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YEAR 2 - The Nervous System > 25. Psychiatric Disorders and Psychopharmacology (HT) > Flashcards

25. Psychiatric Disorders and Psychopharmacology (HT) Flashcards

1
Q

Name the medicines that were classed by the WHO as essential for the treatment of psychiatric illnesses.

A
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2
Q

What are psychotropic drugs?

A
  • They are drugs that affect the way we think and behave.
  • Since the 1950s, they have revolutionised the treatment of psychiatric illnesses.
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3
Q

Summarise the general way in which psychotropic drugs have their effect.

A
  • Molecular targets include receptors, transporters, enzymes and ion channels.
  • There may also be slowly-developing changes that are triggered by action on the primary target (neuroadaptive changes).
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4
Q

Name the main categories of psychotropic drugs and their effects.

A
  • Anxiolytic/Sedative -> Drugs that reduce anxiety and cause sleep
  • Antidepressant -> Drugs that alleviate the symptoms of depression
  • Antipsychotic (antischizophrenics) -> Drugs that alleviate the symptoms of schizophrenia
  • Psychostimulant -> Drugs that cause euphoria and wakefulness
  • Psychotomimetic (hallucinogens) -> Drugs that cause disturbances in perception and behaviour that cannot be classified into stimulant or sedative.
  • Anticonvulsants -> Drugs used to reduce seizures.

Also:

  • Mood stabilisers -> Drugs used to treat disorders characterised by mood swings. Not really a mechanism, so can be sub-categorised into lithium, anticonvulsants and antipsychotics.
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5
Q

Name some psychotropic drug types, their alternative names and their applications.

A
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6
Q

What other classes of drugs act on the brain, but are not usually classified as psychotropic?

A
  • General anaesthetics
  • Analgesics
  • Nootropics
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7
Q
A
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8
Q

What neurotransmitter system do psychotropic drugs target?

A

They can target various NT systems.

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9
Q

What are some common symptoms of anxiety?

A
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10
Q

What mechanism is thought to cause anxiety?

A

An increase in 5-HT transmission.

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11
Q

What are some types of drugs used to treat anxiety? State their mechanism of action.

[IMPORTANT]

A
  • Barbiturates -> GABA potentiation
  • Benzodiazapines -> GABA potentiation
  • 5HT1 pre-synaptic agonists (buspirone)
  • β-blockers
  • Antidepressants [EXTRA]
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12
Q

Are barbiturates still used?

A

No

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13
Q

Give two examples of benzodiazepines.

A
  • Chlordiazepoxide (Librium)
  • Diazepam (Valium) [IMPORTANT]
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14
Q

What is the mechanism of action of buspirone? What is it used for?

A
  • 5-HT1 inhibitor
  • Used to treat anxiety
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15
Q

What are some antidepressants that can be used to treat anxiety?

A
  • SSRIs
  • Clomipramine
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16
Q

What is the mechanism of action of barbiturates?

A

Facilitate GABAergic transmission

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17
Q

For benzodiazepines, summarise the mechanism of action, uses and side effects.

[IMPORTANT]

A
  • Facilitate GABA transmission (at GABAA receptors)
  • Uses: Anxiety, sleep disorder, epilepsy, muscle relaxation
  • Side effects: Sedation, motor incoordination and memory loss
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18
Q

What are the problems with long-term use of benzodiazepines?

A
  • Tolerance
  • Dependence
  • Withdrawal
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19
Q

Describe what receptor barbiturates and benzodiazepines act on. How do they act?

A

Act on a GABAA receptor, which leads to Cl- influx:

  • Benzodiazepines bind to a modulatory site that increases the affinity of the receptor for GABA
  • Barbiturates are channel modulators that can open the channel directly
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20
Q

Summarise the different pscyhotropic drugs (and other drugs) that can bind to GABAA channels.

A

At the benzodiazepine site:

  • Benzodiazepines -> Increases the affinity of the receptor for GABA (i.e. indirect action)
  • Z-drugs -> Similar to benzodiazepines, but shorter duration of action, so mostly used for sedation.
  • Inverse agonists -> Have anxiogenic effects and can even lead to convulsion
  • Antagonists -> Block both the effects of benzodiazepines and inverse agonists

At other modulatory site:

  • Barbiturates and Neurosteroids (e.g. propofol) -> Are channel modulators that can open the channel directly, leading to anxiolytic effects and sedation
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21
Q

Describe the structure of the GABAA receptor and how this is clinically relevant.

[EXTRA?]

A
  • The GABAA receptor is a pentamer
  • An α, β and γ subunit is required in each receptor, but there is still a wide range of diversity within GABA receptors
  • The benzodiazepine receptor is between the α and γ subunits, meaning that the type of α subunit have been related to different binding properties and different behaviours:
    • α1 -> Sedative effects
    • α2/α3 -> Anxiolytic
  • This means that development of subunit-specific benzodiazepines for the treatment of anxiety without side effects is a promising area of research
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22
Q

Name some anxiolytic drugs that influence 5-HT transmission.

A

5-HT transmission is thought to be conducive to anxiety:

  • Buspirone [IMPORTANT] -> Agonist of the 5-HT1 receptor on the pre-synaptic membrane, leading to decreased 5-HT release.
  • SSRIs [EXTRA] -> Paradoxically increase the concentration of 5-HT in the synapse, which should be anxiogenic, but they are also proposed to decrease the sensitivity of 5-HT2C receptors on the post-synaptic membrane of certain synapses. Thus, they have anxiolytic effects in some parts of the brain, despite increasing 5-HT.
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23
Q

Explain why SSRIs can be used to treat anxiety and depression.

[EXTRA]

A
  • Anxiety is thought to be caused by increased 5-HT signalling, while depression is thought to be caused by decreased monoamine (e.g. 5-HT signalling)
  • SSRIs treat depression by increasing 5-HT signalling
  • Therefore they would be expected to be anxiogenic, but they are actually anxiolytics. Some explanations:
    • They may decrease the sensitivity of 5-HT2C receptors on the post-synaptic membrane of certain synapses that are important in anxiety.
    • Anxiety and depression are often seen together, so the SSRI may treat anxiety by treating the depression.
    • In some types of anxiety, the increase in 5-HT may actually be beneficial. For example, in panic disorders, 5-HT may reduce the excess activity of the periaqueductal grey.
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24
Q

Aside from use in treating anxiety, what important clinical function do benzodiazepines have?

[IMPORTANT]

A

They are hypnotics (induce sleep), used in insomnia and general anaesthesia.

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25
Q

Summarise the symptoms of depression.

A
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26
Q

What are the two types of depression?

[IMPORTANT]

A
  • Unipolar depression
  • Bipolar depression -> Features extreme mood swings from periods of mania to periods of depression
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27
Q

Name some drugs used to treat depression.

A
  • Tricyclic antidepressants (TCA)
  • Monoamine oxidase inhibitors (MAOI)
  • Selective serotonin reuptake inhibitors (SSRI)
  • Selective serotonin and noradrenaline reuptake inhibitors (SNRI)
  • Atypical antidepressants
  • Lithium and other mood stabilisers
  • New antidepressant treatments (ketamine, psilocybin)
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28
Q

Describe the mechanism of action of tricyclic antidepressants.

A

Non-selectively inhibit the reuptake of monoamines, such as 5-HT and noradrenaline.

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29
Q

Give an example of tricyclic antidepressants.

