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Neuroscience > Lecture 8 - Neurobiology and Pharmacology of Schiz > Flashcards

Lecture 8 - Neurobiology and Pharmacology of Schiz Flashcards

1
Q

Outline Otto Loewi 1921 study on neurotransmitters in frog heart chambers

A

Isolated 2 hearts in bath solution liquid saline
1 each side connected by saline solution
Electrical impulse 1 heart cause it to best
2nd heart beats at same ear

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2
Q

What is the criteria of a neurotransmitter

A

Produced within a neuron
Found within a neuron
Neuron stimulated (depolarised) neuron must release the chemical
Chemical released acts on post synaptic receptor causing biological effect
After be inactivated. Through reputable or analyse stops activation
Chemical applied on post synaptic membrane same effect when released by neuron

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3
Q

What are the 4 classes of neurotransmitters

A

Amino acids

Biochemical amines

Peptides

Others

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4
Q

Why is glutamate a major excitatory neurotransmitter

A

Gets things done quickly
Multiple pathways use it
Abundant
Synthesised from glutamate in astrocytes
Released synaptic cleft
Removed synapse by glutamate transporters

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5
Q

Outline what pathways use glutamate

A 
Cortical Association
Cortico-Thalamic 
Cortico-Spinal 
Basal Ganglia 
Hippocampal 
Cerebellar
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6
Q

Summary of the pathways in glutamate location and how it is released

A

Pathway from VTA substantia nigra going PFC. To struts thalamus to PFC

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7
Q

What happens presynaptically for glutamate

A

Stored vesicles released into extracellular space
Synaptic glutamate stimulate glutamate receptors both pre and post synaptic neurons
Before cleared by EAAT locates glial cells to begin cycle again

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8
Q

Outline presynaptic dopamine role

A

Transported to vesicles release contents increase Ca2+
Stimulate dopamine receptors both pre and post synaptic neurons
Before cleared DAT or metabolism
VTA projects PFC and substantia nigra

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9
Q

Outline modulatory dopaminergic neurons

A

Project dorsal striatum via substantia nigra, central striatum, pre frontal cortex via VTA
Thalamus reciprocal excitatory glutamate connections to striatum and PFC

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10
Q

Outline prefrontal cortical efferent and glutamate

A

Prefrontal cortical efferent excitatory glutamate neurons extent to striatum nucleus accumbens and VTA

Located number different regions

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11
Q

What are the subtypes are glutamate receptor

A

Different effects depending which receptor NT binding to

NMDA
AMPA and Kainate
Metabotropic

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12
Q

What are the 2 classes of glutamate receptors

A

Ionotropic

Metabotropic

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13
Q

Outline Ionotropic glutamate receptor

A

Receipts act really fast
Gateway
Vision, perception
Glutamate

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14
Q

Outline metabotropic receptors

A

Stimulate other molecules
In turn stimulate other molecules etc
Slower, tasting, pain
Dopamine

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15
Q

What is the role of a neurotransmitter

A

Enhance synthesis - increase rate being produced

Increase release

Block reuptake

Reduce metabolism

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16
Q

Outline role of a receptor

A

Mimic effect
Antagonist
Allosteric modulator

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17
Q

What does reduced function of NMDA glutamate receptors lead to according to glutamate Hypothesis

A

Reduced glutamate transmission

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18
Q

Outline Kim 1980 on glutamate Hypothesis

A

Reduced glutamate in cerebrospinal fluid in Schiz ppts

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19
Q

Outline role of PCP and Ketamine in Glutamate Hypothesis of Schiz

A

NMDA antagonists = block glutamate receptor
Produce positive and negative symptoms
Hallucinations, delusions, psychotic episodes
Depressive, lack of motivation

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20
Q

How do genes associate with the glutamate Hypothesis of Schiz

A

Genes associated increased risk Schiz
Influence function modulatory sites NMDA receptor or intracellular receptor interacting proteins
Link glutamate receptors signal transduction pathways

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21
Q

Outline an example of genes associated with glutamate in Schiz

A

Associated allergic variants of genes for neuregulin 1
Influence expression NMDA receptors through activation of Erb4 receptors and GRM3
Encodes the mGlu3 subtype of metabotropic glutamate receptors

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22
Q

What do post mortem studies tell us of glutamate Hypothesis of Schiz

A

Show changes in glutamate receptor binding transcription and subunit protein expression
In pre frontal cortex thalamus and hippocampus Schiz
Down regulated levels

