Evaluation of antipsychotic drugs
Need for new drugs:
- 30% patients have resistant schizo who don’t respond to even clozapine.
- Recent meta-analysis by Leucht et al showed that except a few atypical antipsychotics (amisulpiride, clozapine, olanzapine and risperidone) other atypical one’s don’t show better results than typical even for negative symptoms.
In vitro evaluation
D2 receptor assay: 3H-spiroperidol binding.
- Dopamine receptor binding assays employing DA antagonists in mammalian striatal tissues, a DA enriched area of brain have been shown to be predictive of in vivo dopamine receptor antagonism and anti- psychotic activity.
- Significant correlation exists between neuroleptic binding affinities and anti- psychotic activity in man.
- Spiroperidol is considered to be an antagonist specific for D2 receptors
Mammalian striatal tissue is isolated b/c it has the max DA receptors and prepared appropriately for further experimentation.
- It is incubated with 3H spiroperidol and the test drug for 45 minutes. The test drug if having D2 antagonistic activity displaces the spiroperidol which is the measured in the filtrate using liquid scintillation counter.
Two methods are used.
1) lesions or drugs to alter specific systems in the brain.
2) Developing models with cognitive deficit which resemble the disorder which might have translational reliability. However the disadvantages are that symptoms related to thoughts, memory cannot be assessed. Also there is no gold standard medication to be used as positive control.
Golden hamster test.
The aggressive behavior of male golden hamsters is suppressed by neuroleptics in doses which do not impair motor function.
- Around 20 are kept together for 2 weeks in a crowded environment to induce aggression.
- Then each hamster is kept in a glass jar and probed with a forcep.
- The animal which elicits a characteristic response for 6 times of turning, vocalization and biting are selected.
- Test drugs are administered which should present this aggressive response and the animals are called tamed.
EVALUATION: The stimuli are applied every 20 min for 3 hrs.
- Number of stimuli until response
- Suppression of the defense reactions
An animal is regarded to be completely “tamed”, if all defense reactions are suppressed even after punching with the forceps at least once during the test period.
Cotton rat model.
- It’s a very shy animal and hides reflexly.
- This innate flight reflex is suppressed by centrally active drugs.
- Young cotton rats of about 40 g are used for the test.
- The cages have a tunnel of sheet metal. The cotton rats hide immediately in the tunnel, even if the tunnel is lifted and kept on the other side.
- Rats which consistently behave as described are selected for the test.
- They are treated with the test compound s.c. or orally.
- These animals are administered test drugs and those animals not showing a flight response even on blowing of air stream are said to be positively influenced.
Cook’s Pole climbing avoidance test
Catalepsy in rats
Amphetamine group toxicity.
Amphetamine stereotypy in rats.
Apomorphine stereotypy in rats.
PCP induced locomotor activity.
Human epidemiology states that neurological insults like environmental trauma, maternal stress during fetal or neonatal stage can increase likelihood of developing schizophrenia later in adulthood. Hence developing such models is useful.
Post weaning social isolation.
- Hyperactivity in open field at 2- 3 wks of isolation,
- persistent reduction in acoustic startle response (reversed by both typical and atypical),
- deficit in novel object recognition (reversed by glutamate receptor antagonists).
- This model has good face, construct and predictive validity
- Disadvà is that the behavioral effects are fragile àcan be reversed by repeated handling or exposure to too many other tests during developmental period.
- Locomotor hyper-responsiveness to stress
- Amphetamine- induced hyperactivity reversed by acute or chronic anti- psychotic injection.
Genetic models like DISC-1 knockout, dysbindin knock out are also used.
- The heritability of schizophrenia is around 80%.
- But, no single genetic alteration has causally related.
- Genes that have been implicated predominantly segregate to proteins involved in neuronal plasticity, glutamatergic or DA function and synaptogenesis.
- DISC 1- development of cytoskeletal proteins & is involved in cell migration, neuritic outgrowth and receptor trafficking. Plays a crucial role in pre and post natal neuronal development.
- Neuregulin 1 and ErbB4- synaptic development & plasticity, controls NMDA receptor expression.
- Dysbindin- tethers NMDA receptors post- synaptically
- Reelin- Synaptic formation and plasticity in CNS
Disadv- Diversity and lack of consistency of effects. Lack of pharmacologic studies.