[IMPORTANT]

A

Amitriptyline [IMPORTANT]

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30
Q

Aside from treating depression, what are some other uses of tricyclic antidepressants?

A

Treating neuropathic pain.

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31
Q

What are some adverse effects of tricyclic antidepressants?

A
  • Sedation (H1 receptors)
  • Dry mouth, constipation (m3 receptors)
  • Cardiotoxic
  • Toxic in overdose -> This is dangerous in cases of deliberate overdose

These effects occur largely because the tricyclic antidepressants are not selective for just the monoamines.

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32
Q

Describe the mechanism of action of monoamine oxidase inhibitors in treating depression.

A

Inhibit the metabolism of monoamines, including 5-HT and noradrenaline.

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33
Q

Give some examples of monoamine inhibitors used in treatment of depression.

A
  • Isoniazid (no longer prescribed) [IMPORTANT]
  • Phenelzine [IMPORTANT]
  • Moclobemide (MAO A)
  • Selegiline (MAO B)
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34
Q

What are the differences in action of MAO-A and MAO-B?

A
  • MAO-A inhibition (e.g. moclobemide) leads to increases in noradrenaline and 5-HT, so it is better for use in treating depression
  • MAO-B inhibition (e.g. selegiline) leads to increases in dopamine, so it is better for use in treating Parkinson’s
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35
Q

What are some adverse effects of monoamine oxidase inhibitor use in treatinf depression?

A
  • Drug interactions -> Inhibitors are often metabolised by cytochrome P450, which means that there may be reciprocal interactions with other drugs
  • Cheese reaction (tyramine accumulation) -> Tyramine is found in various foods, such as cheese, and is also usually metabolised by MAO. If it is not metabolised, it leads to NA release, which can cause hypertension.
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36
Q

Describe the mechanism of action of SSRIs in treating depression.

A

Selectively inhibit the reuptake of 5-HT.

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37
Q

Are SSRIs effective in all patients?

[EXTRA]

A
  • No, they are ineffective in certain patients.
  • Studies are looking at the biological differences between drug responders and non-responders to understand what could underlie this.
  • There have been some studies that suggest that SSRIs increase the risk of suicide, perhaps by increasing the motivation of the individual sufficiently to commit suicide. However, these studies have been largely dismissed.
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38
Q

Compare the mechanism of action of tricyclic antidepressants and SSRIs.

A

Tricyclic antidepressant are not selective in their inhibition of reuptake of neurotransmitters, while SSRIs are.

(CHECK IF THIS IS THE MAIN DIFFERENCE)

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39
Q

Give some examples of SSRIs.

A
  • Fluoxetine (Prozac) [IMPORTANT]
  • Paroxetine (Seroxat)
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40
Q

What are some adverse effects of SSRIs?

A
  • Insomnia
  • GI disturbance
  • Sexual dysfunction
  • Withdrawal effects (emerging evidence)

These can occur despite the SSRIs being selective.

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41
Q

Aside from use in treating depression, what are some other applications of SSRIs?

A

Treating anxiety.

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42
Q

Describe the mechanism of action of lithium in treating depression.

A
  • It is used mostly in bipolar depression as a mood stabiliser (prophylactically)
  • It is thought to act by inhibiting the IP3 pathway that may be overactive in bipolar disoder
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43
Q

What are some adverse effect of lithium?

A
  • Narrow therapeutic index
  • Thirst, diarrhoea, tremor
  • Renal damage

There is also poor compliance due to the side effects.

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44
Q

Aside from lithium, what are some other mood stabilisers?

A
  • Carbamazepine [IMPORTANT]
  • Valproate [IMPORTANT]
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45
Q

Give some experimental relevance of lithium treatment in bipolar disorders.

[EXTRA]

A

(Singh, 2013):

  • Studied ebselen, which is a lithium mimetic with fewer side effects thamn lithium
  • More recent small-scale clinical trials show that it has promise in treating the manic symptoms of bipolar
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46
Q

What is the monoamine hypothesis of depression?

[IMPORTANT]

A

The idea that depression is due to a deficit in monoamine transmission (Schildkraut, 1965).

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47
Q

What is some evidence for and against the monoamine hypothesis of depression?

A
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48
Q

What are some slow-acting changes that antidepressants induce and what are the implications of this?

A
  • Increased neurogenesis (neuron synthesis) is one form of neural plasticity induced by antidepressant treatment (Santarelli, 2003)
  • New theories suggest that depression may be linked to a failure in neural plasticity, which is increased by antidepressants.
  • Thus, this argues against the monoamine hypothesis of depression.
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49
Q

Give an example of an SNRI.

A

Venlafaxine [IMPORTANT]

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50
Q

Describe the symptoms of schizophrenia.

A

Positive symptoms (acute):

  • Disordered thinking
  • Hallucinations
  • Persecutory ideas
  • Delusions

Negative symptoms (chronic):

  • Social withdrawal
  • Poverty of speech
  • Cognitive deficits
  • Emotional blunting
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51
Q

What are some proposed causes of schizophrenia?

A
  • It is thought to be a developmental disorder, based on histological post-mortem findings
  • This is also supported by the prodromal state, which is the idea that schizophrenia is marked by other behavioural changes during childhood before it is diagnosed during adolescence/early adulthood
  • Thirdly, adverse early life events are a risk factor
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52
Q

What are antipsychotic drugs?

A

Drugs used to relieve the symptoms of schizophrenia.

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53
Q

What are the two main categories of anti-psychotic drugs used to treat schizophrenia?

[IMPORTANT]

A
  • Typical antipsychotic drugs (1st generation)
  • Atypical antipsychotic drugs (2nd generation)
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54
Q

Give some examples of typical and atypical antipsychotic drugs used to treat schizophrenia.

A
  • Typical antipsychotic drugs (1st generation)
    • Haloperidol [IMPORTANT]
    • Chlorpromazine [IMPORTANT]
  • Atypical antipsychotic drugs (2nd generation)
    • Clozapine [IMPORTANT]
    • Risperidone
    • Aripiprazole
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55
Q

Describe the mechanism of action of typical and atypical antipsychotic drugs used to treat schizophrenia.

A

They inhibit D2 dopamine receptors at synapses.

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56
Q

What are some adverse effects of typical and atypical antipsychotic drugs used to treat schizophrenia?

A
  • Increased prolactinn secretion
  • Parkinsonian-like motor deficits
  • Increased weight gain
  • Tardive dyskinesia
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57
Q

What is tardive dyskinesia and what causes it?

[IMPORTANT]

A
  • Involuntary movements of the face and upper limbs
  • This can be use to the use of dopamine antagonists, for example as antipsychotics in treatment of schizophrenia
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58
Q

Give some experimental evidence relating to the dopamine inhibition mechanism of action of antipsychotic drugs used in treating schizophrenia.

[EXTRA]

A

(Seeman, 1976):

  • The potency of an antipsychotic drug is directly proportional to its affinity for dopamine receptors
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59
Q

Compare the efficacy and side effects of 1st and 2nd generation antipsychotic drugs.

A
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60
Q

What underlies the different efficacy and side effects of different antipsychotics?

A

The different antipsychotics have different pharmacological profiles and act on various other receptors, which may explain their different efficacies and side effects.

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61
Q

What is the dopamine hypothesis of schizophrenia?

[IMPORTANT]

A

The idea that schizophrenia symptoms are due to a hyperactive DA system (Carlsson, 1963).

