WEEK 10 - psychiatric diseases

Question 1

schizophrenia
onset

Answer 1

onset in adolescence

1% of population

Question 2

schizophrenia
symptoms:

Answer 2

positive symptoms (not present in healthy people): psychosis, hallucinations, delusions, paranoia

negative symptoms: social withdrawal, lack of motivation, cognitive and attention impairment

Question 3

schizophrenia
pathology

Answer 3

alterations in dopamine regulation

Question 4

schizophrenia
treatment

Answer 4

treatment with antipsychotic drugs that interfere with dopamine function

reserpine
- discovered for hypertension
- acts by interfering with the metabolism of all monoamine neurotransmitters: dopamine, norepinephrine, and serotonin

chlorpromazine
- synthesised as a potential aesthetic
- blocks dopamine receptors

Question 5

schizophrenia
action of reserpine

Answer 5

reduces psychosis by lowering neurotransmitter levels

neurotransmitter recycling:
- monoamine neurotransmitters - dopamine, norepinephrine, serotonin - are taken up by plasma membrane and vesicular monoamine transporters (PMAT and VMAT)
- NTs are degraded by monoamine oxidase (MAO).

reserpine is an inhibitor of VMAT, blocks neurotransmitter recycling thus depleting levels of NTs

secondary effect: Parkinsonism due to low dopamine

Question 6

schizophrenia
neurotransmitter recycling

Answer 6

neurotransmitter recycling:
- monoamine neurotransmitters - dopamine, norepinephrine, serotonin - are taken up by plasma membrane and vesicular monoamine transporters (PMAT and VMAT)
- NTs are degraded by monoamine oxidase (MAO).

Question 7

schizophrenia
chlorporomazine

Answer 7

an antipsychotic drug that blocks dopamine receptors

drugs affinity for binding dopamine receptor 2 correlates with antipsychotic action

secondary effect: parkinsonism due to low dopamine
Need to find a balance
- Need to test the affinity of drug to receptors
- Radioactive labelled dopamine

challenge: to generate an antipsychotic drug without side effects

Question 8

schizophrenia
negative symptoms are linked to

Answer 8

reduced NMDAR function

antipsychotic drugs do not alleviate the negative symptoms

drugs that act as NMDAR antagonists
e.g. ketamine induce psychosis that resembles schizophrenia

reduction function of NMDAR causes schizophrenia

Question 9

schizophrenia
genetic contribution?

Answer 9

strong genetic contribution

Question 10

schizophrenia
developmental disorder?

Answer 10

possibly

could be a developmental disorder of brain organisation that results in thinning of the prefrontal cortex

could be due to:
- abnormal neuronal migration resulting in defective neural circuits
- excessive synaptic pruning during development

Question 11

mood disorders
bipolar

Answer 11

1%

swing between manic and depressive phases

Question 12

mood disorders
major depression

Answer 12

5%

Question 13

mood disorders

Answer 13

bipolar and major depression are major causes of suicide

Question 14

mood disorders
antidepressants

Answer 14

first discovered by chance:

iproniazid was developed for treating tuberculosis, noticing that patients were happier

Question 15

mood disorders
treatment

Answer 15

mood disorders have been treated by manipulating monoamine neurotransmitter metabolism:

1. MAO inhibitors (Iproniazid)
2. neurotransmitter reuptake inhibitors

Question 16

mood disorders
antidepressants inhibit…

Answer 16

neurotransmitter reuptake by the brain

antidepressants block the reuptake of dopamine, serotonin and/or norepinephrine so that they function for longer at the synapse

Question 17

mood disorders
depression linked to

Answer 17

reduced levels monoamine neurotransmitter

dopamine, serotonin and/or norepinephrine

Question 18

mood disorders
antidepressants act by

Answer 18

prolonging neurotransmitter action

Question 19

mood disorders
antidepressant examples

Answer 19

iproiazid
- functions by inhibiting MAO thus increasing NT levels at synaptic cleft

MAO inhibitors have many side effects, replaced by:

imipramine:
- inhibits monoamine NTs reuptake by PMAT at plasma membrane for norepinephrine and serotonin

fluoxetine (prozac):
- blocks serotonin reuptake

selective serotonin reuptake inhibitors (SSRIs):
- are the most widely used today
- increase serotonin levels

Question 20

anxiety disorders

Answer 20

5%

anxiety, phobia, panic, obsessive compulsive disorder (OCD), fatigue, muscle tension, sleep problems, mood disorders

