Drug design for the CNS Flashcards
why are there so few drugs for neuropsychological diseases
pharmaceutical companies are decreasing their funding in CNS research programmes
why is less money being put into CNS research
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
why are CNS diseases difficult to target with drugs
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)
animal models mainly used for CNS disorders
rodents
zebra fish
fruit flies
advantages of rodents as animal models
Mammalian –> lots of similarities in endocrine systems
Well characterized
easily genetically modified –> Humanized or introduction of mutations
Genome mapped –> we know their full genome
disadvantages of rodents as animal models for CNS diseases
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
how are transgenic mice used to test validation and efficacy of drugs
test whether that drug works on that specific target (knock out gene and see if it still performs function)
DREADD technology used in rodents for pharmaceutical production
Artificially introduce into the mice GM receptors
This enables you to specifically control activity of neuronal populations using artificial drugs
how do optogenetics work
Genetically modify the mice by implanting light emitting fibres into the brain to target specific neurons
creates light-sensitive ion-channels
categories of non-genetic models
pharmacological/surgical
behavioural
examples of behavioural models to induce stress
Maternal separation (early-life stress)
Acute stress (e.g. restraint, predator exposure)
Chronic stress
examples of pharmacological or surgical models
Neurochemical lesions e.g. MPTP
Middle cerebral artery occlusions
Drug administration
chronic stress can lead to
depression
effect of stress and anxiety on rodents brain
changes the way the rodents brain works
rodent more likely to be stressed or anxious as an adult
what does MPTP do
inject into rodents brain (substantia nigra)
specifically targets dopamine neurons
which disease can MPTP induce in mice
parkinsons
features of tests used to model depression and anxiety in rodents
conditioned or unconditioned
examples of unconditioned tests to model depression and anxiety
Open field Elevated plus maze /zero maze Barnes maze Social interaction Tail suspension Forced swim
examples of conditioned tests to model depression and anxiety
Conditioned startle
Learned helplessness
Active/passive avoidance
Defensive burying
what are behavioural tests used for
to assess markers of depression or anxiety in rodents
relationship between social interaction-ness and anxiety
the more anxious a rodent is, the less it will partake in social interaction with other animals
what do you measure in the social interaction test
overall locomotion
level of social interaction with other animal
variants of social interaction test
1, 2 or 3 chambers
e.g. stranger chamber and empty chamber
fluoxetine is an
SSRI (selective serotonin re-uptake inhibitor)
antidepressant drug
process of forced swim test
Rodent put in bucket of water where it cannot escape
Observe how long the animal spends trying to escape
what do you measure in the forced swim test
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
effect of antidepressants on forced swim test results
decreased immobility –> rodent feels less resigned to its fate
rodent swims for longer, spends more time trying to get out
what do you measure in conditioned fear test
Freezing type behaviour of rodent
How long after they hear the stimulus do they stop freezing
process of conditioned fear test
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
effect of antidepressants on conditioned fear test results
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
what do tests looking at addiction aim to measure
determine how much the animals want something
determine how much the animals like what they’ve got once they’ve got it
examples of behavioural tests to measure addicition
Operant conditioning – lever pressing
Self-administration (drugs, intracranial) – lever pressing
Conditioned place preference
example of potential conditional taste learning in humans
aversion to a particular food that once gave you food poisoning
process of conditioned place preference test
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
what is conditioned place preference test important for
measuring psychological effects of drugs
limitations of conditioned place preference test
confounding factors such as locomotion and sedation
why are there 3 chambers in conditioned place preference test
compartment in which drug is applied
neutral zone
compartment in which saline is applied
examples of behavioural tests to look at memory
Novel object recognition
Morris water maze
Y-maze/T-maze
Conditioned fear
which test looks at spatial memory
morris water maze
what is measured in the morris water maze test
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
process of morris water maze
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
limitations of neurobehavioural tests
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
how do you test baseline locomotion activity of rodent
open field assay
how do you test coordination of rodent
rota rod test
why must sex differences be controlled
drugs can affect women differently to men
half population is female
what must be controlled for females
menstrual cycle variations in females
experimental methods for controlling for cyclical variations in female mice
Staging –> Noting the stage of the oestrus cycle of the female mice used
Ovariectomy + oestrogen replacement
what does DREADD stand for
designer receptors exclusively activated by designer drugs
what is DREADD technology
chemogenetic tool
used to identify cellular signals and circuit behind behaviours, emotions etc
why is optogenetics useful
you can use light to specifically activate just the neurons and neuronal areas that you want