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62
Q

What is some evidence for and against the dopamine hypothesis of schizophrenia?

A
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63
Q

How is brain imaging relevant to schizophrenia?

[IMPORTANT]

A
  • Imaging studies are evidence for the dopamine hypothesis of schizophrenia
  • They show that there is increased dopamine signalling in the striatum in individuals with schizophrenia
  • (Laurelle, 1999) used a radioligand for D2 receptors, which loaded up the dopamine receptors in the brain. They then gave a dose of a dopamine-releasing drug (e.g. amphetamine), which causes the radioligand to be displaced from the receptor. This is a measure of dopamine release. Compared to control, the schizophrenics have much higher displacement (at least in the striatm), which is evidence for the greater dopamine signalling in schizophrenics.
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64
Q

Is dopamine the only neurotransmitter of interest in schizophrenia?

[IMPORTANT]

A

The dopamine theory of schizophrenia is not the only theory. There are also alternative neurotransmitter theories (e.g. glutamate, GABA, 5-HT).

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65
Q

Summarise some new targets for schizophrenia treatment.

A
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66
Q

Give some statistics for the health and social burden of recreational drugs.

[EXTRA]

A
  • Recreational drug use
    • 2.7 million adults use an illegal drug each year
    • 24% of 15 year-olds have tried drugs at least once
    • 294,000 heroin and crack users
    • 40% of prisoners have used heroin
  • Drug misuse damages health
    • Psychiatric disorder
    • Cardiovascular disease
    • Liver and lung damage
    • Overdose and drug poisoning
  • Families and communities
    • 1.2 million families affected by drug addiction
    • Alcohol misuse linked to ~50% of domestic violence and marital breakdown
  • Annual cost of drug addiction
    • Total cost to society £15.4bn (crime, loss of productivity, NHS)
    • A typical heroin user spends around £1,400 per month on drugs.
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67
Q

What are recreational drugs?

A
  • Recreational drugs are psychotropic drugs with a diverse range of pharmacological targets
  • Some drugs used recreationally have important therapeutic uses (eg. pain relief from morphine)
  • Not all psychotropic drugs are used recreationally (eg. antidepressants and antipsychotics)
  • Prolonged use of many (but not all) recreational drugs leads to dependence and compulsive drug-seeking behaviour (drug addiction).
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68
Q

When does drug addiction become prpblematic?

A

Drug addiction becomes problematic when:

  1. It dominates lifestyle to damage quality of life
  2. The habit causes harm to drug-user and society
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69
Q

Give some experimental evidence for the harm caused by different types of recerational drugs.

[EXTRA]

A

(Nutt, 2010):

  • Blue shows the harm to user
  • Red shows the harm to others
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70
Q

State the dependence liability of recreational drugs. Why is it important?

A

The dependence liability is a good predictor of the harm caused by various drugs.

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71
Q

What are some determinants of dependence liability of recreational drugs?

A
  • Rate at which drugs reach the brain
  • How pleasurable the drug is (positive reinforcement)
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72
Q

How can the rewarding effects of a drug be measured?

A
  • Positive reinforcement can be measured in animals by spontaneous self administration.
  • Pressing of lever results in drug administration via indwelling cannula.
  • If the drug has reinforcing properties then lever pressing increases.
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73
Q

Define tolerance.

A

A decrease in pharmacological effect on repeated administration of the drug.

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74
Q

Define dependence.

A

A state in which drug-taking becomes compulsive, taking precedence over other needs.

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75
Q

Define withdrawal.

A

Stopping drug intake results in unpleasant physical and psychological effects (negative reinforcement).

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76
Q

What things sustain compulsive drug seeking behaviour (addiction)?

A
  • Positive reinforcement (euphoria)
  • Negative reinforcement (avoidance of withdrawal)
  • Environment (behavioural conditioning)
  • Genes
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77
Q

What are tolerance, dependence and withdrawal evidence for?

A

These processes reflect compensatory neuroadaptive changes associated with continued presence of the drug.

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78
Q

For opiates, state:

  • Examples
  • Molecular effects
  • Behavioural effects
A
  • Examples
    • Morphine [IMPORTANT]
    • Heroin
    • Fentanyl
  • Molecular effects
    • µ opiate receptors are inhibitory (Gi )
    • µ opiate receptors inhibit transmitter release & neuronal excitability
  • Behavioural effects
    • Intense euphoria
    • Strong sense of tranquillity
    • Drowsiness, slowed movement
    • High dependence liability linked to high mortality
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79
Q

Describe the molecular mechanisms underlying morphine tolerance, dependence and withdrawal.

[EXTRA]

A
  • Acute morphine inhibits adenylate cyclase and reduces cAMP levels.
  • Over time, continued morphine use results in return of cAMP levels due to increased expression of adenylate cyclase.
  • Removal of morphine results in rebound increase in cAMP.

The mechanism of tolerance in other drugs may be different to that in morphine.

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80
Q

What are the symptoms of opiate withdrawal?

A
  • Yawning
  • Pupillary dilation
  • Hyperthermia
  • Sweating
  • Piloerection
  • Nausea and diarrhoea
  • High anxiety
  • Insomnia
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81
Q

How can the symptoms of opiate withdrawal be precipitated and relieved?

A
  • Precipitated by opiate antagonist (naloxone)
  • Relieved by opiate agonist (methadone)
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82
Q

What brain mechanism underlies the addiction of many recreational drugs?

[IMPORTANT]

A
  • Many recreational drugs activate the mesolimbic dopamine pathway, which is a reward pathway
  • This means that drug use leads to aberrant positive reinforcement, leading to addiction
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83
Q

What brain pathway is involved in the addiction to recreational drugs? What are the different components?

[IMPORTANT]

A

Mesolimbic pathway:

  • Ventral tegmental area (VTA) sends dopaminergic outputs to the nucleus accumbens (NA) (part of the striatum)
  • The dopamine binds to D2 (inhibitory) receptors, leading to reduced nucleus accumbens neuron firing, which is an indicator of reward
  • Thus, there is aberrant positive reinforcement that leads to addiction
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84
Q

How does morphine activate the mesolimbic pathway, causing addiction?

A
  • Morphine binds to inhibitory μ-opioid receptors on GABAergic neurons in the ventral tegmental area (VTA)
  • This leads to disinhibition of mesolimbic dopaminergic output from the VTA to the nucleus accumbens
  • Thus there is increased dopamine release in the nucleus accumbens, leading to decreased nucleus accumbens firing, which is a marker of reward
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85
Q

What is some evidence for the fact that morphine activates the mesolimbic reward pathway?

A
  • Intra-VTA morphine increases lever pressing
  • Morphine increases DA cell firing in VTA and DA release in nucleus accumbens
  • DA antagonists block morphine-induced lever pressing
86
Q

For psychostimulants, state:

  • Examples
  • Molecular effects
  • Behavioural effects
A
  • Examples
    • Amphetamine
    • Cocaine
    • Mephedrone
    • Cathinone (Khat leaves)
    • Nicotine [IMPORTANT]
  • Molecular effects
  • They increase dopamine signalling:
    • Cocaine, mephedrone, cathinone -> Inhibit dopamine reuptake
    • Amphetamines, nicotine -> Increase dopamine release
  • Behavioural effects
    • Euphoria
    • Increased wakefulness
    • Reduced fatigue
    • Decreased appetite

Methylxanthines are also psychostimulants, but we consider them seperately.

