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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
How is the bursting of dopamine neurons implicates in glutamate Hypothesis
Integral component of response to environmental stimuli | Depending on activation of NMDA receptors these neurons
26
How are D2 receptors linked to glutamate Hypothesis
Localised presynaptically in glutamate terminals and work inhibit release glutamate Reduced D2 receptor function produces modest increases glutamate release
27
What pathways are involved in the glutamate Hypothesis
From VTA to PFC (glutaminergic pathways) VTA to nucleus accumbens (Mesolimbic dopamine pathway) Under active and kept in check by glutaminergic pathway
28
How does the glutamate hypothesis explain the positive symptoms of Schiz
Glutamate System hypoactivate Consequence Dopamine System overactive
29
What are the consequences of glutaminergic hypofunction
Reduced brain function | Negative cognitive and affective symptoms
30
What is the dopamine hypothesis of Schiz
Overactivity of dopaminergic synapses likely Mesolimbic pathway coming from VTA
31
How do we measure dopamine synthesis
Measure in cerebral spinal fluid | Measure dopamine levels
32
What is the synthesis of dopamine
Tyrosine DOPA Dopamine DOPAC / NORADRENALINE
33
How does the Mesolimbic dopamine hypothesis produce proposition symptoms Schiz
Overactivity Mesolimbic System produce positive symptoms
34
How does the Mesolimbic dopamine hypothesis explain affects of amphetamine
Amphetamine releases dopamine mid brain creating visual and auditory hallucinations Drugs block dopamine these regions attenuation symptoms
35
How does the Mesolimbic dopamine hypothesis explain both positive and negative symptoms
Reduced activation mesocortical VTA to DL cortical regions Increased VTA to nucleus accumbens Decreased activity frontal regions
36
How does the Mesolimbic dopamine hypothesis use a see saw analogy
Balance between mid and frontal brain Like see saw Mid down frontal high Frontal low midbrain high
37
Outline Weinberger extended dopamine hypothesis for positive symptoms
Positive symptoms caused overactivity dopaminergic synapses likely in Mesolimbic pathway
38
Outline Weinberger extended dopamine hypothesis for negative and cognitive symptoms
Coming from VTA consequent hypoactivity of dopaminergic synapses in prefrontal cortical regions - negative and cognitive symptoms
39
Outline prefrontal cortex and Schiz symptoms
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
What are the 2 dopamine receptor subclasses
Activation of adenylate Cyclase Inhibition of adenylate cyclase
41
What makes up the Activation of adenylate Cyclase
D1 D5 Slow receptors
42
What makes up the Inhibition of adenylate Cyclase
D2 D3 D4
43
What are the 2 main classes of dopamine receptors receives dopamine signal
D1 and D2 | Perform balancing act to control a neurons response
44
Outline the D1 receptor
When D1 receptor bound by dopamine Stimulates cell by activating enzyme adenylate cyclise And signally molecule cyclic AMP turn on gene transcription
45
Outline D2 receptors
Opposite effect Inhibiting cyclic AMP production Preventing cell activation Regulation DA release by acting as auto receptors on somatodendritic region midbrain dopamine neurons
46
Where are D1-5 receptors locates in brain
Most abundant frontal cortical region | Cerebral cortex limbic system
47
Where are D3 and D5 receptors located
Hypothalamus
48
Where are D1 and D2 receptors located in brain
Corpus striatum Dopamine do different things depending which area bind to and what receptors bind to
49
Drugs used to treat people with Schiz
Antipsychotics Neuroleptics Major tranquillisers
50
What is an agonist
Drug occupies receptors and actives the Full activation Structurally similar to NT to activate receptor
51
What is an antagonist
Drugs occupy receptors but do not activate them Block receptor activation by agonists No activation Diverse structures often unrelated to NT
52
What happens when agonist and antagonist are together
Less activation
53
What was the trend of treatment of mentally ill until 50s
Increasing number resident patients increased until 50s | When drugs introduced and numbers declined
54
Examples of Typical Antipsychotics
``` Chlorpromazine largactil Thioridizine Mellaril Fluphenazine Prolixin Loxapine Loxitane Haloperidol Haldol Molindone Moban ```
55
Examples of Atypical Antipsychotics
``` Clozapine Clozaril Risperidone Risperdol Remozipride Seroquel Olanzapine ```
56
Outline which receptors are associated with Typical Antipsychotics
Antagonists at D2 receptors
57
Outline which receptors are associated with Atypical Antipsychotics
D2 and Bind serotonin subtypes 5HT2A
58
What is the Law of Thirds for treatment of mental illnesses
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
Parkinson’s side effects of anti psychotics
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
How can we reduce Parkinson’s symptoms
Anticholinergic drugs block ACh receptors reducing Parkinson’s
61
Affects of Risperidone on symptoms of Schiz
Acts 5HT2 and dopamine Best medication all 2 symptoms - positive negative psychopathology
