Lecture 11 - CNS drug design

Question 1

Why is research into drugs for CNS disorders difficult?

Answer 1

Poor understanding of disease mechanisms
Lack of biomarkers to measure biological states and therapeutic effects
High failure rates
Animal models don’t fully replicate the disorder
Limited human brain tissue for research

Question 2

What are the stages of drug development?

Answer 2

1. Identify targets
2. Identify compounds
3. Establish activity
4. Select clinical candidates
5. Pre clinical development (animal trials)
6. Human clinical trials (phases I-IV)

Question 3

Why are rodents good animal models for CNS drug research?

Answer 3

Many similarities with humans - mammalian, similar GI tracts etc
Well characterised
Genome has been mapped
(Relatively) easily genetically modified

Question 4

Why are rodents NOT good animal models for CNS drug research?

Answer 4

Difficult to model many elements of CNS disorders such as delusions, poor memory, low mood etc
Can only be used to test a single element of a disorder at a time
Obviously not identical to humans - so findings don’t always translate

Question 5

Name two other animals that are used as disease models for CNS disorders

Answer 5

Flies

Fish

Question 6

Name 4 ways in which genetic models are useful in drug discovery and development

Answer 6

1. Target discovery
2. Target validation
3. Generation and refinement of molecules
4. Preclinical development - eliminating molecules and advancing molecule efficacy

Question 7

Name a technique that can be used to create genetic models

Answer 7

CRISPR

Question 8

Name 3 ways in which a disease model can be made by behavioural (non-genetic) mechanisms

Answer 8

1. Maternal separation - induces stress and anxiety
2. Restraint or exposure to predators (acute stress)
3. Exposure to chronic stress

Question 9

Name 3 ways in which a disease model can be made by pharmacological (non-genetic) mechanisms

Answer 9

1. Neurochemical lesions by injecting MPTP into a certain area of the brain - used to mimic Parkinsons
2. Middle cerebral artery occlusions - to mimic stroke
3. Drug administration

Question 10

How are symptoms such as depression and anxiety measured in rodents?

Answer 10

Using neurobehavioral tests

Question 11

What are the the two types of neurobehavioral tests and what is the difference between them?

Answer 11

Unconditioned tests and Conditioned tests

Unconditioned tests look at behaviour under normal conditions. Conditioned tests requiring conditioning a response to a stimulus before they are carried out.

Question 12

Name 3 unconditioned neurobehavioral tests

Answer 12

1. Forced swim test
2. Social interaction test
3. Tail suspension test

Question 13

Name 2 conditioned neurobehavioral tests

Answer 13

1. Conditioned fear test

2. Learned helplessness

Question 14

Describe the procedure (and result) for the social interaction test

Answer 14

Rat can freely explore two chambers: one with another rat in, one which is empty (or contains a novel object)
Measure the amount of time spent in each chamber
Anxious rats spend more time away from the other rat

Question 15

Describe the procedure (and result) for the conditioned fear test

Answer 15

Contextual fear conditioning (foot shock in certain environment) or cued fear conditioning (foot shock after auditory cue)
After conditioning, context/cue repeatedly delivered without footshock
Measure how long it takes until fear extinction

Question 16

Name 3 neurobehavioral tests that can be used to measure addiction

Answer 16

1. Operant conditioning
2. Self administration of drugs
3. Conditioned place preference

Question 17

Describe the procedure (and result) for the conditioned place preference test

Answer 17

Rat can access two chambers connected by a doorway
Each chamber has different cue e.g. wall pattern
Rat administered drug in one chamber
Will come to prefer (conditioned place preference) or avoid (conditioned place aversion) that chamber depending on preference for the drug
Can see whether they still get preference when lesions are place in specific areas of the brain

Question 18

Describe the procedure (and result) for the morris water maze test

Answer 18

Tests the ability of the rat to recall the location of a hidden platform in a wading pool, over repeated trials.
The time taken to find the platform, and the distance travelled to the platform is measured.
Rats with normal cognitive function find the platform quicker and travel a shorted distance to it.

Question 19

What characteristic does the morris water maze test

Answer 19

Spatial learning and memory

Question 20

What are the limitations of neurobehavioral tests?

Answer 20

If administering a drug, it may cause locomotor impairments, sedation, or even increased affinity for exploration of novel objects, which would impact the results

No single test is sufficient to measure the effects of a drug - multiple tests should be used to examine to same phenotype