anxiety & depression?
What is the focus?
How is pathological anxiety different to normal?
What is the ethological way of testing anxiety in animals?
What is the conditioned way of testing anxiety in animals?
Precedes depression - 60% comorbidity
Chronic stress
When it interferes with normal productive everyday activities
Taking advantage of animal’s natural behaviour
Train an animal & see its response
What kind of testing is the elevated plus maze?
What is the structure of the elevated plus maze?
What is put on either enclosed side?
What does the mouse do?
What does this show?
Ethological
Cross-shaped maze 50cm above ground with two open arms which is avoided due to height aversion & two arms with enclosed sides
One is control (nothing) & other is anxiogenic (cat urine)
When in anxiety state (cat urine) induces behavioural suppression & natural tendency to explore is decreased & spends more time in low anxiety control box - higher avoidance of other box
Conflicts induce behavioural suppression (e.g mice natural tendency for exploration)
What is the basis of the contextual fear conditioning test?
What is the basis of the acoustic-cued fear conditioning test?
What kind of test uses both ethological & conditioned tests?
How does it work?
How can anxiety be measured?
What happens when the rats are given an anxiolytic drug?
Mouse is given shocks in one cage & moved to cage without shocks - shows no symptoms
Mouse given shocks at the same time as a noise - moved to cage without shocks but when noise played displays same symptoms
Geller-Seifter conflict test
Animal presses button for food where 10% chance of electric shock (light shines)
How much the animal stops pressing
Number of responses increase - fear of being shocked decreases
What is the problem with measuring anxiety with these tests?
How can this be overcome?
What is the type of drug used to treat anxiety?
State anxiety (of an unpleasant event - transient) and trait anxiety (long-term tendency related to health) - all models measure state anxiety
Chronic stress used to induce trait anxiety & genetically select rats/mice over multiple generations for lines of anxious rats which can be compared to non anxious/wildtype ones
Benzodiazepines
On what receptors do benzodiazepines work on?
How do they act on it?
What do they hence mediate?
What mutation in GABA-A blocks BZD sensitivity?
Which subunits can have this mutation & which don’t?
Therefore what does this say about different bzds?
What are the side effects of BZDs? 5
GABA-A (ion-ligated) inhibitory receptor
Agonist - binds to binding site positioned at alpha-gamma subunit junction resulting in increased Cl- entering post-synaptic neurone & hence inhibition - acts allosterically such that when GABA binds further induces inhibitio
Inhibition of fast synaptic transmission
Histidine 101 in alpha subunit - prevents binding
a1, a2, a5 have it - a4, a6 don’t
Different affinities, specificities & half-lives for subunits
Aggression, sedation, anterograde amnesia (can’t remember new things), acute toxicity & dependence (addiction)
How can buspirone act as an anxiolytic drug?
What else can it bind to?
Therefore, how does it act as anxiety medication?
How could it be better than BDZs?
Worse?
What other type of drug binds to GABA-A receptors at a different binding site?
Why are they no longer used to treat anxiety? 4 things
Partial 5HT1A receptor agonist - inhibitory autoreceptor which reduces serotonin/5-HT release
Inhibits dopaminergic & noradrenergic receptors but mainly acts through 5-HT
Decrease blood pressure & heart rate by inducing peripheral vasodilation
Fewer side effects & no dependence
Takes days/weeks to work
Barbiturates
- Sedative - induces sleep by reducing REM which causes rebound in REM after withdrawal
- Cognitive side effects - mental clouding, loss of judgement, slowed reflexes
- Increase liver microsomal enzymes - enhancing drug metabolism & reducing its effectiveness & other drugs
- Dependence - termination leads to hyperexcitability withdrawal syndrome (like alcohol)
How is benzodiazepine onset of action determined?
What are the short acting BDZs and how do they work?
What are other side effects of bdzs?
Why are they the best form of medication?
Lipid solubility - higher it is more quickly absorbed across BBB & readily move out of brain into other tissues
Temazepam & lorazepam - metabolised in 1 step into inactive metabolites
Mild sedation (decreases with use), hypnotics (shorten time to fall asleep & increase duration sleep), anticonvulsants (seizures/epilepsy), muscle relaxants
Most effective, safer/high therapeutic index (don’t increase number of liver microsomal enzymes), no withdrawal symptoms on termiantion, lower dependence
What SSRI is used to treat anxiety?
How does it do this?
What part of the brain is responsible largely for anxiety?
What happens to this part of the brain in social anxiety?
Fluoxetine/prozac
Prevent re-uptake of 5-HT/serotonin - related to depression
Amygdala
Over activation in response to emotional faces - severity of symptoms - since social anxiety is the fear of being evaluated/criticised by others
What is the amygdala connected to?
