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Neuroscience: From Molecules to Behaviour > Anxiety Disorders > Flashcards

Anxiety Disorders Flashcards

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1
Q

Anxiety disorder manifestations are both ______ and ______.

A

Psychological

Physical

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2
Q

We can think of anxiety disorders as…

A

…a continuum of a normal bodily response to your environment. E.g. fight or flight response (common among many mammalian taxa).

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3
Q

Much of what we see at a physiological level in someone who is highly anxious … e.g…

A

…is what we see when fight or flight response is activated e.g. increased cortisol, increased noradrenaline etc.

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4
Q

Anxiety disorders are not necessarily “stand-alone ______”

A

pathological

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5
Q

What are potential stressors?

A

They are a number of real or imagined stressors that are perceived as a threat.

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6
Q

What are some examples of potential stressors?

A
  • Failures
  • Personal losses
  • Frightening events
  • Time pressures
  • Insults
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7
Q

What bodily (physiological) effects are observed when stressors are perceived as a threat?

A
  • Autonomic emergency response
  • Shallow breathing
  • Pounding heart
  • Tense muscles
  • Digestive problems
  • Sleep disturbances
  • Fatigue
  • Psychosomatic illness
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8
Q

What psychological effects are observed when stressors are perceived as a threat?

A
  • Anger
  • Fears
  • Preoccupations
  • Self-doubts
  • Negative self-talk
  • Repeated “danger” thoughts
  • Worry about body reactions and health
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9
Q

Is there a link between bodily effects and upsetting thoughts?

A

Yes!

E.g. if you’re particularly fearful of an event, that may lead to certain bodily effects such as pounding heart AND changes to cardiovascular system can actually also effect upsetting thoughts (by leading to worry about physiological changes)!!

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10
Q

What is the end result of the bodily effects and upsetting thoughts?

A

Ineffective behaviour, such as:

  • Escape
  • (Inappropriate) avoidance of a certain event/situation
  • Indecision
  • Aggression
  • Inflexible responses
  • Poor judgement
  • Inefficiency
  • Drug use
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11
Q

What are the different types of anxiety disorder?

A
  • Generalised anxiety disorder
  • Phobias
  • Obsessive compulsive disorder (OCD) e.g. repeated hand washing which causes damage to skin
  • Post traumatic stress disorder (PTSD)
  • Panic attacks
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12
Q

Neurobiological substrates relevant to anxiety disorders include …

A

… limbic system structures (mesolimbic system, hippocampus) and the locus coeruleus

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13
Q

The ______ represents an important brain structure involved in anxiety.

A

amygdala

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14
Q

How is the amygdala involved in anxiety?

A

Involved in the recognition of external cues associated with fearful responses. I.e. allows attachment of fearful response to external stimuli.

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15
Q

Where is the amygdala found in the brain in relation to its function?

A

It’s found quite centrally. Depending on which part of the amygdala is involved, different additional brain regions can become affected.

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16
Q

What is the role of the hippocampus in anxiety?

A

Certain areas of the amygdala (involved in associated fear to external stimuli) lead to responses in the hippocampus, which is important in forming memories and memories can be associated with anxiety i.e. in PTSD.

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17
Q

The amygdala is extremely important in ______.

A

Fear conditioning.

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18
Q

Outputs from the amygdala go beyond the hippocampus and medulla. Examples are…

A
  • Leads to the activation of the periaquaductal gray and this leads to cessation of behaviour (physiological effect) -> freezing (component of emotional response). This is one example of a significant output from the amygdala.
  • Leads to activation of the motor nucleus of Vagus and this leads to parasympathetic activation (physiological response) -> ulcers, urinanation and defecation (component of emotional response)
  • Leads to activation of the lateral hypothalamus and this leads to sympathetic activation (physiological effect) -> increased heart rate and blood pressure, paleness, pupil dilation (component of emotional response)
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19
Q

How is the locus coeruleus involved in anxiety?

A

There is evidence that locus coeruleus neurons are also under the effect of GABAergic neurons. This was GABA neurotransmitter dysfunction underlies theories of anxiety.

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20
Q

If we record electrophysiologically, what’s happening in the cell bodies within the locus coeruleus, we see a change in activity dependent upon an individuals behaviour:

A
  • An experimental rodent that is quiescent, this is shown to inhibit electrophysiological activity in the locus coeruleus
  • If there are sensory stimuli that cause an increase in levels of alertness, you see an increase in electrophysiological activity in the locus coeruleus
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21
Q

Summarise how the amygdala and locus coeruleus are important in anxiety.