Question 21

anxiety disorders
treatment

Answer 21

modulate GABAergic inhibition

GABA is the endogenous ligand

GABAa receptors have 5 subunits: 2 alpha, 2 beta, 1 gamma

GABA binds between alpha and beta

benzodiazepine binds between alpha and gamma

Question 22

anxiety disorders
treatment:
Anxiolytic drugs:

Answer 22

bind to GABAa receptors to enhance GABA transmission

Question 23

anxiety disorders
treatment:
barbiturates:

Answer 23

sedative, overdose is lethal
activate GABAa receptors independently of GABA

Question 24

anxiety disorders
treatment:
benzodiszepine

Answer 24

less sedative, only lethal at much higher dose
enhance receptor’s affinity for GABA but cannot activate the receptor alone

Facilitate function dependent on GABA
Need to have GABA there for it to do anything

Question 25

anxiety disorders modulating GABAergic inhibition to treat anxiety disorders: benzodiazepine

Answer 25

anxiolytic allosteric agonist enhancing the action of endogenous GABA safer because its effect is limited by the amount of GABA side effect: sedation and long-term use lead to addiction

Question 26

anxiety disorders can drugs separate the anxiolytic from the sedative effects?

Answer 26

in humans GABAa receptors have 6 genes encoding alpha subunits: a1 to a6 differently expressed in the brain a1, 2, 3 and 5: have His that makes them sensitive to benzodiazepine a4, and 6: have Arg that disrupts benzodiazepine binding i.e. insensitive

Question 27

anxiety disorders develop drugs that are specifically anxiolytic but not sedative

Answer 27

knock-in m ouse and treatment with benzodiazepine (e.g. diazepam) - replacing H101 to R101 in a1: anxiolytic effect ok, mice no longer sedated - replacing H101 to R101 in a2: mice sedated, no anxiolytic effect key: DIFFERENTIAL EXPRESSION: a2: is expressed in amigdala --> aim for drugs that increase function of GABAa receptors in a2

Question 28

anxiety disorders develop drugs that are specifically anxiolytic but not sedative experimentation in mice

Answer 28

In mouse Seeing how much the mouse walk around (sedative) - E.g. if was sedative would be drowsy and wouldn’t walk around as much Arena with light and dark area - If mouse doesn’t care to walk in all areas this is a marker for low anxiety

Question 29

anxiety disorders targeting mGluR

Answer 29

aim to reduce levels of Glu Balance between treatment and allowing normal function

Question 30

drug addiction

Answer 30

compulsive drug use despite long term negative consequences loss of self control propensity to relapse

Question 31

drug addiction how?

Answer 31

most drugs have a common effect: increase dopamine concentration at the output targets of ventral tegmental area (VTA) dopamine neurons: - VTA itself: recieve inputs from many parts of the brain - nucleus accumbens: where processing of reward information occurs - prefrontal cortex: goal selection and decision making

Question 32

drug addiction can cause...

Answer 32

psychosis e.g. ket

Question 33

drug addiction different mechanisms

Answer 33

different addictive substances enhance dopamine through different mechanisms: nicotine opium and cannabinoids cocaine amphetamine and ecstasy morphine alcohol

Question 34

drug addiction engages the...

Answer 34

dopaminergic system (reward)

Question 35

addictive drugs hijacks the brains...

Answer 35

reward system by increasing the concentration of dopamine in targets of VTA neurons reward based learning Different drugs modulate dopamine signalling in slightly different ways

Question 36

drug addiction different mechanisms nictoine

Answer 36

activates ACh receptors to excite dopamine neurons

Question 37

drug addiction different mechanisms opium and cannabinoids

Answer 37

inhibit GABAergic neurons in the VTA causing disinhibition of dopamine neurons

Question 38

drug addiction different mechanisms cocaine

Answer 38

blocks the plasma membrane dopamine transporter and dopamine re-uptake

Question 39

drug addiction different mechanisms amphetamine and ecstasy (MDMA)

Answer 39

reverse the dopamine membrane transporter causeing vesicle-independent release of dopamine, increasing dopamine synthesis and preventing its degradation

Question 40

drug addiction most drugs alter...