87
Q

How are psychostimulants used therapeutically?

A
  • Anorectic (fenfluramine - withdrawn)
  • ADHD (amphetamine, ritalin)
  • Substitution therapy (nicotine)
88
Q

For methylxanthines, state:

  • Examples
  • Molecular effects
  • Behavioural effects
A
  • Examples
    • Caffeine
    • Theophylline
  • Molecular effects
    • Increase overall dopamine signalling by either:
      • Inhibiting the degradation of cAMP downstream of D1 receptors
      • Block adenosine A2A receptors, which usually counteract D2 receptor action
  • Behavioural effects
    • Increased wakefulness
    • Reduced fatigue
    • Decreased appetite
    • Weak reinforcing effects and not euphoric
89
Q

Summarise the way in which different recreational drugs can activate the mesolimbic dopamine pathway.

A
90
Q

Give some experimental evidence for the brain differences in individuals with cocaine addictions.

[EXTRA]

A

(Volkow, 2004):

  • Cocaine addicts show fewer D2 receptors in the mesolimbic dopamine pathway -> This may explain why look for drugs like cocaine to supplement this
  • Brain glucose metabolism is another marker of neuronal activity and it shows that in addicts there are deficits in:
    • Orbitofrontal cortex -> May explain loss of awareness of drug habit
    • Cingulate gyrus -> May explain loss of control of drug intake
91
Q

Give some experimental evidence against the dopamine model of addiction.

[EXTRA]

A

(Hnasko, 2005):

  • Morphine was shown to still have a rewarding effect in dopamine deficient (tyrosine hydroxylase KO) mice.
  • This implies that dopamine is not required for the reward and addiction.
92
Q

Summarise 4 main types of psychotomimetics and thier mechanism of action.

A
  • LSD [IMPORTANT], Mescaline [IMPORTANT], Psilocybin -> Agonists of 5-HT2A receptors
  • MDMA -> Stimulate 5-HT release
  • Cannabinoids [IMPORTANT] -> CB1 receptor agonists, leading to inhibition of NT release
  • Ketamine, Phencyclidine -> Inhibit NMDA receptors
93
Q

What are psychotomimetics?

A
  • Drugs that mimic the symptoms of psychosis, including delusions or delirium, as well as hallucinations.
  • They cause disturbances in perception and behaviour that cannot be classed as either sedative or stimulant.

a.k.a. Hallucinogens

94
Q

For psychotomimetic drugs LSD, mescaline and psilocybin, state:

  • Molecular mechanisms
  • Behavioural effects
  • Therapeutic uses
A
  • Molecular mechanisms
    • Agonists of 5-HT2A receptors
  • Behavioural effects
    • Distorted perceptions
    • Hallucinations
    • Illogical thinking
    • Heightened sensory awareness
    • Not euphoric
  • Therapeutic uses
    • In the 1960s, some therapists used these as an aid to psychotherapy (e.g. low-doses of LSD helped other treatments be more effective)
    • Potential antidepressants
95
Q

Why are psychotomimetics no longer used as part of many psychotherapies?

[EXTRA]

A
  • Not because they are ineffective, but because governments have deemed them too dangerous and harmful
  • However, note how this contradicts the data from (Nutt, 2010), where many psychotomimetics drugs are some of the least dangerous drugs
96
Q

Give some experimental evidence for the mechanism of action of psilocybin.

[EXTRA]

A

(Madsen, 2019):

  • Carried out PET scanning in humans using a radioligand for the 5-HT2A receptor
  • This showed that psilocybin binds to these receptors and that occupancy of the receptors by psilocybin is correlated to the intensity of hallucinations
97
Q

Give an example of experimental evidence for psychedelics (e.g. psilocybin) having potential as antidepressants.

[EXTRA]

A

(Cameron, 2021):

  • Showed that psychedelic drugs induce fast changes in the plasticity of neurons
  • This could be a potential mechanism for antidepressant action
  • The experiment involved two-photon imaging neurons in vivo, which showed that the rate of dendritic spine formation in a mouse cortex increased in the 24 hours after psychedelic drugs are administered
98
Q

For the psychotomimetic drug MDMA, state:

  • Molecular mechanisms
  • Behavioural effects
  • Therapeutic uses
A
  • Molecular mechanisms
    • Stimulates 5-HT release
  • Behavioural effects
    • Euphoria
    • Hallucinations
    • Feelings of intimacy, empathy
    • Bruxia, lockjaw
    • Hyperthermia
    • May increase the risk of 5-HT neurotoxicity
  • Therapeutic uses
    • In the 1960s, some therapists used these as an aid to psychotherapy and also in PTSD
    • No current clinical use
99
Q

For the psychotomimetic cannabinoids, state:

  • Molecular mechanisms
  • Behavioural effects
  • Therapeutic uses
A
  • Molecular mechanisms
    • Act on C1 receptors
    • This leads to inhibition of neurotransmitter release
  • Behavioural effects
    • Feeling of well-being, disinhibition
    • Sharpening of senses
    • Amnesia, confusion
    • May produce dependence
  • Therapeutic uses
    • Nausea & vomiting (nabilone)
    • Neuropathic pain (Sativex)
    • Anticonvulsant
100
Q

Give some experimental evidence relating to the link between cannabis use and schizophrenia.

[EXTRA]

A

(Di Forti, 2015):

  • Showed that everyday or very frequent use of skunk was linked to an increased risk of having psychotic episodes
101
Q

For the psychotomimetics ketamine and phencyclidine, state:

  • Molecular mechanisms
  • Behavioural effects
  • Therapeutic uses
A
  • Molecular mechanisms
    • Block NDMA (glutamate) channels
  • Behavioural effects
    • Stimulant/depressant
    • Hallucinations
    • Feelings of detachment
    • Staggering gait
    • Slurred speech
  • Therapeutic uses
    • General anaesthetic
    • Analgesia
    • Antidepressant
102
Q

Give some experimental evidence for the efficacy of ketamine as an antidepressant.

[EXTRA]

A

(Marcantoni, 2020):

  • This systematic review of the efficacy of IV ketamine for treating drug-resistant depression showed that it is an effective antidepressant
  • The mechanism of action as an antidepressant is uncertain.
  • Ketamine has recently been made available for prescription for depression.
103
Q

For alcohol, state:

  • Molecular mechanisms
  • Behavioural effects
  • Therapeutic uses
A
  • Molecular mechanisms
    • GABAA potentiation
    • Inhibition of NMDA receptors
    • Inhibition of voltage-gated Ca2+ channels
  • Behavioural effects
    • CNS depressant
  • Therapeutic uses
    • N/A
104
Q

How does tolerance to alcohol occur?

A

Elevated expression of voltage-gated Ca2+ channels

105
Q

Why is chronic use of alcohol harmful?

A
  • Metabolites are damaging
  • Thiamine deficiency (usually due to a poor diet)
106
Q

For benzodiazepines as recreational drugs, state:

  • Molecular mechanisms
  • Behavioural effects
  • Therapeutic uses
A
  • Molecular mechanisms
    • Facilitate the GABAA receptor
  • Behavioural effects
    • Anxiolytic effects
  • Therapeutic uses
    • Anxiety
    • Insomnia
107
Q

What is responsible for the withdrawal symptoms of benzodiazepines?

A

Altered expression of GABAA receptor subunits.

108
Q

Name some pharmacological treatments for various aspects of recreational drug addiction.