A

Amygdala is important in terms of making sense of what might be fearful for an individual and the locus coeruleus is important in terms of governing the overall level of activity within the brain

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22
Q

How can psychopharmacology be beneficial in the locus coeruleus?

A
  • SSRIs- they inhibit locus coeruleus neurons through an inhibitory effect on the cell body
  • there is a GABAergic input to locus coeruleus neurons (and being a GABA input, it’s going to have an inhibitory effect on locus coeruleus neurons) so using benzodiazepines (BDZs) can increase the effect of GABA and locus coeruleus neurons.
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23
Q

How do anxiolytics (e.g. benzodiazepines and barbituates) exert their effects on neurons?

A
  • They are not DIRECT agonists but benzodiazepines act as benzodiazepine binding site to potentiate the action of GABA and produce:
    - Sedation
    - Sleep
    - Anxiolysis
    - Anticonvulsant activity
  • Since GABA receptors are chloride ion channels, opening them (via BDZs) will lead to a hyperpolarisation effect as chloride ions move into the cell

I.e. they both have their own binding sites, to which they can bind and lead to opening on the ion channel, resulting in hyperpolarisation of the cell (which mimics activity of GABA)

24
Q

Historically, which group of compounds were the first to be used to treat anxiety?

A

Barbituates
However, in addition to treating anxiety, they have a low therapeutic index (easy to overdose on them, which can be fatal). Also, when consumed with alcohol you get side effects (such as respiratory depression). They also lead to dependence issues.

I.e. although effective for the treatment of anxiety, they were superseded by another group of compounds (the benzodiazepines)

25
Q

Why do you get sleep and sedation along with anxiolysis when taking benzodiazepines?

A

Because they activate GABA responses, which effectively cause an “inhibitory” tone within the CNS.

26
Q

Explain the anticonvulsant activity induced by benzodiazepines.

A

When at rest, the brain is not quiescent. There is lots of spontaneous electrochemical activity going on and this is only kept under control through inhibitory neurons, such as GABA neurons. So when there is an under-activity of GABA, you can get seizures. Hence why when you give someone benzodiazepines, you lead to an increase in GABAergic activity, which leads to anticonvulsant activity.

27
Q

Why are benzodiazepines a good group of compounds?

A
  • Chlordiazepoxide was the prototypical compound
  • They have a low incidence of tolerance
  • They have less severe withdrawal
  • They have a high therapeutic index
28
Q

The structure of benzodiazepines can affect their … and that can have some influence on whether …

A

…rate of metabolism
…the drug is used for anxiety or other conditions like sleep disorder/insomnia i.e. if a drug isn’t broken down too quickly and has a relatively longer half-life it’s better for the treatment of anxiety, whereas if you’re treating sleep disorders you want a drug with a shorter half-life so that you can get to sleep but in the morning you feel awake again!

29
Q

Chlordiazepoxide was followed by:

What is use of each compound dependent on?

A

Long-acting BDZs:

  • Diazepam
  • Oxazepam
  • Flurazepam

Short-acting BDZs:

  • Lorazepam
  • Midazolam
  • Temazepam

Use of each compound is dependent on:
- Speed and duration of action

30
Q

There exists a positive correlation between … (in benzodiazepines)

A

the effective anxiolytic dose and how potent the drug is in displacing a compound (in this case, displacing diazepam) from the GABA-A receptor. This suggests that binding to GABA-A receptors is indeed what leads to the anxiolytic effects observed.

31
Q

How has the effectiveness of benzodiazepines been tested?

A

Behavioural pharmacology:

  • Widely used to determine effectiveness of any drug being developed for treating anxiety
  • An example is the elevated plus maze where experimental animals are placed on the centre of the maze, they will go off and have a look around. Normal animal behaviour: once exploring the maze, the animal will gravitate towards somewhere where it feels more “safe” i.e. in the closed arm.
  • However, if you observe time spent in closed arms and open arms over a period of 10 mins you get a measure of the general level of anxiety of an individual
  • What you see is when you give an animal diazepam, you see that there is an increase in entries into the open arms, suggesting that the animal is a lot less anxious and able to follow its exploratory drive and spend more time on the open times
32
Q

What is a vehicle control?

A

Controls for the fact that you’re injecting stuff into the animal without actually injecting anything into it. I.e. fluid injected here is the fluid used to dissolve drugs (no drug administered here)

33
Q

What does modulation of GABA-stimulated chloride flux (%) mean?

A

This is a measurement of the movement of chloride ions into the neurons.

34
Q

What does an increase in chloride ion flux mean?

