Lecture 8 - Neurobiology and Pharmacology of Schiz Flashcards
Outline Otto Loewi 1921 study on neurotransmitters in frog heart chambers
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
What is the criteria of a neurotransmitter
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
What are the 4 classes of neurotransmitters
Amino acids
Biochemical amines
Peptides
Others
Why is glutamate a major excitatory neurotransmitter
Gets things done quickly
Multiple pathways use it
Abundant
Synthesised from glutamate in astrocytes
Released synaptic cleft
Removed synapse by glutamate transporters
Outline what pathways use glutamate
Cortical Association Cortico-Thalamic Cortico-Spinal Basal Ganglia Hippocampal Cerebellar
Summary of the pathways in glutamate location and how it is released
Pathway from VTA substantia nigra going PFC. To struts thalamus to PFC
What happens presynaptically for glutamate
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
Outline presynaptic dopamine role
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
Outline modulatory dopaminergic neurons
Project dorsal striatum via substantia nigra, central striatum, pre frontal cortex via VTA
Thalamus reciprocal excitatory glutamate connections to striatum and PFC
Outline prefrontal cortical efferent and glutamate
Prefrontal cortical efferent excitatory glutamate neurons extent to striatum nucleus accumbens and VTA
Located number different regions
What are the subtypes are glutamate receptor
Different effects depending which receptor NT binding to
NMDA
AMPA and Kainate
Metabotropic
What are the 2 classes of glutamate receptors
Ionotropic
Metabotropic
Outline Ionotropic glutamate receptor
Receipts act really fast
Gateway
Vision, perception
Glutamate
Outline metabotropic receptors
Stimulate other molecules
In turn stimulate other molecules etc
Slower, tasting, pain
Dopamine
What is the role of a neurotransmitter
Enhance synthesis - increase rate being produced
Increase release
Block reuptake
Reduce metabolism
Outline role of a receptor
Mimic effect
Antagonist
Allosteric modulator
What does reduced function of NMDA glutamate receptors lead to according to glutamate Hypothesis
Reduced glutamate transmission
Outline Kim 1980 on glutamate Hypothesis
Reduced glutamate in cerebrospinal fluid in Schiz ppts
Outline role of PCP and Ketamine in Glutamate Hypothesis of Schiz
NMDA antagonists = block glutamate receptor
Produce positive and negative symptoms
Hallucinations, delusions, psychotic episodes
Depressive, lack of motivation
How do genes associate with the glutamate Hypothesis of Schiz
Genes associated increased risk Schiz
Influence function modulatory sites NMDA receptor or intracellular receptor interacting proteins
Link glutamate receptors signal transduction pathways
Outline an example of genes associated with glutamate in Schiz
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
What do post mortem studies tell us of glutamate Hypothesis of Schiz
Show changes in glutamate receptor binding transcription and subunit protein expression
In pre frontal cortex thalamus and hippocampus Schiz
Down regulated levels
Examples of findings from post mortem studies on glutamate Hypothesis of Schiz
Decreases in NR1 subunits of NMDA receptor in hippocampus and frontal cortical areas
What do glutamate neurons regulate according to the glutamate Hypothesis
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
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
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
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
How does the glutamate hypothesis explain the positive symptoms of Schiz
Glutamate System hypoactivate
Consequence
Dopamine System overactive
What are the consequences of glutaminergic hypofunction
Reduced brain function
Negative cognitive and affective symptoms
What is the dopamine hypothesis of Schiz
Overactivity of dopaminergic synapses likely Mesolimbic pathway coming from VTA
How do we measure dopamine synthesis
Measure in cerebral spinal fluid
Measure dopamine levels
What is the synthesis of dopamine
Tyrosine
DOPA
Dopamine
DOPAC / NORADRENALINE
How does the Mesolimbic dopamine hypothesis produce proposition symptoms Schiz
Overactivity Mesolimbic System produce positive symptoms
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
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
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
Outline Weinberger extended dopamine hypothesis for positive symptoms
Positive symptoms caused overactivity dopaminergic synapses likely in Mesolimbic pathway
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
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
What are the 2 dopamine receptor subclasses
Activation of adenylate Cyclase
Inhibition of adenylate cyclase
What makes up the Activation of adenylate Cyclase
D1
D5
Slow receptors
What makes up the Inhibition of adenylate Cyclase
D2
D3
D4
What are the 2 main classes of dopamine receptors receives dopamine signal
