Privet Flashcards
There are two types of symptoms of Schizophrenia, positive and negative symptoms. What is meant by positive and negative symptoms and name them.
Positive symptoms: change in behaviour (behaviours that are not experienced under normal conditions)
- delusional
- hallucination
- disordered thoughts
Negative symptoms: deficit or lack of behaviours which are well-propagated under normal conditions (withdrawal or isolation)
- apathy
- lack of speech
- loss of drive and emotions
- social isolation
Between positive and negative symptoms of schizophrenia, which responds well to pharmacological treatment and which does not?
Positive symptoms usually respond well to pharmacological treatment
Negative symptoms usually showed a limited response to drug treatment
Name the causes of schizophrenia and which factor contributes the most to the development of schizophrenia?
- Heritability
- Environmental factors
Genetic factor contributes the most to the cause of schizophrenia (83%)
Environmental factor contributes about 17% of the cause
There are at least 43 genes associated with Schizophrenia, name four of these genes and state what are their roles.
DISC1 (Disrupted in Schizophrenia 1)- participating in the regulation of cell migration, proliferation and differentiation.
NRG1 (Neuroregulin-ERBB4 signalling pathway) - neural migration, signalling axon guidance. The receptors for NRG1 are known to be the ERBB family.
NRX1- synaptic protein
KCNH2 - potassium channel
Name examples of environmental factors that could promote development of Schizophrenia.
The important point is that schizophrenia is a multifactorial process involving both genetic and environmental factors.
Brain injury, stress, infection (particularly in the pre- and postnatal period - critical period of development)
Activation of the hypothalamic-pituitary-adrenal (HPA) axis is also associated to development of schizophrenia.
name three events that happened in the course of development of normal brain and explain how alteration in this changes may contribute to the development of schizophrenia
- pruning and excitation of excitatory synapses
- proliferation of inhibitory synapses, dendritic aborisation
- increase in myelination
the overall effect of this is to provide balance between excitatory and inhibitory synapses.
in schizophrenia brain, the balance is disrupted, more inhibitory than excitatory. excessive pruning of excitatory pathways in the PREFRONTAL CORTEX
why is late adolescences / early adulthood (18-25) is a peak period of schizophrenia onset? what does this tell you about schizophrenia development?
late adolescences, precise inhibition/excitation balance is required for regulatory pathway
the development of schizophrenia is progressive
name the characteristic features in schizophrenia brain
- cortical atrophy in the amygdala, hippocampus and thalamus (HPA axis)
- reduce volume fo basal ganglia
- reduce blood flow in prefrontal cortex
name three hypothesis for schizophrenia
- dopamine
- glutamate
- GABA hypothesis
which dopamine receptors dysregulation were thought to underlie schizophrenia? which symptoms were associated with this dysregulation?
D1 and 2
dysregulation of these two receptors were thought to correlate with cognitive deficit and psychotic symptoms
dopamine signalling pathway:
- which pathway is associated with positive symptoms when elevated?
- which symptom does the mesocortiyal pathway is associated with?
- mesolimbic pathway, increase DA release in mesolimbic generates +ve symptoms (HYPERACTIVITY)
- associates with the negative, cognitive and affective symptoms caused by DA HYPOACTIVITY - prefrontal dopaminergic pathway
what is the pharmacological evidence supporting the dopamine theory?
drugs that elevated dopamine in dopaminergic neurones promotes positive symptoms and drugs that antagonise the action of dopamine control the development of positive neurones
- D2 antagonists
- Amphetamine (dopamine releaser)
- L-dopa therapy -> hallucinations
- D2 agonists
which dopaminergic pathway does the 1st gen anti-schizophrenia target? name their mechanism of action and its side effects
targets the hyperactivity of the mesolimbic dopaminergic pathway
mechanism: dopamine antagonist
side effects:
-extrapyrimidal symptoms (EPS) which is a movement disorders
describe the mechanism of action of second generation anti-schizophrenia drugs. name its side effects and one example
antagonism at 5-HT2/D1/2 receptors
limited effect on negative symptoms
side effects: less severe than 1st gen includes obesity and low BP
e.g. clozapine
what are the criticism for dopamine hypothesis?
- no increase in [DOPA] in post-mortem tissue of schizophrenia patient
- d1 and d2 antagonist do not alleviate negative symptoms
- effects of d1 and d2 are often delayed
what is ketamine and what does it induces?
NMDAR antagonist induces both positive and negative symptoms of schizophrenia
describe the glutamate hypothesis and how it causes both negative and positive symptoms
- reduced NMDAR tone -> disinhibition of GABAergic interneurons -> increase dopamine release in the mesolimbic pathway -> positive symptoms
- reduced NMDAR tone -> decrease release of DA from mesocortical pathway -> negative symptoms
describe the GABA hypothesis
post-mortem studies demonstrate deficit in GABAergic interneuron populations in schizophrenic brain
altered GABA A receptor subunit expression and signalling -> schizophrenia symptoms
GABAergic conductance directly correlated to activation/suppression of dopaminergic neurones
what is the role of gabaergic neurones in the prefrontal cortex?
generation of gamma-rhythms important in cognition
there are three major targets for anti-schizophrenia drugs: glutamate, dopamine and GABA
name three others
- cannabinoid system: cannabidiol
- cholinergic system: modulation od dopaminergic pathways (remember Dawn Livingstone’s lecture tacrine, etc)
- serotonin system: 5HT3 receptors modulate dopamine receptors activity (5HT3 antagonist improved schizophrenia-associated cognitive disorder)
(for typical anti-psychotics)
first generation antipsychotics is effective at controlling which symptoms?
does schizophrenia patients under treatment of antipsychotics demonstrate deficit intellectual function?