Answer 40

synaptic plasticity potentiating excitatory synapses onto VTA neurons and preventing subsequent NMDAR Long term potentiation

Question 41

why are drugs addictive

Answer 41

VTA neurons are involved in reinforcement-based learning: - if dopamine neurons signal a reward, that action is immediately preceded and the reward is rein forced through dopamine regulation of neural circuits - drugs bypass the natural regulation and mimic neuronal activation which reinforces preceding actions drug consumption itself - addictive drugs hijack the brain reward system and exploit mechanisms that the brain normally uses for learning and motivation Associative learning - Condition brain to think that if you take drug things will be good - Exploiting existing system of learning

Question 42

dopamine and reward system in healthy brain

Answer 42

In healthy brain dopamine required for learning (main role to assign value to stimulus) Associative learning - Condition brain to think that if you take drug things will be good - Exploiting existing system of learning

Question 43

epilepsy

Answer 43

a disorder of network excitability Synchronisation patterns - Groups of neurons that fire together

Question 44

epilepsy causes:

Answer 44

head injury, infection, stroke, brain cancer, brain surgery, drug abuse genetic predisposition: mutations in channels (channelopathies) - Inherited forms usually due to this (not always) seizure predisposes to having future seizures

Question 45

epilepsy treatment

Answer 45

GABAa receptor agonists (benodiazepines) to boost inhibition drugs that activate Na+ channels to reduce excitation drugs that inhibit Ca2+ channels to reduce synaptic transmission brain surgery for focal epilepsy resistant to drug treatment

Question 46

epilepsy absence seizure

Answer 46

abnormal balance between the actions of excitatory and inhibitory neurons stopping movement (without noticing)

Question 47

epilepsy abnormal balance between

Answer 47

the actions of excitatory and inhibitory neurons

Question 48

epilepsy seizure

Answer 48

episode of abnormal synchronous firing of large groups of neurons

Question 49

epilepsy

Answer 49

chronic condition with recurrent seizures

Question 50

epilepsy tonic-clonic seizure

Answer 50

uncontrollable shaking

Question 51

epilepsy focal

Answer 51

small region

Question 52

epilepsy generalised

Answer 52

all cortex

Question 53

neurodevelopment disorder autism

Answer 53

deficits in communication and reciporcal social interaction, reduced emotions and difficulty adapting behaviour to a changing environment reduced neural synchrony patterns predominant cause is genetic gene regulating synapse development and synaptic function, transcription and chromatin not known how they affect neural development

Question 54

neurodevelopment disorder: fragile X syndrome

Answer 54

intellectual disability and autism spectrum disorder (ASD), developmental delay in speech and motor skills affects 1:5000 boys defects in FMR-1 gene: >200 repeats of CGG triplet at 5' end which causes extensive methylation and repression of the FMR-1-gene

Question 55

neurodevelopment disorder: fragile X syndrome cause

Answer 55

FMRP represses protein translation required for learning FMRP is an RNA binding protein expressed highly in all neurons throughout life represses translation normally phosphorylated dephosphorylation. relieves repression allowing local translation target mRNAs are involved in synaptic plasticity and learning e.g. Arc and CaMKII

Question 56

what is a common mechanism for psychiatric and developmental disorders

Answer 56

synaptic disfunction

Question 57

summary schizophrenia and psychosis: schizophrenia can have a

Answer 57

genetic component, developmental 1% population

Question 58

summary schizophrenia and psychosis: associated with

Answer 58

increased levels of dopmaine

Question 59

summary schizophrenia and psychosis: symptoms

Answer 59

psychosis hallucinations withdrawal cognitive impairment

Question 60

summary schizophrenia and psychosis: treatment

Answer 60

treated with antipsychotics lower levels of monoamine neurotransmitters or block dopamine receptors

Question 61

summary bipolar disorder and major depression: associated with

Answer 61

low levels of dopamine and serotonin

Question 62

summary bipolar disorder and major depression: treatement

Answer 62

antidepressants to prevent neurotransmitter degradation or reuptake so stay in system longer (increasing levels)

Question 63

summary anxiety: treatment

Answer 63

anxiolytics increase GABA binding to its receptor or inhibit mGluR

Question 64

summary drug addiction:

Answer 64

recreational drugs work by up-regulating dopamine and hijacking the normal reward system in the brain forming an association between drug and reward

Question 65

summary synaptic dysfunction: epilepsy

Answer 65

mutation in channels too much synchronization in neural circuits

Question 66

summary synaptic dysfunction: autism

Answer 66

not enough synchrony in neural circuits

Question 67

summary synaptic dysfunction: fragile X

Answer 67

dysregulation of protein synthesis required for learning and long term memory