Drug Development- Animal efficacy models

Question 1

What is ethology

Answer 1

Study of animal behaviours as a research tool

Question 2

Face validity

Answer 2

Has features/symptoms of the human disorder

Useful for physiological sx but harder for behaviours (animal behaviours don’t correlate)

Many diseases have multiple symptoms

Question 3

Predictive validity

Answer 3

Testing new compounds against drugs of known efficacy

Test against similar drug
-Difficult for truly novel compounds

Question 4

Construct validity

Answer 4

Best possible type of validity but hard to establish
Animal models analogous to human disease
- Same causes, RFs, genes
- Knowledge of human disease relies on animal research

Question 5

Features of peripheral pain models

Answer 5

Animals show reliable, objective responses to pain

Lack absolute face validity so relies more on predictive validity

Question 6

Freund’s Adjuvant-Induced Oedema (Paw Swelling) Assay

Answer 6

Tests mechanical pain
Formalin/ Carrageenan/ Capsaicin
Plethysmometer measures water displacement

Question 7

Paw Withdrawal Test

Answer 7

Adjustable weight placed on paw, time taken for withdrawal recorded

Question 8

Thermal tests of pain

Answer 8

Hotplate test
- Licking paws

Tail-flick assay

• IR beam
• Confounding variables

Question 9

Opioids example for testing pain efficacy

Answer 9

MORa vs DORa for pain treatment
SNC80 studies
- Paw withdrawal, tail flick used to predict antinociceptive properties

• Models typically used DOR knock in to overexpress
• Side effects (convulsions, hyperlocomotion)- affect response?
• Measured against morphine (true predictive validity?)

Question 10

Schizophrenia positive sx

Answer 10

Delusions, hallucinations

-Unmeasurable in animal models

Question 11

Schizophrenia negative sx

Answer 11

Social withdrawal, decreased motivation/interests

Question 12

Schizophrenia cognitive sx

Answer 12

Reduced working memory, visual learning

Question 13

Typical Antipsychotics

Answer 13

Dopamine D2 Antagonists e.g. Haloperidol

SEs: Mainly EPS

Question 14

Atypical Antipsychotics

Answer 14

D2/Serotonin Antagonists e.g. Clozapine, Olanzapine, Risperidone

Reduced EPS but weight gain, sedation, agranulocytosis

Question 15

Isolation rearing and PPI (SZ Disease model)

Answer 15

Isolation weaning for 8w causes
- Hyperactivity, impaired cognitive performance, neurochemical changes, neuroanatomical changes

• Sensorimotor gating defects- reduced PPI
• Prepulse inhibition is normally deficient in SZ
• Startle chamber assess PPI with/without antipsychotics
• Face and predictive validity

Question 16

Catalepsy (SZ side effect model)

Answer 16

EPS produced by typical antipsychotics

Time length of catalepsy indicates efficacy

Question 17

Apomorphine Induced Climbing (SZ PD assay)

Answer 17

Apomorphine is a DAr agonist; induces climbing behaviour
Climbing behaviour reduced by antipsychotics with D2 antagonism activity
-Predictive but not face validity

Question 18

APO-SUS rats as a model with construct validity

Ellenbroek et al

Answer 18

APO-SUS rats

• Heightened responses to external stimuli reminiscent of SZ
• Deficits in Latent inhibition (cognitive deficit)
• Increased PPI deficits

Pathological similarities e.g. increased Dopamine binding in striatum
Reduced RA sensitivity- similar to SZ patients

Question 19

SZ D3R antagonists model for SZ treatment

Sun et al 2016

Answer 19

Y-QA31 development (novel Dopamine-3 R antagonist)
In vivo efficacy tests include:
-MK801-Induced Hyperlocomotion Assay (similar to APO climbing behaviour, APs reduce hyperlocomotion)
-Conditional Avoidance Response (CAR)
-Novel Object Recognition (cognitive defects)
-Catalepsy

Tested predictive validity against Haloperidol/ Clozapine
Dose reqd for alleviation of cognitive sx 10x lower than positive/negative sx