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23
Q

Examples of findings from post mortem studies on glutamate Hypothesis of Schiz

A

Decreases in NR1 subunits of NMDA receptor in hippocampus and frontal cortical areas

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24
Q

What do glutamate neurons regulate according to the glutamate Hypothesis

A

Function of other neurons
Dopamine - target of antipsychotic drugs.
Glutamate acts as break on dopamine:
Loss receptors remove break increase dopamine release
Causing dopamine hyperactivity by reduced glutamate function

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25
Q

How is the bursting of dopamine neurons implicates in glutamate Hypothesis

A

Integral component of response to environmental stimuli

Depending on activation of NMDA receptors these neurons

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26
Q

How are D2 receptors linked to glutamate Hypothesis

A

Localised presynaptically in glutamate terminals and work inhibit release glutamate
Reduced D2 receptor function produces modest increases glutamate release

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27
Q

What pathways are involved in the glutamate Hypothesis

A

From VTA to PFC (glutaminergic pathways)
VTA to nucleus accumbens (Mesolimbic dopamine pathway)
Under active and kept in check by glutaminergic pathway

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28
Q

How does the glutamate hypothesis explain the positive symptoms of Schiz

A

Glutamate System hypoactivate
Consequence
Dopamine System overactive

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29
Q

What are the consequences of glutaminergic hypofunction

A

Reduced brain function

Negative cognitive and affective symptoms

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30
Q

What is the dopamine hypothesis of Schiz

A

Overactivity of dopaminergic synapses likely Mesolimbic pathway coming from VTA

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31
Q

How do we measure dopamine synthesis

A

Measure in cerebral spinal fluid

Measure dopamine levels

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32
Q

What is the synthesis of dopamine

A

Tyrosine

DOPA

Dopamine

DOPAC / NORADRENALINE

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33
Q

How does the Mesolimbic dopamine hypothesis produce proposition symptoms Schiz

A

Overactivity Mesolimbic System produce positive symptoms

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34
Q

How does the Mesolimbic dopamine hypothesis explain affects of amphetamine

A

Amphetamine releases dopamine mid brain creating visual and auditory hallucinations
Drugs block dopamine these regions attenuation symptoms

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35
Q

How does the Mesolimbic dopamine hypothesis explain both positive and negative symptoms

A

Reduced activation mesocortical VTA to DL cortical regions
Increased VTA to nucleus accumbens
Decreased activity frontal regions

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36
Q

How does the Mesolimbic dopamine hypothesis use a see saw analogy

A

Balance between mid and frontal brain
Like see saw
Mid down frontal high
Frontal low midbrain high

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37
Q

Outline Weinberger extended dopamine hypothesis for positive symptoms

A

Positive symptoms caused overactivity dopaminergic synapses likely in Mesolimbic pathway

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38
Q

Outline Weinberger extended dopamine hypothesis for negative and cognitive symptoms

A

Coming from VTA consequent hypoactivity of dopaminergic synapses in prefrontal cortical regions - negative and cognitive symptoms

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39
Q

Outline prefrontal cortex and Schiz symptoms

A

Increased release dopamine in nucleus accumbens produces positive symptoms
Loss neurons dorsolateral prefrontal cortex
Reduced its inhibitory effects
On release DA in nucleus accumbens - negative symptoms

40
Q

What are the 2 dopamine receptor subclasses

A

Activation of adenylate Cyclase

Inhibition of adenylate cyclase

41
Q

What makes up the Activation of adenylate Cyclase

A

D1

D5

Slow receptors

42
Q

What makes up the Inhibition of adenylate Cyclase

A

D2
D3
D4

43
Q

What are the 2 main classes of dopamine receptors receives dopamine signal

A

D1 and D2

Perform balancing act to control a neurons response

44
Q

Outline the D1 receptor

A

When D1 receptor bound by dopamine
Stimulates cell by activating enzyme adenylate cyclise
And signally molecule cyclic AMP turn on gene transcription

45
Q

Outline D2 receptors

A

Opposite effect

Inhibiting cyclic AMP production
Preventing cell activation

Regulation DA release by acting as auto receptors on somatodendritic region midbrain dopamine neurons

46
Q

Where are D1-5 receptors locates in brain

A

Most abundant frontal cortical region

Cerebral cortex limbic system

47
Q

Where are D3 and D5 receptors located

A

Hypothalamus

48
Q

Where are D1 and D2 receptors located in brain

A

Corpus striatum

Dopamine do different things depending which area bind to and what receptors bind to