[EXTRA]

A
109
Q

What are designer drugs?

[EXTRA?]

A

New psychoactive substances that are designed to mimic drugs that are already banned, but are not yet illegal.

110
Q

What category of psychiatric disorder is schizophrenia?

A

It is one of the psychoses.

It is NOT a mood disorder.

111
Q

What are the main psychoses?

A

The psychoses can be considered related to the late term “madness”, although that term is not used anymore.

112
Q

What are some symptoms of psychoses, such as schizophrenia?

[IMPORTANT]

A
  • Delusions (false beliefs)
    • Fully believed despite contrary evidence
    • Usually have personal signficance
    • Often are percusatory (e.g. someone is out to get me)
  • Hallucinations (sensations without an external stimulus)
  • Lack of insight (unaware of having schizophrenia)
113
Q

What are the positive and negative symptoms of schizophrenia?

A
  • Positive -> Delusions, hallucinations, thought disorder
  • Negative -> Lack of drive, social interaction, speech
114
Q

How can schizophrenia be diagnosed?

A
  • Number and nature of psychotic symptoms (including ‘first rank symptoms’)
  • Positive and negative symptoms
  • Duration
  • Evidence for functional impairment
  • Lack of evidence for an ‘organic’ psychosis, mood disorder, autism

There are two diagnostic systems:

  • ICD-11 (World Health Organisation)
  • DSM-5 (American Psychiatric Association)
115
Q

What is considered a good predictor of the outcome of shcizophrenia?

[EXTRA]

A
  • Cognitive impairment is frequently seen in patients with schizophrenia
  • The degree of impairment is a good predictor of the outcome, rather than just the severity of the symptoms at diagnosis
  • However, it is rarely used as a diagnostic criterion, since it is hard to measure, etc.
116
Q

What is the age of onset of schizophrenia?

A

Around 7-70 years, although it is most commonly diagnosed in the 20s.

117
Q

How does gender affect schizophrenia?

A

Equal sex ratio, but men get it earlier and more severely.

118
Q

What are the outcomes of schizophrenia?

[EXTRA]

A
  • 20% recover
  • 40% remit and relapse
  • 40% have chronic symptoms and impairment
119
Q

How does schizophrenia affect mortality?

[EXTRA]

A
  • Increased mortality (x3)
  • This is due to both suicide (~10%) and natural causes, which can be explained by various mechanisms, including lifestyle choices and medication
  • Life expectancy reduced by >15 years
120
Q

Summarise the treatment of schizophrenia.

A
  • Antipsychotic drugs are D2 receptor blockers (e.g. chlorpromazine, haloperidol, clozapine) -> Work in about 70% of patients, except clozapine which is more effective but limited by toxicity. Only treat positive symptoms.
  • CBT for delusions and hallucinations.
  • Nothing to treat the negative symptoms.
121
Q

What is some evidence that schizophrenia has a genetic component?

A

Genetic studies show heritability:

  • If both parents have schizophrenia, the risk is 40%
  • If an identical twin has schizophrenia, the risk is 48%

Studies have led to the conclusion that schizophrenia is about 80% heritable.

122
Q

Describe some types of studies used to study whether schizophrenia is genetic.

A
  • Adoption studies
    • Study the children of mothers with schizophrenia who were taken away from the mother by adoption
    • The children appear to retain the expected increased risk of illness
    • This supports the idea that schizophrenia is genetic, but does not control for pre- or perinatal environment
  • Family history
    • 90% of patients don’t have an affected parent
    • 60% have no family history at all
    • This may appear to dismiss the idea that schizophrenia is genetic, but in fact it can be explained by the idea that many genes of small effect underlie schizophrenia
123
Q

Is there a schizophrenia gene?

A

No

124
Q

What are the 3 types of genetic changes that can affect risk of schizophrenia?

A
  • SNPs (single nucleotide polymorphisms) -> Cumulatively explain majority of heritability, but individual SNP effects are tiny
  • CNVs (copy number variants) -> Lengths of DNA deleted or duplicated. Very rare, but big effect size when present.
  • Rare variants. (SNVs, indels) -> Role uncertain, probably minor.
125
Q

What do schizophrenia risk genes tend to do?

A

The risk genes converge on several biological pathways:

  • Glutamate synapses and synaptic plasticity
  • Immune function (not certain what the importance of this is)
  • Calcium signalling
  • Epigenetic regulation

The mutations tend to affect regulation of the gene, rather than the actual amino acid sequence of the protein.

126
Q

Describe the neuroanatomical changes in schizophrenia.

[IMPORTANT]

A
  • Ventricular enlargement (due to smaller brain)
  • Decreased brain volume and weight (-3%)
  • Larger basal ganglia (due to antipsychotics)

Most changes in brain size are seen in first episode patients, but many are also seen in at risk individuals. There is essentially a shift towards a smaller mean brain volume, but there is still large overlap with normal patients so this cannot be used as a diagnostic. It is not progressive and there does not appear to be a correlation between brain size and severity of the symptoms.

127
Q

What do fMRI studies of schizophrenia show?

A
  • Hypofrontality (decreased frontal lobe activity)
  • Other features depending on symptoms:
    • Temporal lobe activation during auditory hallucinations
    • Increased hippocampal activation/blood flow during delusions
128
Q

Describe some psychological models of schizophrenia.

[IMPORTANT]

A
  • It used to be thought that schizophrenia was caused by upbringing, but this has now been largely dismissed.
  • Current models are grounded in cognitive neuroscience (e.g. Delusion formation based on failure to integrate sensory perceptions with internal world, or failure to distinguish the two)
  • Such problems theorised to arise either from perceptual/attentional problems (‘bottom up’) or from cognitive impairments and prefrontal dysfunction (‘top down’)
  • ‘Aberrant salience’ theory (Kapur) links neuropsychology to dopamine hypothesis
129
Q

Describe the dopamine hypothesis of schizophrenia.

[IMPORTANT]

A
  • The dopamine hypothesis is the idea that excess dopamine underlies positive symptoms
  • PET and SPET show an excess in striatal dopamine:
    • Is a state not trait -> Correlates with severity of psychotic symptoms
    • Begins during the prodrome
    • The greater the excess, the better the response to antipsychotic drugs
  • There is reciprocal regulation of striatal and cortical dopamine, so cognitive and negative symptoms may be due to insufficient cortical dopamine
130
Q

What is an alternative to the dopamine hypothesis of schizophrenia?

[EXTRA?]

A

Glutamate model -> Schizophrenia is due to NDMA receptor hypofunction:

  • NMDA receptor antagonists induce psychosis; agonists can improve it (in patients and animal models)
  • Similarly, in schizophrenia, there may be genetic differences in NMDA receptor pathways or antibodies against NMDA receptors

It is not certain whether these glutamate abnormalities precede the dopamine abnormalities, or whether they are seen in different cases of schizophrenia.

131
Q

What is some evidence for schizophrenia being a neurodevelopmental disorder?

[IMPORTANT]

A
  1. Nature of the neuropathology
    • Present at onset, if not earlier
    • Some of the histological changes appear prenatal in origin
    • Absence of gliosis or neurodegeneration
  2. Risk factors are mostly pre- or peri- natal
  3. ‘Pre-schizophrenic’ children impaired in motor, behavioural and intellectual functioning
  4. Increased rate of minor physical anomalies in schizophrenia
  5. Relevant models e.g. neonatal hippocampal lesions
132
Q

What are some risk factors for schizophrenia?