A

It means an increased activation of GABA-A receptors (because they are chloride ion channels).

35
Q

With BDZ agonists (e.g….) you see ______ in chloride ion flux into the neurons.

A

E.g. Diazepam, Midazolam, Clonazepam, Flunitrazepam

an increase

36
Q

If you use a competitive antagonist (e.g.______), you see ______ in chloride ion flux into the neurons.

A

E.g. Flumazenil

No change (not surprising since you’re not modulating GABA receptors in any way)

37
Q

If you use Beta-Carboline inverse agonists (e.g….) you see ______ in chloride ion flux into the neurons.

A

E.g. DMCM, Beta-CCM, Beta-CCE

a decrease (this is because inverse agonists have a directly opposite effect to normal agonists i.e. in the case of GABA-A receptors, this means that they will actually reduce the effect of GABA by binding to their binding sites

38
Q

What sort of response do Beta-Carbolines provoke?

A

An anxious/panicked response.

39
Q

What is the evidence for GABA-A receptors being the important receptors in anxiety disorders?

A
  • Behavioural evidence (i.e. benzodiazepines lead to anxiolytic effects)
  • Benzodiazepines lead to an increased flux of chloride ions into neurons (which we know is mediated by GABA-A receptors, which function as chloride ion channels)
40
Q

What is the endogenous ligand for benzodiazepine binding sites on GABA-A receptors?

A

There is some evidence for a natural ligand for the benzodiazepine binding site called Endozepines:

  • Natural anxiety-reducing agents
  • May be released when an individual learns how to cope with stress
  • PET scans show distribution of these binding sites throughout the cerebral cortex, so they’re quite widespread within the brain
41
Q

Which drugs are better for which types of anxiety disorder?

A

Benzodiazepines are good for GAD, PTSD, panic disorder

SSRIs are good for social phobia, panic disorder, OCD, PTSD

42
Q

What is an alternative to benzodiazepines for anxiety when they are not effective?

A

Azapirones (e.g. Buspirone) are used as an alternative to benzodiazepines.

This is a mixed full/partial agonist at 5-HTA receptors
- Initially exacerbate anxiety, and takes longer to produce anxiolytic effect BUT fewer side effects

43
Q

What is an alternative to benzodiazepines in OCD and panic disorders?

A

SSRIs

- As with buspirone, there is a delay before anxiolytic effect is produced

44
Q

How can stressful events lead to anxiety? And how does this support the serotinergic view of anxiety?

A

Corticotrophin releasing factor (CRF) is normally thought of as regulating HPA function by leading to release of ACTH and subsequently glucocorticoids.

However, there is evidence than CRF might also be functioning as a neurotransmitter in the CNS.

CRF has specific effects upon the serotinergic system e.g. Forster et al, shows that rodents are exposed to fear inducing stimuli and their behaviour is recorded, as is their levels of serotonin in distinct brain regions using micro dialysis. They found that if they look in the central nucleus of the amygdala and compare it to 5-HT in the medial pre-frontal cortex, they see that when you administer CRF we can induce freezing behaviour, irrespective of whether or not we expose them to a fearful stimulus or not. This suggests that CRF is potentially anxiogenic. The site of origin of serotinergic neurons is the dorsal raphe. Interestingly, if they administer CRF outside the dorsal raphe or inject a control fluid they don’t see freezing behaviour. So take-home message: CRF can induce anxiety response, but ONLY if you inject it into a region of the brain with serotinergic cell bodies (dorsal raphe and central nucleus of the amygdala), suggesting that the anxiogenic effects of CRF are serotonin-mediated.

There is correlation between freezing behaviour and increased levels of 5-HT in the amygdala, but the increase in 5-HT in the medial pre-frontal cortex comes much later (after you’ve lost the freezing behaviour). This suggests that 5-HT in the medial pre-frontal cortex may be associated with extinction of the freezing behaviour. So perhaps it’s involved in reducing the freezing behaviour? This is a nice example of how one neurotransmitter is potentially having diametrically opposed effects depending on WHERE in the brain they are found I.e. when serotonin is increased in the amygdala it leads to freezing behaviour, whereas when it’s elevated in the medial pre-frontal cortex it leads to a reduction in freezing behaviour.
Also a good example of how one neurotransmitter (i.e. CRF) can have knock-on effects on another neurotransmitter (i.e. 5-HT)

45
Q

What is PTSD?

A

A form of anxiety occurring after a traumatic event (war, rape, child abuse, physical assault, terrorist attacks, car accidents, natural disaster)

46
Q

What is PTSD characterised by?

