Anti-psychotic screening models

1. Preclinical screening models
for
Anti-psychotic activity.
Subject: Pharmacology screening methods
A.Surendhar
B.Pharm IVYear
College of pharmacy
Jaya college of paramedical sciences ,Chennai.

2. Introduction.
Classification of antipsychotics.
Screening methods of antipsychotics.
Conclusion.

3. Definition: Antipsychotics drugs having
therapeutic effect in psychoses.
Psychoses:
1) Functional disorder-
Schizophrenia.
2) Cognitive disorder-
Delirium, dementia.

4. Classifications:

5. Screening methods of Anti-psychotics:
Behavioral tests:
1)Catalepsy in rodents
2)Golden hamster test
3)Pole climb avoidance in rats
4) Conditional avoidance reflux in rats
Test based on pharmacologic antagonism:
1)Inhibition of Amphetamine-induced stereotype in rats
2)Inhibition of Apomorphine-induced stereotype in mice
3)Phencyclidine-induced bizarre pattern locomotor activity and stereotype
4)Neuro development model.

6. AIM OF SCREENING:
 Tests designed to exhibit a drug action
 The specific effect of a test drug is compared to a reference drug already known to be clinically
effective.
 Screening tests are done in experimental models of the disease.
MODEL SPECIFICATION:
 Experimental preparation developed to study a particular condition in same or different species
 Typically models are animals that mimic a human condition.
 Rats & mice behavioural models used for screening of antipsychotics
 small size , easy to handle
 sensitive to small doses of drugs
 easily trained
 sturdy to long periods of experimentation
 easily bred
 cheap

7. Characteristics of an ideal model.
 Behaviour assessed is relevant to clinical condition
 Behaviour paradigm used to index the action of antipsychotics can be used in rats/mice
& humans
 Model is selective & specific for antipsychotics.
 Model is able to differentiate between typical & atypical antipsychotics
 Model doesn’t require previous pharmacological manipulation to manifest the
behavioural index of antipsychotic activity.
 Model is able to shed light on the mechanism of action of antipsychotics.
Behaviour paradigms assessed in the tests.
 Locomotor activity (hyperactivity , stereotypy)
 Social behaviour
 Sensorimotor gating measures (PPI)
 Catalepsy
 Conditioned responses Cognition (attention memory)

8. EXPERIMENT-1
Study of Catalepsy in rats.
Aim: To study cataleptic activity of Haloperidol & Clozapine in rats.
Principle:
• Catalepsy is the long term maintenance of an animal in abnormal posture.
• Catalepsy is used as a model to study EPS associated with antipsychotic usage in man.
Requirements:
Animal - Rats (150-200g)
Drugs - Haloperidol & Clozapine(1mg/kg)[dose at which they block amphetamine induced
hyperactivity)
Equipment's - 3cm & 9cm high wooden blocks.
Procedure:
• Weigh & number the rats.
• Divide the rats into 2 groups with 5 animals in each group.
• Inject Haloperidol into one group & Clozapine into second group. Observe severity of
catalepsy at different time intervals in the 2 groups as follows:-
Stage I: Rat moves normally when placed on table (score = 0)

9. Stage II: Rat moves only when pushed (score = 0.5)
Stage III: Rat placed on the table with front paws set on a 3cm high block fails to correct the
posture in 10 secs.(score 0.5 for each paw)
Stage IV : Rat fails to remove its front paws when placed on a 9cm block.(score = 1 for each
paw)* Observe the onset & severity of catalepsy at 5,15,30,45,60,90 ,120 mins.
Observation:
Catalepsy is observed in haloperidol group at the dose that inhibits amphetamine induced
hyperactivity but is absent in clozapine group at the dose that inhibits hyperactivity.

10. Experiment-2
Golden Hamster test.
Aim: This test is to innate the behavior of the species (Mesocricetus auratus) for differentiation
between neuroleptics & sedative-hypnotic activity.