49
Q

Drugs used to treat people with Schiz

A

Antipsychotics

Neuroleptics

Major tranquillisers

50
Q

What is an agonist

A

Drug occupies receptors and actives the
Full activation
Structurally similar to NT to activate receptor

51
Q

What is an antagonist

A

Drugs occupy receptors but do not activate them
Block receptor activation by agonists
No activation
Diverse structures often unrelated to NT

52
Q

What happens when agonist and antagonist are together

A

Less activation

53
Q

What was the trend of treatment of mentally ill until 50s

A

Increasing number resident patients increased until 50s

When drugs introduced and numbers declined

54
Q

Examples of Typical Antipsychotics

A 
Chlorpromazine largactil 
Thioridizine Mellaril
Fluphenazine Prolixin
Loxapine Loxitane
Haloperidol Haldol 
Molindone Moban
55
Q

Examples of Atypical Antipsychotics

A 
Clozapine Clozaril 
Risperidone Risperdol
Remozipride
Seroquel
Olanzapine
56
Q

Outline which receptors are associated with Typical Antipsychotics

A

Antagonists at D2 receptors

57
Q

Outline which receptors are associated with Atypical Antipsychotics

A

D2 and
Bind serotonin subtypes
5HT2A

58
Q

What is the Law of Thirds for treatment of mental illnesses

A
  1. Significant time hospitalised - unemployed, poor social interaction, institutionalised
  2. Respond well drug therapy. Employable. Relatively normal socially
  3. Significant improvement symptoms. Relapses and hospitalisation. Reduced employment, social isolation. Assistance.
59
Q

Parkinson’s side effects of anti psychotics

A

Blocking dopamine striatum in mid brain restricts slows movement
Degeneration DA cells removes inhibitory influence on ACh neurons fires more causing movement disorder

DA receptors normally inhibits Cholinergic cells. Blocking receptors leads motor effects as degeneration cells in Parkinson’s

60
Q

How can we reduce Parkinson’s symptoms

A

Anticholinergic drugs block ACh receptors reducing Parkinson’s

61
Q

Affects of Risperidone on symptoms of Schiz

A

Acts 5HT2 and dopamine

Best medication all 2 symptoms - positive negative psychopathology

62
Q

Affects of Haloperidol on symptoms of Schiz

A

Relatively pure D2 antagonist

Improvement positive symptoms only

63
Q

Outline the correlation between antipsychotic drugs binding to dopamine receptors by Seeman et al 1976

A

Direct correlation anti psychotics binding dopamine receptors
Relationship between dosage and binding
More bound receptors better clinical results

64
Q

Outline correlation between anti psychotics binding to serotonin receptors

A

No correlation between binding serotonin receptors and anti psychotics and clinical effectiveness

65
Q

Outline how to use PET scanning to identify dopamine D2 receptor occupancy by anti psychotics

A

Gamma waves detected from radio labelled ligand bound chemically to molecule activated D2 receptors

66
Q

What is the D2 occupancy in different Antipsychotics through PET scanning

A

Haloperidol - typical antagonist reduction D2 receptor

Clozapine - atypical not as strong reduction D2

Risperidone - atypical strong reduction D2

67
Q

What is the 5HT2 occupancy in different atypical antipsychotics

A

Haloperidol - typical D2 antagonist - same 5HT2 as control group

Clozapine - atypical reduction 5HT2

Risperidone - atypical, lesser degree reduction 5HT2

Different effect in newer drugs

68
Q

Side effects of antipsychotic drugs

A 
Long term effects
Involuntary movements
Weight gain - newer drugs 
Clozaril highest weight gain 10 pounds 
Moban lose weight
Issues compliance drug taking
69
Q

Cumulative incidence of tar dive dyskinesia

A

Taken drug for 1 year - 6%

5 years - 32%
10 years - 49%
15 years - 57%
20 years - 65%
25 years - 68%
70
Q

Why do we need animal models

A

Understand disease process
Predict which drugs be developed
Work out side effects profiles of drugs

71
Q

Who is Arvid Carlsson

A

Nobel prize functions of dopamine

Link between Schiz and dopamine abnormality

72
Q

Outline animal models types validity by Willner 1991

A

Construct - whether induce dopamine abnormality in animal

Predictive - do antipsychotic drugs have effect in model

Face - look like Schiz? Look how form associations and role dopamine forming associations and effects drugs