A
  • Increased physiological reactivity to reminders of trauma
  • Flashbacks to the traumatic event
  • Sleep disturbance/nightmares
  • Avoidance of cues associated with trauma
  • Numbing of emotional responses/detachment
47
Q

What do imaging studies show in PTSD?

A

Imaging studies show high levels of responsiveness of amygdala to trauma cues and less activity in anterior cingulate and medial prefrontal cortices

48
Q

What is one experimental procedure for study of PTSD and brain circuits involved?

A

Fear conditioning

Determined these regions to be important in PTSD: medial pre-frontal cortex (which feeds into the amygdala). The hippocampus, feeding also into the amygdala is important in creating associations between light/sound/external stimuli with events.

The experiment: the animal undergoes a training period, during which the animal is presented with an US (inescapable electric shock) and that is paired with a CS (a tone). The animal undergoes this training period within a particular environment. After the training period, they put the animal into another chamber (might have different environmental cues) and when it hears the CS (tone) it has been conditioned to expect a foot shock (i.e. high levels of fear are observed, manifesting as freezing behaviour). Similarly, you don’t need the CS (tone) to scare the animal, sometimes just placing the animal in an environment similar to that of the training period (i.e. original chamber) will lead to fear. In this case, even without the CS stimulus you get high levels of fear (freezing behaviour).

In terms of looking at ways of treating PTSD, you need to look at how to “un-condition” that animal. After the training period, you put them into a new environment and present them repeatedly with the CS (tone) and if you do that enough, the animal will eventually break the link between the CS and the foot shock- levels of fear will be reduced (less freezing behaviour). Eventually you reach a phase known as “extinction” = link between US and CS is broken.

49
Q

How do fear conditioning studies help elucidate regions of the brain involved in PTSD?

A

The studies undoubtedly show that an element of memory must be playing a role in the association between external cues/stimuli and a fear response (caused by the previous trauma).

When memories go from short- to long-term, you see changes in the brain in the form of LTP. Initially, it’s electrical changes, followed by eventual gene transcription changes (i.e. certain genes important in increasing synaptic strength are expressed).

This means that from an epigenetic POV we can ask “can these processes involved in long-term memory be modified by epigenetically manipulating the animal?”

50
Q

What are some examples of where we get epigenetic regulation of gene expression?

A
  • Acetylation of histone proteins (relaxes the winding)
  • De-acetylation of histone proteins (more tightly winding DNA = more likely to be transcribed)
  • Methylation of histone proteins
  • DNMT (DNA methyltransferases) add methyl groups to DNA, sometimes associated with DNA silencing
51
Q

What might happen if we inhibit some of the epigenetic regulators such as HAT and HDAC?

A

We can administer them during the consolidation phase (fear conditioning is happening), or when the extinction phase is occurring (link between CS and US is broken)

52
Q

Extinction is ______ rather than “un-learning” of…

A

new learning

of…the association between the US and CS

53
Q

Are there other mechanisms that can potentially be used to treat PTSD, in terms of breaking the association of US and CS?

A

This is where the relevance of the glutamatergic mechanisms come in.

There’s been some interesting research going on with exposure of conditioned individuals’ (rodents) to xenon (noble gas, antagonist of glutamatergic NMDA receptors). What we see is that after the conditioning phase if you expose them to xenon (compared to air, nothing etc.) in the consolidation period, and then test them again in 48 hours, followed by another 48 hours, followed by 2 weeks, you see that rodents exposed to xenon you get significantly decreased freezing behaviour (both 48 hours after and longer) AND this effect is maintained even at 2 weeks. This shows that xenon leads to an interruption between association of US and CS. This is seen in both “context alone” and “context+tone” results.

I.e. xenon leads to disruption of the consolidation of association between US and CS, as shown by reduced freezing behaviour when given xenon.

54
Q

What are current pharmacological PTSD therapies and what are their problems?

A
  • Benzodiazepines and Beta-adrenoreceptor blockers

- Some individuals don’t respond as well

55
Q

What are current behavioural therapy options for PTSD?

A

Exposure-based therapy in which the individual is exposed to a reimagining of original trauma/a cute associated with the original trauma in the absence of an aversive outcome

HOWEVER, over time the original association can return

56
Q

What are potential future therapies to explore, to counteract the return of the association?

A
  • Targeting epigenetic mechanisms in the infralimbic medial pre-frontal cortex (a region linked specifically with extinction) to improve strength and persistence of extinction

Neuroscience: From Molecules to Behaviour (5 decks)

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