12. EXPERIMENT 1:Inhibition of Amphetamine induced
hyperactivity in mice/rats.
Principle:
• Amphetamine (lower doses) causes increased activity in rats/mice due to excessive dopamine
activity in limbic system.
• Typical antipsychotics can inhibit this hyperactivity by blocking D2 receptors.
• Atypical antipsychotics weakly or do not inhibit this hyperactivity due to weak D2 blockade.
• Hyperactivity studied with help of actophotometer.
Actophotometer:
I. Cage 30cm long & 30 cm deep with wire mesh at the bottom
II. 6 lights & 6photo cells in outer periphery of bottom.1 mouse can block only 1 beam of light.
III. Photo cell activated when rays of light falling on it blocked by mice crossing the beam of
light.
IV. Photo cells connected to electronic counter that counts the number of ‘cut offs’

13. Requirements:
Animal : Mice/rats
Equipment’s :Actophotometer, syringes , needles
Drugs : Saline, Amphetamine (1.5mg/kg),CPZ(chlorpromazine) (3mg/kg),Test drug (x mg/kg).
Procedure:
 Weigh animals & divide into 3 groups of 3 each.
 Inject saline into 1 group (control), CPZ into 2nd group & test drug into 3rd group.(i.p route).
 After 30 mins ,inject Amphetamine into all groups.(i.p. route)
 Place each group of animals in actophotometer separately & no. of cut off recorded for 10
mins at the interval of 30 mins.

14. Inference:
Counts are decreased in CPZ treated group compared to the control
 Test drug has antipsychotic property due to D2 blockade if it decreases the counts compared to
the control.
Drawbacks:
• Hyperactivity is not seen in schizophrenic patients the model doesn’t mimic human disease
(however dopamine overactivity in limbic system is similar in both hence the model is
predictive for antipsychotic activity)
• Screens only antipsychotic activity due to D2 blockade .
• Atypical antipsychotics not screened in this model.

15. EXPERIMENT 3:Inhibition of amphetamine induced stereotypy.
Principle:
• High doses of amphetamine induces stereotypy in rats/mice (rearing,sniffing,licking ) similar to
behavioural disorder in schizophrenics.
• Stereotypy occurs due to increased dopamine activity in the limbic system.
• Typical antipsychotics can block stereotypy.
Requirements:
Animal : mice/rats
Equipment: 250ml clean beakers , syringes , needles
Drugs : Saline,Amphetamine (5mg/Kg), CPZ (3mg/kg) Test drug.

16. Procedure:
• Weigh animals & divide into 3 groups with 3 in each group.
• Inject saline to 1st group(control), CPZ to 2nd group & test drug to 3rd group.
• After 30 mins , inject amphetamine into all animals & place them into separate beakers
• Observe the intensity of stereotypy at 15,30,60 mins after amphetamine inj.
Score the responses as below:-
i. presence of response
ii. moderate response
iii. severe response
Inference:
 Stereotypy induced by amphetamine is blocked by pre treatment with CPZ as evidenced by
decreased scores in this group.
 Test drug has antipsychotic activity due to D2 blockade if scores are decreased compared to
control.

17. Drawbacks:
• Similar to previous experiment
• Recent evidence suggests that stereotypy is mediated through dopamine over activity in
nigro-striatal pathways . Hence inhibition of stereotypy is more predictive of propensity to
produce EPS than the antipsychotic activity.

18. Future approaches:
PCP induced models of cognitive deficits in rats:
• Delayed matching or non matching to sample indicates deficits in memory
• Maze based strategy shift task used to depict deficits in behaviour flexibility , strategy shifting
• 5 choice serial reaction time task to show deficits in attention
Reversal of these deficits has been demonstrated by some of the atypical antipsychotics.
Developmental models.
Systemic administration of L-nitroarginine to rat neonates produces morphological & post
pubertal behavioural change similar to schizophrenia.
Transgenic mice:
Chakragati mouse: insertional transgenic mouse that has morphological and behavioural
abnormalities mimicking schizophrenia, Can become effective screening models for Anti-
psychotics.
*Note:PCP induced disruption of PPI & inhibition of CAR are the 2 screening tests most widely
used.

19. Reference:
• Screening of Anti-psychotic models by Dr.Divya krishana (Calicut Medical college,
Calicut,IN)
• https://doi.org/10.2174/1872211310666161216111515.
• Swalve N, Li M. Parametric studies of antipsychotic-induced sensitization in the
conditioned avoidance response model: roles of number of drug exposure, drug dose, and
test-retest interval. Behav Pharmacol. 2012 Aug;23(4):380-91. doi:
10.1097/FBP.0b013e32835651ea. PMID: 22732209; PMCID: PMC4756434.
• https://link.springer.com/article/10.1007/BF02246184
• Images from www.google.com