73
Q

What are the dose response curves for haloperidol

A

Dissociate good effects from side effects
Mice D2 agonist receptor induces behaviour hyperactivity
Drugs blocks D2 receptor induce sedation
Define effects drug of hyperactivity from catalepsy
Side effect very far away from good effects = safer use

74
Q

When looking at a graph how can we tell is there are high or low potential motor side effects

A

Distance between curves small = high motor side effect

Distance between curve large = low motor side effect potential

75
Q

How do psychological therapies enhance effectiveness of drug treatments

A

Family and social skills training alongside drugs leads lowest percentage relapsing

Family therapy and drugs middle

Social skills and drugs highest relapsing

Drugs alone highest relapse

76
Q

What do psychological therapies tell us about biology and psychology

A

What is happening biologically and psychologically 2 way system
Behaviour inducing effects in dopamine
Similarly dopamine effecting behaviour

77
Q

What is the schematic representation of neurodevelopmental model of Schiz

A

Reduced inhibitory feedback

No mesocortical pathway feeding to VTA

78
Q

How animal models relevant to Schiz

A

Work out biology
PCP amphetamine apomorphine induced hyperactivity
PCP amphetamine induced disruption of attentional functions = deficit Schiz

Early developmental lesion hippocampal or pre frontal cortical regions
Maternal separation or social isolation
Genetic mutation genes increase risk

79
Q

How does D-Amphetamine abolish latent Inhibition but show reduced locomotor hyperactivity in DRD2

A

Delete D2 receptor generically mouse
Look affects amphetamine
No D2 receptors amphetamine not produce hyperactivity = blocks affects
Latent Inhibition not find these affects.
Something not D2 monitoring effects of latent Inhibition and amphetamine

80
Q

What is pre pulse Inhibition

A

Startle response something unexpected
Pre warning won’t jump as much = response inhibited
Sensory motion grating = how filter info

81
Q

How is pre pulse Inhibition disrupted

A

Disrupted by drugs that induce psychosis
Amphetamine PCP
Reversed by Antipsychotics = haloperidol and clozapine
Increase dopamine directly into nucleus accumbens

82
Q

Animal model correlations of pre pulse Inhibition

A

Correlation between doses drugs used restore pre pulse Inhibition and relative clinical potency

83
Q

Outline Latent Inhibition by Lubow and Moore 1959 study

A

Prior exposure stimulus without consequence

Retards subsequent learning stimulus

84
Q

Outline Latent Inhibition by Lubow and Moore 1959 disrupted by amphetamine

A

Disruption reversed by antipsychotic drugs

85
Q

Outline Latent Inhibition by Lubow and Moore 1959 study how latent Inhibition enhanced

A

Enhanced by antipsychotic drugs given alone

86
Q

Outline Latent Inhibition by Lubow and Moore 1959 study on water restriction in thirsty rats

A

Pre training: rat trained lick from spout

Pre exposure/non pre exposure: either exposed 20-60 tones or no tones

Conditioning: mild foot shock paired with tone twice

87
Q

Outline Latent Inhibition by Lubow and Moore 1959 study on water restriction in thirsty rats test conditions

A

Rats put in Skinner box and allowed drink from spouts

Group not pre exposed stop drinking when hear tone. Associate tone with shock

Pre exposed - keep drinking Think tone irrelevant to shock

88
Q

Outline Schiz as a disorder of salience

A

Dysregulated hyperdopaminergic state leads faulty assignment of salience to elements of experience

Critical understand how dopamine acts mediate aberrations in salience allocation understand this aspect Biological basis these symptoms

89
Q

Outline Delusion symptom of Schiz as disorder of salience

A

Delusions arise try make sense aberrantly salient experiences

90
Q

Outline Hallucinations symptom of Schiz as disorder of salience

A

Hallucinations reflect direct experience of aberrant salience of internal representations

91
Q

Outline antipsychotic drugs and a Schiz as disorder of salience

A

Antipsychotics through actions on D2 receptors
“Dampen the salience”
These abnormal experience thus alleviating symptoms

92
Q

Outline treatment of Amphetamine on effect of Latent Inhibition

A

Amphetamine disrupts latent Inhibition

93
Q

Outline treatment of D2 antagonist on latent Inhibition

A

D2 antagonist enhance latent Inhibition

94
Q

Outline treatment of Amphetamine and D2 antagonist on latent Inhibition

A

Amphetamine and D2 antagonist restore latent Inhibition after amphetamine disruption

95
Q

Outline D1 antagonist and D1 agonist treatment effect on latent Inhibition

A

Both no effect

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