What did Kluver & Bucy in 1939 discover?
What is the amygdala in humans responsible for?
How can this be shown?
What is seen in patients with anxiety?
What about healthy people?
How can the degree of anxiety be measured?
What is also seen in anxious people?
What do animal models demonstrate?
Nucleus accumbens, hippocampus & PFC - all involved with mood
Bilateral lesions (abnormal tissue) of amygdala associated with fear - monkeys with temporal lobe lesions didn’t respond to aversive stimuli (snakes) or learned fear (classical fear conditioning)
Recognising emotional faces - fear/threatening ones - Ekman faces
functional MRI
Increased activation of amygdala in response to emotional faces & fearful stimuli
Negative emotional stimuli activate amygdala
More overactivation = more severe disorder
Amygdala inactivation/lesions inhibit tests for anxiety & inhibit learnt fear
High amygdala volume
Where do BDZ’s go once crossed the BBB?
What happens when BDZs/anxiolytics given to animals with inactivated amygdala?
What isoform of the GABA-A receptor is found in the amygdala?
Where else?
where is a1 expressed & what do either isoform control?
Directly to amygdala - binds there
Animals do not respond
a2
hippocampus
other areas - results in sleep effects & no axiolytic activity
a2 - anxiolytic activity without sleep disturbance
How does the septohippocampal pathway contribute towards anxiety?
How does the neurogenesis in the dentate gyrus contribute towards anxiety?
Structures between hippocampus & septum - septum contains cholinergic, GABAergic & glutamatergic receptors projecting to hippocampus
Neural stem cells in ventricles & hippocampal dentate gyrus - decreased neurogenesis results in depression/anxiety & that effective treatment requires intact neurogenesis
What is optogenetics?
What is channel rhodopsin 2?
How is it activated?
What is halorhodopsin?
how is it activated?
Therefore how can you use these to resolve complex circuitry?
What is the limitation?
What are the 2 ways of putting this into practice?
Allows genetically defined activation/inhibition of neurones
Calcium channel that allows calcium/cations & activates neurones
Exposure to blue light
Chloride channel that inhibits neurones with Cl- entry into neurone
Exposure to yellow light
Shine light at projections of the amygdala & this affects the neurones in a specific area of the brain - not to the extent to which they are projected - allows to separate out the roles of different projections of the amygdala
Opsins are genetic - can only be expressed in certain cells
- Genetically mutating amygdala neurones & shine light on them to fire an action potential
- Shine light on the amygdala neurone axon terminals (point where they connect to downstream neurones) to identify effect on downstream structures of amygdala neurone
If you were to shine a light on genetically modified mice amygdala neurones inside the elevated plus maze, what would you expect to occur? 2 outcomes
How could you use optogenetics and avoidance/preference to test the amygdala?
If the amygdala projections had an effect on anxiety - mouse would go between two closed/walled arms. If the amygdala projections did not however - then the mouse would keep its nature to explore & go within 4 arms equally
Control stimulation box & other box has light to stimulate amygdala neurones - if amygdala projection confers anxiogenic activity then mouse will spend more time in control
What is the BNST?
How is optogenetics used to inhibit the BNST signalling?
What happens to the open-arm time of the mouse with this mutation?
What happens to respiratory rate?
What happens with the same experiments when channelrhodopsin 2 has been inserted into amygdala axons & blue light shone onto the BNST terminals?
What does BNST do?
Therefore what is it?
How can you test the effects of the projections from the BNST?
Bed nucleus of stria terminalis that receives input from the amygdala & projects to the hypothalamus, ventral tegmental area & parabrachial nucleus
Halorhodopsin inserted into amygdala axons & yellow light shone - inhibiting signalling to BNST (as amygdala upstream)
When amygdala axons inhibited, much lower open-arm time suggesting that signalling from amygdala to BNST is promoting open-arm time - therefore inhibiting suggests there is increased anxiety
Increases - arousal & alertness after inhibition
Increase open-arm time & reduce respiratory rate - activity of connection decreases anxiety (amygdala projection to the BNST)
Controlled by amygdala input & activation results in relief from anxiety
Anxiolytic
Channel rhodopsin in the BNST projections & shine blue light on the projection axon terminals of the 3 designated brain areas
What did the open-arm test of the hypothalamus result in? (measure of risk avoidance)
What did the respiratory rate test of the hypothalamus result in? (measure of anxiety/arousal)
What did the 2-chamber preference test (avoidance-preference) of the hypothalamus result in?
What does this suggest?
Increased open-arm time on activation - showing relief in anxiety - anxiolytic
No effect
No effect
Activation of the BNST axons in the hypothalamus controls risk avoidance