D1 and D2
Perform balancing act to control a neurons response
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
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
Where are D1-5 receptors locates in brain
Most abundant frontal cortical region
Cerebral cortex limbic system
Where are D3 and D5 receptors located
Hypothalamus
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
Drugs used to treat people with Schiz
Antipsychotics
Neuroleptics
Major tranquillisers
What is an agonist
Drug occupies receptors and actives the
Full activation
Structurally similar to NT to activate receptor
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
What happens when agonist and antagonist are together
Less activation
What was the trend of treatment of mentally ill until 50s
Increasing number resident patients increased until 50s
When drugs introduced and numbers declined
Examples of Typical Antipsychotics
Chlorpromazine largactil Thioridizine Mellaril Fluphenazine Prolixin Loxapine Loxitane Haloperidol Haldol Molindone Moban
Examples of Atypical Antipsychotics
Clozapine Clozaril Risperidone Risperdol Remozipride Seroquel Olanzapine
Outline which receptors are associated with Typical Antipsychotics
Antagonists at D2 receptors
Outline which receptors are associated with Atypical Antipsychotics
D2 and
Bind serotonin subtypes
5HT2A
What is the Law of Thirds for treatment of mental illnesses
- Significant time hospitalised - unemployed, poor social interaction, institutionalised
- Respond well drug therapy. Employable. Relatively normal socially
- Significant improvement symptoms. Relapses and hospitalisation. Reduced employment, social isolation. Assistance.
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
How can we reduce Parkinson’s symptoms
Anticholinergic drugs block ACh receptors reducing Parkinson’s
Affects of Risperidone on symptoms of Schiz
Acts 5HT2 and dopamine
Best medication all 2 symptoms - positive negative psychopathology
Affects of Haloperidol on symptoms of Schiz
Relatively pure D2 antagonist
Improvement positive symptoms only
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
Outline correlation between anti psychotics binding to serotonin receptors
No correlation between binding serotonin receptors and anti psychotics and clinical effectiveness
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
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
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
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
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%
Why do we need animal models
Understand disease process
Predict which drugs be developed
Work out side effects profiles of drugs
Who is Arvid Carlsson
Nobel prize functions of dopamine
Link between Schiz and dopamine abnormality
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
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
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
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
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
What is the schematic representation of neurodevelopmental model of Schiz
Reduced inhibitory feedback
No mesocortical pathway feeding to VTA
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
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
What is pre pulse Inhibition
Startle response something unexpected
Pre warning won’t jump as much = response inhibited
Sensory motion grating = how filter info
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
Animal model correlations of pre pulse Inhibition
Correlation between doses drugs used restore pre pulse Inhibition and relative clinical potency
Outline Latent Inhibition by Lubow and Moore 1959 study
Prior exposure stimulus without consequence
Retards subsequent learning stimulus
Outline Latent Inhibition by Lubow and Moore 1959 disrupted by amphetamine
Disruption reversed by antipsychotic drugs
Outline Latent Inhibition by Lubow and Moore 1959 study how latent Inhibition enhanced
Enhanced by antipsychotic drugs given alone
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
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
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
Outline Delusion symptom of Schiz as disorder of salience
Delusions arise try make sense aberrantly salient experiences
Outline Hallucinations symptom of Schiz as disorder of salience
Hallucinations reflect direct experience of aberrant salience of internal representations
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
Outline treatment of Amphetamine on effect of Latent Inhibition
Amphetamine disrupts latent Inhibition
Outline treatment of D2 antagonist on latent Inhibition
D2 antagonist enhance latent Inhibition
Outline treatment of Amphetamine and D2 antagonist on latent Inhibition
Amphetamine and D2 antagonist restore latent Inhibition after amphetamine disruption
Outline D1 antagonist and D1 agonist treatment effect on latent Inhibition
Both no effect