A
133
Q

Give some experimental evidence for how genetic and environmental risk factors for schizophrenia converge.

[EXTRA]

A

(Ursini, 2018):

  • Described how placental biology (i.e. environmental risk factors) converge to determine whether the risk genes are expressed and play a role in predisposing to schizophrenia
134
Q

Draw a summary of the pathogenesis of schizophrenia.

A
135
Q

Give some experimental statistics about neurodegenerative diseases.

[EXTRA]

A
  • Prevalence of dementia rises from 5% to over 30% between the ages of 65 and 85 year old
  • Each year 150,000 people in UK develop cognitive impairment and memory loss; within 5 years half will have dementia
  • Alzheimer’s disease costs the country ~£17 billion per year, approximately 20% of the UK health budget
  • Parkinson’s: second most common neurodegenerative disease: 1% of population at 65; 5% at 85
  • Number of people in UK over 60, now out number those under 16
136
Q

Define dementia.

A
  • A term for the impaired ability to remember, think, or make decisions that interferes with doing everyday activities.
  • It is a collection of symptoms, not a disease in itself.
  • It usually occurs with age and is often caused by diseases such as Alzheimer’s.
137
Q

What are some ways in which the brain changes as it ages that could lead to dementia and other neurodegenerative problems?

A
  • Decreased ability to cope with oxidative stress
    • For example, Nrf2 is a protein that regulates genes that are crucial for metabolism of drugs/toxins and protection against oxidative stress.
    • The expression of Nrf2 falls with age.
  • Altered permeability of BBB:
    • Decreased secretion towards the brain
    • Decreased removal of toxic compounds from the brain
  • Increased mitochondrial mutations:
    • Reactive oxygen species (ROS) damage DNA and lead to mutations that decrease their function
    • Mitochondria mutations may, in part, cause ageing
138
Q

What is the main risk factor in dementia?

A

Age

139
Q

What is the most common cause of dementia?

A

Alzheimer’s disease

140
Q

What are the symptoms of Alzheimer’s disease?

A
  • Progressive decline in memory
    • Factual memory
    • Short-term memory
    • Impaired word-finding
  • Visual and spatial disorientation
  • Alteration in personality
  • Agitation, irritability, aggression
  • Anxiety
141
Q

Describe the physical changes seen in Alzheimer’s disease.

A

Anatomical level:

  • Progressive cortical pathology with very consistent disease progression
  • It progresses from the entorhinal cortex progressing to hippocampus

Cellular level:

  • Extracellular plaque formation
  • Intracellular neurofibrillary tangle formation
142
Q

Describe the structure of amyloid peptide in Alzheimer’s disease. What is it made of?

A
  • Extracellular deposits of insoluble Aβ peptide
  • Activates astrocytes and microglia
  • Aβ peptide is a neurotoxin that requires tau protein for toxicity, meaning that cells lacking tau protein are resistant to toxicity
143
Q

Describe the structure of intracellular tangles in Alzheimer’s disease. What are they made of?

A
  • Neurofibrillary tangles are made of microtubule associated protein tau (tau protein)
  • These tau proteins take on a paired helical filament structure and are hyperphosphorylated, as well as ubiquinated.
144
Q

Is Alzheimer’s disease an inevitable part of ageing?

A
  • No
  • The threshold hypothesis (Roth, 1986) suggests that all aspects of AD pathology are seen to a lesser extent in normal aged individuals and that AD symptoms occur when normal ageing passes a threshold
  • However, this has been largely dismissed, since “By the age of 85 virtually everyone will have some neurofibrillary tangles in their cerebral cortex and yet not everyone develops AD.” (Smith, 2002)
145
Q

Which part of the brain is most affected by intracellular neurofibrillary tangles in Alzheimer’s disease?

A

Temporal lobe (e.g. hippocampus, etc.)

This can be detected by post-mortem histology or by CT scans that show progressive atrophy of the medial temporal lobe, which is correlated with cognitive decline.

Spec mentions the “basal forebrain cholinergic systems”

146
Q

What parts of the brain are involved in Alzheimer’s disease according to the spec?

A

Basal forebrain cholinergic systems

147
Q

Compare the rate of thinning of the medial temporal lobe in Alzheimer’s disease and normal ageing. What is the signficance of this?

A

OPTIMA study found that:

  • The rate of medial temporal lobe thickness decline is up to 10 times greater in Alzheimer’s
  • This suggests that Alzheimer’s is a separate disease process and not just a normal part of ageing where AD happens once a threshold is reached
148
Q

When does neurofibrillary tangle formation begin in Alzheimer’s disease pathogenesis?

A

The tau tangles can start forming up to 50 years before diagnosis in the parahippocampal gyrus.

149
Q

Give some experimental evidence for the risk factors of Alzheimer’s disease.

[EXTRA]

A

The Nun Study (1991-1993):

  • Studies 678 nuns who were isolated and had a shared environment and life-style
  • The nuns wrote a short hand-written autobiography aged ~22
  • There was a correlation between the “idea density” and “grammatic complexity” of original autobiography in 93 nuns with cognitive ability and incidence of AD in 1995

“Our findings support a strong relationship between cognitive ability in early life, as indicated by linguistic ability, and cognitive function and Alzheimer’s disease in late life.”

150
Q

Compare late onset and early onset Alzheimer’s disease.

A

Late Onset Alzheimer’s Disease (LOAD):

  • Late onset >65 years
  • Vast majority of AD cases
  • Sporadic, with complex genetic susceptibility

Early Onset Alzheimer’s Disease (EOAD):

  • Early onset <65 years
  • More aggressive than LOAD
  • Accounts for <1% of AD cases
  • Mendelian single gene cause

They are clinically and neuropathologically extremely similar, meaning that EOAD can be studied to get a better understanding of LOAD.

151
Q

Give an example of a gene mutation that can lead to early onset Alzheimer’s disease.

A

Amyloid precursor protein (the precursor to Aβ):

  • Aβ peptide isolated from blood vessels of AD brain, then APP gene mapped to chromosome 21
  • Some cases of EOAD linked to chromosome 21
  • Now 25 mutations of APP characterised in AD
152
Q

Describe how amyloid precursor protein (APP) is involved in Alzheimer’s disease.

A
  • APP is a membrane protein with uknonw function
  • It can be cleaved at various sites
  • If it is cleaved sequentially at two points by β-secretase and γ-secretase, it can form Aβ peptides
  • Aβ peptides, especially Aβ 42, are amyloidogenic and form the amyloid that is seen in Alzheimer’s disease
  • The Aβ are usually cleared, but they accumulate in AD
  • Some early onset AD can be explained by:
    • Dominant mutations of APP gene
      • Near the cleavage sites
      • Increase production of Aβ peptide
      • Increase production of Aβ 42 peptide
      • Increase Aβ peptide fibrillisation
    • Gene dosage (duplications of the APP gene), which increase production of APP
    • γ-secretase mutations, which increase the formation of Aβ peptide
  • Early onset AD is rare compared to late onset, but these mutations tell us something about the pathogenesis of AD
153
Q

Describe the pathogenesis of Alzheimer’s disease.

