Drug design for the CNS Flashcards

1
Q

why are there so few drugs for neuropsychological diseases

A

pharmaceutical companies are decreasing their funding in CNS research programmes

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2
Q

why is less money being put into CNS research

A

No/little knowledge on underlying causes of the diseases
Harder to carry out clinical trials –> lots of side effects
Very hard to get drugs into the brain (BBB) –>we don’t know much about how to get the drugs past it
Direct brain infusion not ideal
Difficult to model the diseases in animals

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3
Q

why are CNS diseases difficult to target with drugs

A

Very hard to get drugs into the brain (BBB)

Difficult to target a disease when you don’t know its etiology (how the disease comes about)

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4
Q

animal models mainly used for CNS disorders

A

rodents
zebra fish
fruit flies

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5
Q

advantages of rodents as animal models

A

Mammalian –> lots of similarities in endocrine systems
Well characterized
easily genetically modified –> Humanized or introduction of mutations
Genome mapped –> we know their full genome

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6
Q

disadvantages of rodents as animal models for CNS diseases

A

Difficult to model many elements of CNS disorders e.g. delusions, mood and memory
Models/assays generally only test a single element of a phenotype –> CNS diseases are usually complex/many elements
Findings don’t always translate to humans
Rodents handle lipids differently to humans
Cant talk to the mice

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7
Q

how are transgenic mice used to test validation and efficacy of drugs

A

test whether that drug works on that specific target (knock out gene and see if it still performs function)

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8
Q

DREADD technology used in rodents for pharmaceutical production

A

Artificially introduce into the mice GM receptors

This enables you to specifically control activity of neuronal populations using artificial drugs

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9
Q

how do optogenetics work

A

Genetically modify the mice by implanting light emitting fibres into the brain to target specific neurons

creates light-sensitive ion-channels

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10
Q

categories of non-genetic models

A

pharmacological/surgical

behavioural

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11
Q

examples of behavioural models to induce stress

A

Maternal separation (early-life stress)

Acute stress (e.g. restraint, predator exposure)

Chronic stress

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12
Q

examples of pharmacological or surgical models

A

Neurochemical lesions e.g. MPTP

Middle cerebral artery occlusions

Drug administration

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13
Q

chronic stress can lead to

A

depression

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14
Q

effect of stress and anxiety on rodents brain

A

changes the way the rodents brain works

rodent more likely to be stressed or anxious as an adult

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15
Q

what does MPTP do

A

inject into rodents brain (substantia nigra)

specifically targets dopamine neurons

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16
Q

which disease can MPTP induce in mice

A

parkinsons

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17
Q

features of tests used to model depression and anxiety in rodents

A

conditioned or unconditioned

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18
Q

examples of unconditioned tests to model depression and anxiety

A
Open field
Elevated plus maze /zero maze
Barnes maze
Social interaction
Tail suspension
Forced swim
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19
Q

examples of conditioned tests to model depression and anxiety

A

Conditioned startle
Learned helplessness
Active/passive avoidance
Defensive burying

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20
Q

what are behavioural tests used for

A

to assess markers of depression or anxiety in rodents

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21
Q

relationship between social interaction-ness and anxiety

A

the more anxious a rodent is, the less it will partake in social interaction with other animals

22
Q

what do you measure in the social interaction test

A

overall locomotion

level of social interaction with other animal

23
Q

variants of social interaction test

A

1, 2 or 3 chambers

e.g. stranger chamber and empty chamber

24
Q

fluoxetine is an

A

SSRI (selective serotonin re-uptake inhibitor)

antidepressant drug

25
Q

process of forced swim test

A

Rodent put in bucket of water where it cannot escape

Observe how long the animal spends trying to escape

26
Q

what do you measure in the forced swim test

A

time spent swimming before they give up
how long they are immobile for (panicking)
amount of time swimming and time spent actively trying to get out

27
Q

effect of antidepressants on forced swim test results

A

decreased immobility –> rodent feels less resigned to its fate
rodent swims for longer, spends more time trying to get out

28
Q

what do you measure in conditioned fear test

A

Freezing type behaviour of rodent

How long after they hear the stimulus do they stop freezing

29
Q

process of conditioned fear test

A

learning phase:

  • create association between electric shock and environmental context or cue
  • rodents response is to freeze

expose rodent to same context without electric shock
rodents expect shock so freeze

how many exposures to the context do they need before they stop freezing

30
Q

effect of antidepressants on conditioned fear test results

A

decrease the time before the rodent forgets about the fear

e.g. if rodent is more anxious it will keep freezing even after 20 cues

31
Q

what do tests looking at addiction aim to measure

A

determine how much the animals want something

determine how much the animals like what they’ve got once they’ve got it

32
Q

examples of behavioural tests to measure addicition

A

Operant conditioning – lever pressing
Self-administration (drugs, intracranial) – lever pressing
Conditioned place preference

33
Q

example of potential conditional taste learning in humans

A

aversion to a particular food that once gave you food poisoning

34
Q

process of conditioned place preference test

A

give animal cocaine
creates association with compartment in which it was given cocaine e.g. smell or colour of compartments differ
animals then spends more time in that compartment

35
Q

what is conditioned place preference test important for

A

measuring psychological effects of drugs

36
Q

limitations of conditioned place preference test

A

confounding factors such as locomotion and sedation

37
Q

why are there 3 chambers in conditioned place preference test

A

compartment in which drug is applied
neutral zone
compartment in which saline is applied

38
Q

examples of behavioural tests to look at memory

A

Novel object recognition
Morris water maze
Y-maze/T-maze
Conditioned fear

39
Q

which test looks at spatial memory

A

morris water maze

40
Q

what is measured in the morris water maze test

A

how long it took rodent to escape
Swimming speed
How long it takes them to find the platform (escape latency )
How long they remember where the platform used to be once its taken away

41
Q

process of morris water maze

A

mice put in bucket of water with hidden platform
swim around to find platform
time spent swimming decreases as they remember where the platform location is after more training

42
Q

limitations of neurobehavioural tests

A

Typically depend on the animals not having locomotor changes (impaired movement/coordination or hyper or hypoactivity)

Initial assessment of locomotor activity should be performed – e.g. open field and/or rota-rod

If a drug induces sedative effects then this will impact the results

43
Q

how do you test baseline locomotion activity of rodent

A

open field assay

44
Q

how do you test coordination of rodent

A

rota rod test

45
Q

why must sex differences be controlled

A

drugs can affect women differently to men

half population is female

46
Q

what must be controlled for females

A

menstrual cycle variations in females

47
Q

experimental methods for controlling for cyclical variations in female mice

A

Staging –> Noting the stage of the oestrus cycle of the female mice used

Ovariectomy + oestrogen replacement

48
Q

what does DREADD stand for

A

designer receptors exclusively activated by designer drugs

49
Q

what is DREADD technology

A

chemogenetic tool

used to identify cellular signals and circuit behind behaviours, emotions etc

50
Q

why is optogenetics useful

A

you can use light to specifically activate just the neurons and neuronal areas that you want