Why animal models?
- Law dictates that new drugs are tested for efficacy and toxicology in
animals before they are tested in humans
- Detailed mechanistic understanding of health and (brain) disorders
and ultimately the design of new treatments requires animal experiments
- Fundamental understanding of (neuro)biology
- Controlling factors: genetics, environment, short life span → humans are restricted in
those areas (e.g life span is too long to conduct life long research)
Rat vs. Mouse
face validity: similarity in symptoms → but: evaluation is very subjective
predictive validity: similarity in drug effects → but: individual differences in responsivity to
drugs in humans which are not taken into account + several drugs are not disorder-specific
! construct validity: similarity in neural substrates → but: how do we know whether an animal
model has construct validity if mechanisms are not known in humans
Before animal experiment
Three R’s
, ● Replace: avoid using animals when possible
● Reduce: try to use as few animals as possible
● Refine: ensure the greatest respect towards animal
Transgenic rodent models
Import of animals and GGO
Determine best breeding scheme
Rule: breeding animals have to be crossed every generation with commercially purchased
wild-type animals having the same genetic background as the knockout animal has to
prevent inbreeding.
- Best to use heterozygous animals for this outbreeding
, Problems with breeding
- you do not know when female is estrous
- sometimes mice don’t want to have intercourse
- female can be too old for child (6 months)
Pregnancy
- 19-20 days for mice, 21-22 days for rats
- vaginal plug (white) can be used to see if a rodent is pregnant (in rats this plug falls
out, so look in the cage)
Genotyping
- do it yourself with PCR and gel
- Send DNA samples to company
→ you need primers to know the location and sequence of the mutation
Homologous recombination
- Law dictates that new drugs are tested for efficacy and toxicology in
animals before they are tested in humans
- Detailed mechanistic understanding of health and (brain) disorders
and ultimately the design of new treatments requires animal experiments
- Fundamental understanding of (neuro)biology
- Controlling factors: genetics, environment, short life span → humans are restricted in
those areas (e.g life span is too long to conduct life long research)
Rat vs. Mouse
face validity: similarity in symptoms → but: evaluation is very subjective
predictive validity: similarity in drug effects → but: individual differences in responsivity to
drugs in humans which are not taken into account + several drugs are not disorder-specific
! construct validity: similarity in neural substrates → but: how do we know whether an animal
model has construct validity if mechanisms are not known in humans
Before animal experiment
Three R’s
, ● Replace: avoid using animals when possible
● Reduce: try to use as few animals as possible
● Refine: ensure the greatest respect towards animal
Transgenic rodent models
Import of animals and GGO
Determine best breeding scheme
Rule: breeding animals have to be crossed every generation with commercially purchased
wild-type animals having the same genetic background as the knockout animal has to
prevent inbreeding.
- Best to use heterozygous animals for this outbreeding
, Problems with breeding
- you do not know when female is estrous
- sometimes mice don’t want to have intercourse
- female can be too old for child (6 months)
Pregnancy
- 19-20 days for mice, 21-22 days for rats
- vaginal plug (white) can be used to see if a rodent is pregnant (in rats this plug falls
out, so look in the cage)
Genotyping
- do it yourself with PCR and gel
- Send DNA samples to company
→ you need primers to know the location and sequence of the mutation
Homologous recombination