A

Amyloid Cascade Hypothesis:

  • Aβ is involved in both early-onset (EOAD) and late-onset Alzheimer’s disease (LOAD)
  • The mechanism by which the EOAD and LOAD lead to plaques and tangles is different, but the common factor is the build up of Aβ
  • EOAD may involve increased production of Aβ, while LOAD involves decreased clearance
  • Aβ42 forms into amyloid, which leads to a cascade of events
  • There is microglial and astrocyte activation, increased inflammation and then tau tangle formation within cells, leading to widespread neuronal loss and dementia

However, this is just a theory and it has come under some criticism.

154
Q

According to the amyloid cascade hypothesis of Alzheimer’s disease, what is the initiating event of AD?

A

Aβ deposition as amyloid plaque leads to a cascade of events, including neurofibrillary tangles.

155
Q

What are the implications of the amyloid deposition hypothesis of AD?

A

Removal of amyloid plaque should be a useful treatment for AD, since amyloid is the initiating event of the pathogenesis of AD.

156
Q

Give some experimental evidence for clearing plaques in Alzheimer’s disease.

A
  • Active immunisation of patients with AD (via administration of Aβ42 and an adjuvant) leads to the production of antibodies
  • This leads to the removal of Aβ deposits from brain, but the degree of this is highly variable between patients
  • There was also no change in cognitive decline when the plaques were removed
  • This seems to argue against the amyloid cascade hypothesis -> However, it can be explained by the idea that the amyloid initiates the intracellular tangle formation, which is self-sufficient once initiated, meaning that the amyloid removal has no effect.
157
Q

Why is it more difficult to determine risk genes for late-onset Alzheimer’s disease than early-onset Alzheimer’s disease?

A

EOAD is often caused by one dominant gene mutation (e.g. in APP), while LOAD involves multiple genes coming together, which individually might have tiny penetrance and are therefore difficult to find.

158
Q

Give an example of a gene that influences risk of late-onset Alzheimer’s disease.

A
  • ApoE -> Involved in lipoprotein transport in blood
  • Having two ApoE4 alleles increases your risk of LOAD 4-fold compared to the most common ApoE homozygous phenotype
  • The mechanism for why this happens is unknown
159
Q

Name some genes involved in Alzheimer’s disease that GWAS have enabled to be determined.

A
160
Q

What are pure tauopathies?

[EXTRA]

A
161
Q

Describe the symptoms of Parkinson’s disease.

A
  • Slowness to move (bradykinesia)
  • Inability to move (akinesia)
  • Resting tremor
  • Postural instability
162
Q

Describe the pathology of Parkinson’s disease.

A
  • Degeneration of midbrain dopaminergic neurons projecting from substantia nigra pars compacta to striatum
  • This degeneration is due to Lewy bodies, which are aggregations containing α-synuclein
  • Loss of dopamine in the striatum
  • Relentlessly progressive
163
Q

Which protein is the cause of Parkinson’s disease?

A

α-synuclein (it is deposited, forming Lewy bodies)

164
Q

What are some mutations that can underlie familial Parkinson’s disease?

A

α-synuclein mutations. These are most commonly duplications or triplications, which can be detected using fluorescent in situ hybridisation.

165
Q

Why are dopaminergic neurons preferentially vulnerable in Parkinson’s disease?

[EXTRA]

A
  • Enormous metabolic demand -> Predisposes to oxidative stress
  • Dopamine is a highly cytotoxic chemical
166
Q

Is Parkinson’s just a normal part of ageing?

A

(Fearnley and Lees, 1991):

  • Compared controls and PD patients
  • Controls showed a linear loss of pigmented neurons in SNpc, with an average of 4.7% per decade.
  • PD patients showed exponential loss of pigmented neurons, with 45% loss in first decade. The pattern of loss within the brain was also different.
  • This shows that PD is not just a normal part of ageing, but a different disease process.
167
Q

Name another gene involved in Parkinson’s disease.

[EXTRA]

A
168
Q

Name some genes involved in Parkinson’s disease discovered by GWAS.

[EXTRA]

A
169
Q

Name some risk factors and protective factors for Alzheimer’s disease and Parkinson’s disease.

A
170
Q

Name some novel molecular therapies for Alzheimer’s, tauopathies and Parkinson’s disease.

[EXTRA]

A
171
Q

Compare how cognition changes in normal ageing and dementia.

A
  • Cognition is on a specturm, becoming more widely distributed with age
  • Between normality and dementia, there is a state of mild cognitive impairment, which can be considered as the prodrome of dementia
172
Q

Do all types of cognition decline with age?

A
  • Most types of cognition decline with age, including:
    • Working memory
    • Processing speed
    • Long-term memory
    • Reasoning
  • The only exception is semantic memory and crystallised intelligence.
173
Q

Are all parts of the brain atrophied in ageing?

A

No, different parts atrophy to different extents. The hippocampus in particular tends to atrophy significantly.

174
Q

What is the Oxford cognitive screen?

[EXTRA]

A

A chart developed to help record the functional deficiencies that patients with various brain lesions have.

175
Q

Is skill learning affected by ageing?

A

It is preserved, but it might just take longer.

176
Q

Describe what defines successful ageing. Give some experimental evidence.

A

(Cabeza, 2002):

  • Studied participants performing a language task
  • Young participants showed high asymmetry between the hemispheres
  • Low-functioning older participants maintained this symmetry, but had low brain activity
  • High-functioning older participants did not show such great asymmetry but showed much higher activity in both hemispheres

This can be explained by several theories:

  • Compensation -> There is additional recruitment of neural activity to maintain performance
  • De-differentiation -> There is loss of regional specificity
  • Scaffolding -> There is a dynamic ongoing process of plasticity
177
Q

Describe the prevalence of dementia.

A
178
Q

What represents ageing more accurately: cross-sectional or longitudinal studies?

A
  • Cross-sectional studies tend to over-estimate the effects of ageing because younger participants are likely to be more familiar with technology used (e.g. tablets)
  • Longitudinal studies tend to under-estimate the effects of ageing because the participants get used to the method of assessing them and therefore do not appear to decline as much
179
Q

What are 3 commonly reported phenomena seen in ageing?

A
  1. Overactivity of relevant brain areas when performing a task (Smith, 2001)
  2. Reductions in hemispheric asymmetry in functions such as language (Cabeza, 2002)
  3. Shift from posterior to anterior brain activity (Davis, 2008)
180
Q

What are the different causes of Alzheimer’s disease?

A
  • Late onset is typically sporadic
  • Early onset is typically familial (genetic)
181
Q

What are some causes of dementia mentioned in the spec and how common are they?

[IMPORTANT]

A
  • Alzheimer’s disease -> 60-80%
  • Fronto-temporal dementia -> 5-20%
  • Vascular dementia -> 5-15%
  • Lewy body disease -> 2-8%
  • Creutzfeldt–Jakob disease (prion disease) -> Rare
182
Q

For dementia caused by Alzheimer’s disease, describe the prevalence, pathology and the primary site/features.

A
  • Prevalence: 60-80%
  • Pathology: Amyloid plaques and tau tangles
  • Site/Features: Medial temporal lobe and parietal lobe -> Then progresses to frontal areas
183
Q

For fronto-temporal dementia, describe the prevalence, pathology and the primary site/features.

A
  • Prevalence: 5-20%
  • Pathology: Several subtypes involving the aggregation of proteins such as tau, TDP43 or FUS
  • Site/Features: Frontal lobe (behavioural symptoms) or temporal lobe (semantic/aphasia symptoms)
184
Q

For vascular dementia, describe the prevalence, pathology and the primary site/features.