1st gen: positive symptoms only and no negative symptoms
no, they are able to respond accurately to questions
name three side effects of antipsychotics which has no known origin
- weight gain and obesity
- leukopenia (reduce wbc)
- neuroleptic malignant syndromes (cognitive dysfunction)
does atypical neuroleptics have more severe or less severe side effects compare to typical?
less severe therefore more commonly use in nowadays but still have unwanted side effects such as weight gain, leukopenia, impaired glucose tolerance (diabetes)
name one atypical antipsychotic and describe its mechanism of action and side effects
aripiprazole - 3rd gen
- partial agonism at D2 receptors
- 5HT2A antagonist
- 5HT1A partial agonist
therefore display efficacy for NEGATIVE symptoms
side effects: development of neuroleptic malignant syndrome
what is epilepsy?
occasional, unpredictable, disordered rhythmic synchronised firing of AP by LARGE POPULATIONS of CNS neurones
epilepsy causes a change at which molecular level?
network level so not cellular level
which part of the brain is considered the most important in epilepsy?
temporal lobe
what are the causes of epilepsy?
- channelopathies:
- Na+ mutation
- K+ mutation
- auto-immune mechanism - temporal lobe epilepsy associated with abnormal regeneration of interneuronal connections
what are the types of epilepsy? and explain them
partial seizures: simple or complex
- simple: hyper-excitability often remains local, mild symptoms, no loss of consciousness
- complex: associated with temporal lobe focus, complex effects manifest as psychomotor epilepsy
generalised seizures:
- tonic phase: ~1 min of initial strong contraction of the whole musculature
- clonic phase: ~2-4 min, series of violent synchronous jerks
- final phase: several minutes of unconsciousness without seizures
- status epilepticus: ~5 min stares, abrupt termination of activity, insensitivity to surroundings. more common in young children
what is the cellular mechanism of epilepsy?
at cell level: imbalance between inhibitory and excitatory synaptic input
- drugs that mimic excitatory neurotransmitter (Ach or glutamate) or block the action inhibitory neurotransmitters (GABA, glycine) induce seizures in animal models
- drugs that enhance the effect of GAVA are predominantly anti-convulsant
- glu conc. abnormally high around the focus of epilepsy
what are the channels thought to underlie the cause of epilepsy?
inherited, abnormal function of ligand-gated and voltage gated Na+, K+ and Ca2+ channels
abnormal voltage-gated channels causes …
abnormal ligand-gated neurotransmission which increased excitation and decrease inhibition causes …
alteration in external environment causes …
recruitment of normal neuronal circuits causes …
- focus epilepsy
- causes focus epilepsy and synchronisation
- synchronisation and propagation (generalised epilepsy)
- generalised epilepsy
what are the days to control incidence of Epileptic events?
- modifying the burst properties of neurones
- reduce synchronisation in neural networks
- preventing spread of abnormal firing to distant brain areas (generalisation)
name the actions of anti-epileptic drugs
- modulators of Na+, K+ and Ca2+ channels
- stimulators of synaptic inhibition: GABA (glycine) receptors
- inhibitors of synaptic excitation: NMDA, AMPA receptors
- cannabidiol: inhibit Ca2+ channel -> less vesicle release
how does Ca2+ current associated with action potentials?
Ca2+ modulate snare proteins -> regulate the rate of release of neurotransmitters
Na+ and K+ channel regulate opening of Ca2+ channel
lamotrigine:
why does it have a high dissociation probability?
what is the mechanism exhibited by this drug when binding to the channel?
- because have low affinity of Na+ binding site
- use-dependent mechanism can only bind when the channel is open because binding site is inside the channel
why does lamotrigine action can only be useful in the event of epileptic seizures?
lamotrigine has no effect in a single action potential therefore no effect in normal cell functioning
in HFS, more channels are open -> more lamotrigine can bind therefore have an effect
epilepsy is high frequency stimulation
generalised seizures can be generated by the abnormal activity of …
neurotransmitter release
name two positive allosteric modulators of GABA-A receptors which can be use as anti-epileptic. state their mechanism of action
barbiturates and benzodiazepines enhance inhibitory transmission
barbiturates: prolong channel opening time
benzodiazepine: more channels open
name the enzyme that is involve in GABA synthesis and breakdown
name the transporter involve in GABA reuptake
synthesis: GAD - glutamic acid decarboxylase
degradation: GABA-T (transaminase)
GAT- 1,3 GABA transportes
name three glutamate inotropic receptors that is a target for epilepsy therapy
AMPA, NMDA and Kainate
which synaptic activity does cannabidiol more likely to promote?
synaptic inhibition as suppose to excitation
name drugs that:
- block Na+ channel
- inhibits GAT
- GABA-A R potentiators
- block Ca2+ channel
name what type of epilepsy do these drugs treat?
- carbamazepine and valproate
- tiagabine
- barbiturate and benzodiazepine
- ethosuximide
- partial seizures: valproate
- clonic: ethosuximide
- tonic-clonic: carbamazepine
- Status Epilepticus: benzodiazepine
