Screening of antidepressant drugs by animal model.

1. Screening of antidepressant
agents
Dr. Partha Sarkar
(PGT, 1st Yr)
Department of Pharmacology
Medical College, Kolkata

2. Depression

3. Depression
• It is a major affective or mood disorder.
• Characterized by extreme exaggerations and
disturbances of mood.
• It may adversely affect cognition or
psychomotor function.

4. Depression
The biogenic amine hypothesis proposes
Reduction in NE
Reduction in level of
5HT,DA,GABA

5. Antidepressant drugs
• RIMAs: Moclobemide, clorgyline
• TCAs: Imipramine, Amitryptyline,
• SSRIs: Fluoxetine, Sertraline, Citalopram, Escitalopram
• NDRIs: Desipramine, Amoxapine, Nortryptyline
• ATYPICAL ANTIDEPRESSANT:
Venalafexine, Trazodone, Duloxetine, Mianserine

6. Screening Method’s Principles
• To see the relationship between the Clinical
efficacy of known antidepressants and their effects
on various pharmacological test models.
• Motor activity of these tests also allow assessment
of the specificity of antidepressant activity by
establishing a ratio between the antidepressant
dose and sedative or stimulant dose.

7. In vivo methods
• Water Wheel Model
• Learned Helplessness Test
• Tail Suspension Test
• Reserpine Induced Hypothermia
• Amphetamine Potentiation
• Resident Intruder Paradigm
• Muricidal Behavior in Rats

8. Water Wheel Model
• This model demonstrates the antidepressant
property of the test drug by use of the `Behavioral
Despair Activity`
• The animal is forced to swim without any escape in
a water tank. The rotating wheel in the water tank
poses as an option for escape but add-on to the
despair as it turns under the weight of the animal
and it has to keep rotating it in order to stay afloat.

9. Water Wheel Model

10. Water Wheel Model
• The juncture when the animal is
immobile and ceases to struggle and
remains floating motionless in the
water, making only those movements
necessary to keep its head above the
water is denoted as end point or
behavior despair.

11. Water Wheel Model
Mice of either sex and weight range of 20 to25gm
are selected.
Animals are treated with standard drug like
imipramine and rechallenged on water wheel.
A potential antidepressant will increase the
number of counts of water wheel.
Indicating increased effort at escape
behavior.

12. Water Wheel Model

13. Water Wheel Model
• The classical tricyclic antidepressants reduce
immobility time in this model.
• However antidepressants acting selectively on
5HT system are inactive in this test.
• False positive are induced by opiates and
antihistaminics.

14. Modified Traditional Porsolt
Paradigm
• Lucki and co-workers have enchanced the
sensitivity of the traditional porsolt paradigm and
accuracy of its scoring.
• This enables to better detect SSRIs antidepressant
activity

15. Forced Swim Test

16. Forced Swim Test
The adult male rats are forced to swim in a cylinder
with no escape.
The animals become immobile after an initial
struggling phase.
The immobility has been equated to a despair reaction.
Antidepressants decrease the immobility time.

17. Forced Swim Test

18. Learned Helplessness Test

19. Learned Helplessness Test
First Phase
Adult wister rat of either sex and in weight range from 200 to
250g are placed in a compartment with steel mesh grid floor.
Repeated shocks(15 sec duration,0.8mA every min)are applied
this serves as stress to animals.
Rats are exposed for 1 hour without any escape route
This forms the first phase of the animal model where animal is
exposed to `inescapable shock treatment`

20. Learned Helplessness Test
First Phase

21. Learned Helplessness Test
Second Phase
After chronic exposure a cue(buzzer or light signal)precedes
the shock.
Simultaneously a door open for a safe chamber, which is
unelectrified.
The animal is allowed to escape towards it and avoid the noxious
stimulus.
This is termed as the escape response.

22. Learned Helplessness Test
Second Phase

23. Learned Helplessness Test
• Failure to exhibit escape response by an
animal is said to be an indicative of its
depressive state.
• Antidepressants reduce escape failure.
• This classic paradigm has a variable Score of
30 to 80%

24. Tail suspension test

25. Tail suspension test
Mouse(20 to 30 gm, either sex) is hung on a wire in an upside
down posture such that its nostril touches the water surface.
Initially the animal tries to escape by making vigorous
movements, but is unable to escape and become immobile
A computerized system with 16 channels are used to measure the
time of activity, time of immobility of the animal in real time.
Pretreatment with antidepressant drug reduces immobility time.

26. Tail suspension test

27. Amphetamine potentiation test

28. Amphetamine potentiation test
Rats(male wister,250 to 300g)are housed in a controlled
environment with temp 22 2̊ C,12 hr light/dark cycle and free
access to food and water
The rat receives the test drug(antidepressants drugs) in their
home cage usually for 2 weeks
90mins after the last dose of the test drug, D-amphetamine(510mg/kg,ip)is injected and 30mins later they are placed singly
into cages with photocells to record their activity.
Most antidepressants including TCA,MAOI potentiate
amphetamine effects seen as increased locomotor activity.

29. Amphetamine potentiation test

30. Muricidal behavior model
• Female rats of Holtzman strain exhibit
compulsive mouse killing behavior irrespective
of their satiety status.
• Nonmuricidal rats can be rendered muricidal
by pretreatment with pilocarpine(2.5-5mg/kg,
ip).
• Agents reducing muricidal behavior exhibit
antidepressant action.

31. Muricidal behavior in female rats
of Holtzman strain.

32. Pitfalls of classical antidepressant
methods
• A major problem in the search for new
antidepressant drugs is the lack of animal
models that resemble depressive illness in
humans and are selectively insensitive to
simulate effective antidepressant treatment.
• Also novel antidepressant like mianserin
shows little or no antidepressant effect on
laboratory animals.

33. Pitfalls of classical antidepressant
methods

34. Thank you