62
Affects of Haloperidol on symptoms of Schiz
Relatively pure D2 antagonist Improvement positive symptoms only
63
Outline the correlation between antipsychotic drugs binding to dopamine receptors by Seeman et al 1976
Direct correlation anti psychotics binding dopamine receptors Relationship between dosage and binding More bound receptors better clinical results
64
Outline correlation between anti psychotics binding to serotonin receptors
No correlation between binding serotonin receptors and anti psychotics and clinical effectiveness
65
Outline how to use PET scanning to identify dopamine D2 receptor occupancy by anti psychotics
Gamma waves detected from radio labelled ligand bound chemically to molecule activated D2 receptors
66
What is the D2 occupancy in different Antipsychotics through PET scanning
Haloperidol - typical antagonist reduction D2 receptor Clozapine - atypical not as strong reduction D2 Risperidone - atypical strong reduction D2
67
What is the 5HT2 occupancy in different atypical antipsychotics
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
Side effects of antipsychotic drugs
``` Long term effects Involuntary movements Weight gain - newer drugs Clozaril highest weight gain 10 pounds Moban lose weight Issues compliance drug taking ```
69
Cumulative incidence of tar dive dyskinesia
Taken drug for 1 year - 6% ``` 5 years - 32% 10 years - 49% 15 years - 57% 20 years - 65% 25 years - 68% ```
70
Why do we need animal models
Understand disease process Predict which drugs be developed Work out side effects profiles of drugs
71
Who is Arvid Carlsson
Nobel prize functions of dopamine | Link between Schiz and dopamine abnormality
72
Outline animal models types validity by Willner 1991
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
What are the dose response curves for haloperidol
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
When looking at a graph how can we tell is there are high or low potential motor side effects
Distance between curves small = high motor side effect Distance between curve large = low motor side effect potential
75
How do psychological therapies enhance effectiveness of drug treatments
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
What do psychological therapies tell us about biology and psychology
What is happening biologically and psychologically 2 way system Behaviour inducing effects in dopamine Similarly dopamine effecting behaviour
77
What is the schematic representation of neurodevelopmental model of Schiz
Reduced inhibitory feedback | No mesocortical pathway feeding to VTA
78
How animal models relevant to Schiz
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
How does D-Amphetamine abolish latent Inhibition but show reduced locomotor hyperactivity in DRD2
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
What is pre pulse Inhibition
Startle response something unexpected Pre warning won’t jump as much = response inhibited Sensory motion grating = how filter info
81
How is pre pulse Inhibition disrupted
Disrupted by drugs that induce psychosis Amphetamine PCP Reversed by Antipsychotics = haloperidol and clozapine Increase dopamine directly into nucleus accumbens
82
Animal model correlations of pre pulse Inhibition
Correlation between doses drugs used restore pre pulse Inhibition and relative clinical potency
83
Outline Latent Inhibition by Lubow and Moore 1959 study
Prior exposure stimulus without consequence | Retards subsequent learning stimulus
84
Outline Latent Inhibition by Lubow and Moore 1959 disrupted by amphetamine
Disruption reversed by antipsychotic drugs
85
Outline Latent Inhibition by Lubow and Moore 1959 study how latent Inhibition enhanced
Enhanced by antipsychotic drugs given alone
86
Outline Latent Inhibition by Lubow and Moore 1959 study on water restriction in thirsty rats
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
Outline Latent Inhibition by Lubow and Moore 1959 study on water restriction in thirsty rats test conditions
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
Outline Schiz as a disorder of salience
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
Outline Delusion symptom of Schiz as disorder of salience
Delusions arise try make sense aberrantly salient experiences
90
Outline Hallucinations symptom of Schiz as disorder of salience
Hallucinations reflect direct experience of aberrant salience of internal representations
91
Outline antipsychotic drugs and a Schiz as disorder of salience
Antipsychotics through actions on D2 receptors “Dampen the salience” These abnormal experience thus alleviating symptoms
92
Outline treatment of Amphetamine on effect of Latent Inhibition
Amphetamine disrupts latent Inhibition
93
Outline treatment of D2 antagonist on latent Inhibition
D2 antagonist enhance latent Inhibition
94
Outline treatment of Amphetamine and D2 antagonist on latent Inhibition
Amphetamine and D2 antagonist restore latent Inhibition after amphetamine disruption
95
Outline D1 antagonist and D1 agonist treatment effect on latent Inhibition
Both no effect

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