A
  • Prevalence: 5-15%
  • Pathology: Vascular pathology (e.g stroke)
  • Site/Features: Can be anywhere, Sudden changes, Step-wise progression
185
Q

What are some biomarkers for dementia?

A
186
Q

What are some risk factors and protective factors for cognitive decline (e.g. dementia and delirium)?

[IMPORTANT]

A
187
Q

What is the difference between dementia and delirium?

A
  • Both show forgetfulness, impaired memory, confusion and degrees of paranoia.
  • Dementia shows a progressive gradual decline.
  • Delirium shows a fluctuating course, sudden onset, with short duration, and impaired attention and awareness.
188
Q

For dementia with Lewy bodies, describe the prevalence, pathology and the primary site/features.

A
  • Prevalence: 2-8%
  • Pathology: Lewy bodies (also seen in Parkinson’s disease)
  • Site/Features: Motor symptoms, Sleep disturbance (similar to in Parkinson’s disease), Visual hallucinations, Fluctuating deficits
189
Q

For dementia due to Creutzfeldt–Jakob disease, describe the prevalence, pathology and the primary site/features.

A
  • Prevalence: Rare
  • Pathology: Prion protein deposition
  • Site/Features: ADD
190
Q

Define dementia.

A

A set of symptoms including memory loss, mood changes and problems with communicating and reasoning.

191
Q

What are the diagnostic criteria for dementia?

A
  • Multiple cognitive deficits (including amnesia)
  • Functional impairment
  • Clear consciousness
  • Change from previous level
  • Long duration (> 6 months)
192
Q

What are some standard neuropsychological tests for dementia?

A
  • MMSE - Mini-mental state examination. Maximum score 30. MCI < 27; AD < 25
  • ACE-R - Addenbrooke’s Cognitive Examination (revised): Includes MMSE, but more detail. Maximum score = 100, AD < 88
  • MOCA - Montreal Cognitive Assessment: Maximum score 30. HC = 25-29; MCI = 19-25; MD = 11-21
193
Q

What are some other disorders of ageing that may affect cognition?

A
  • Parkinson’s disease
  • Stroke
  • Depression
194
Q

Compare the causes of dementia and delirium.

[IMPORTANT]

A
  • Dementia -> Neurodegenerative, Vascular, etc.
  • Delirium -> Metabolic disturbances (e.g. hypoxia, hypoglycaemia, etc.), etc.

Both can be caused by toxins and infections.

195
Q

Define drug addiction.

A

When drug-seeking and use becomes compulsive despite negative consequences e.g. health risk physical and mental, inability to sustain normal social interactions, relationships or job, dissolution of family, child neglect

196
Q

Is addiction a disease?

A

Yes, the American Society of Addiction Medicine 2011 defines it as:

“A primary, chronic disease of brain reward, motivation, memory and related circuitry” characterized by the “inability to consistently abstain, impairment in behavioural control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response”

197
Q

What are some different components of addiction?

A
198
Q

At what sorts of targets do various addictive drugs act?

A

GPCRs:

  • Opoids
  • Cannabinoids

Ionotropic receptors:

  • Nicotine
  • Alcohol
  • Benzodiazepines

Monoamine transporters:

  • Cocaine
  • Amphetamines
199
Q

What is the defining characteristic of addictive drugs?

A

Their ability to increase dopamine transmission, especially in the nucleus accumbens (part of the striatum) via the mesolimbic (reward) pathway.

Drugs that do not affect dopamine signalling are not addictive.

200
Q

What is mesolimbic pathway and what is its role?

A
  • The mesolimbic pathway features dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NA) in the striatum
  • It is known as the reward pathway, but its role is more refined than that
  • (Hollerman & Schultz, 1998):
    • Found that there is an increase in dopamine firing when an animal receives an unexpected reward after an action/stimulus
    • Also found that there is a decrease in dopamine firing when an animal receives no reward after a action/stimulus (i.e. error)
    • However, this effect is lost once the animal learns to associate the correct action/stimulus with the reward
    • Instead, there is now dopamine firing after the conditioned stimulus, but not after the reward
  • This suggests there are two roles for the mesolimbic pathway:
    • Reward prediction error learning -> Promotes learning about reward
    • Rewarding predictions or cues -> Promotes reward-seeking behaviour
201
Q

How do addictive drugs related to the functions of the mesolimbic pathway?

A
202
Q

What underlies the transition from acute drug action to chronic and compulsive drug-seeking?

A
  • Avoiding negative reinforcement? (i.e. Withdrawal avoidance)
  • Neuroplastic changes in synaptic strength throughout brain and gene expression
  • Maladaptive learning that leads to enhanced response to drug-seeking cues: cue-induced craving and drug-seeking habit
  • Impaired self-regulation (impaired cognitive control)
203
Q

Give some experimental evidence for the neuronal changes that are seen in long-term drug use that may explain the increased sensitization.

[EXTRA]

A

(Ungless, 2001) and (Saal, 2003):

  • Used the ratio of AMPA:NMDA receptors as an indicator of the strength of glutamatergic synapses between glutamate neurons and dopamine neurons of the mesolimbic pathway (i.e. the VTA neurons)
  • Found that there was long-term potentiation at these synapses upon long-term use of cocaine, amphetamines, morphine, nicotine and ethanol

(Robinson & Kolb, 1997):

  • Found that drug sensitization is accompanied by visible changes to neuronal structure, namely changes in dendritic structure in the striatum
204
Q

Describe the genetic changes that are seen in long-term drug use.

A
  • There are changes in drug expression
  • These include up-regulation of growth/transcription/ chromatin/histone regulators e.g. BDNF, cFos, deltaFosB, CREB, epigenetic factors
  • These changes produce long-lasting changes in neuronal function that can last for several months
205
Q

What are drug-seeking cues?

A
  • Stimuli that are related to the drug taking environment, such that have acquired a behavioural salience (i.e. they have become conditioned stimuli).
  • For example, a lighter may be a drug-seeking cue for a smoker.
  • Environmental drug-associated cues drive craving and maintain drug-seeking habits.
206
Q

Which parts of the brain are related to drug-seeking cues?

A
  • Initial acquisition of drug-seeking behaviour depends on dopamine in nucleus accumbens (ventral striatum), but dopamine antagonists in dorsal striatum not nucleus accumbens diminish cue-induced cocaine seeking (Vanderschuren, 2005)
  • Cue-elicited craving in human addicts activates dopamine release in dorsal striatum (Volkow, 2006)
207
Q

Describe how decision-making may be impaired in drug users.

A

Volkow showed that there was decreased prefrontal cortex activity in addicted individuals compared to non-addicted individuals and also suggested that executive control may be insufficient compared to the drive, reward and memory systems, such that there is impaired decision making.

208
Q

Summarise the treatments for addiction.

A
209
Q

What are some reasons why people relapse into drug-taking?

A

3 main causes:

  • Drugs -> Even just taking the drug once (“one more puff”) will reinforce all of the circuit and reset the addiction
  • Drug-associated cues -> Induce craving
  • Stress -> Drives drug-seeking behaviour
210
Q

Name a condition in which sleep may be disrupted.

A

Schizophrenia

211
Q

Describe the principle of pharmacological treatments for dementia.

[IMPORTANT]

A

Anti-cholinesterases may be used to increase cholinergic transmission.

YEAR 2 - The Nervous System (18 decks)

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