SCREEENING OF ANTIDEPRESSANT AGENTS

1. PRESENTED BY : RENEE JOHNSON
MODERATOR: DR AMRITA PARIDA

2.  Depression is characterized by symptoms like
sad mood, loss of interest and pleasure, low
energy, worthlessness, guilt, psychomotor
retardation or agitation , change in appetite
/sleep, suicidal thoughts etc.

3.  Drugs that helps to relieve symptoms of
depression , social anxiety, anxiety disorders,
dysthymia , mild chronic depression as well other
condition.
 Antidepressant were first developed in 1950s,
use has become progressive more common in
last 20 years.

5.  Relationship between the clinical efficacy of
known antidepressant and their effects on
various pharmacological test models.
 Assessment of the specificity of
antidepressant activity by establishing a ratio
between the antidepressant dose and
sedative/stimulant dose.

6.  CHRONIC SOCIAL DEFEAT STRESS(CSDS)
 WATER WHEEL MODEL
 LEARNED HELPLESSNESS TEST
 ISOLATION INDUCED HYPERACTIVITY
 TAIL SUSPENSION TEST
 RESERPINE INDUCED HYPOTHERMIA
 AMPHETAMINE POTENTIATION
 APOMORPHINE ANTAGONISM
 RESIDENT INTRUDER PARADIGM IN RATS
 MURICIDAL BEHAVIOR IN RATS

7.  Chronic social defeat can act as stress for
adolescents.
 The adolescent age animal is exposed for 2
weeks to daily aggression in agonistic interaction
with unfamiliar adult males.
 Rats are placed in two equal compartment
separated by transparent perforated partition for
5 days.

8.  4 week old male adolescents are placed in a
vacant compartment .
 Adult male rats - aggression towards adolescent.
 Young male - defensive behavior.
 Interaction allowed for 5min depending on
intensity of the attack.
 Exposure continued for two weeks. Adolescent
faces repeated defeat and social stress.

11.  Demonstrate the antidepressant property of
the test drug:- ‘behavioral despair activity’.
 The animal is forced to swim without any
escape in a water tank .
 Rotating wheel in the water tank-option for
escape but add on to the despair

12.  END POINT:- The juncture when the animal is
immobile and ceases to struggle and remain
floating motionless in the water, making only
those movement necessary to keep its head
above the water

13. Plexiglas water tank
(20cm x 8cm x 18cm)
Plexiglas shaft
(diameter 3cm, length 6cm)

14.  ANIMAL USED:- Mice of either sex weight (20 to
25gm).
 Animal 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.

15.  The classical tricyclic antidepressants reduce
immobility time in this model.
 However antidepressant acting selectively on
5HT system are inactive in this test.
 False positive are induced by opiates and
antihistaminic.

16.  Lucki and co-worker have enhanced the
sensitivity of the traditional porslot paradigm
and accuracy of its scoring.
 This enables to better detect SSRIs
antidepressant activity.

17.  The adult male rats are forced to swim in a
cylinder with no escape.
 The animal become immobile after an initial
struggling phase.
 The immobility has been equated to a despair
reaction.
 Antidepressant decreases the immobility time.

19.  PRINCIPLE:
Chronic mild stress - naturalistic paradigm of a
hostile environment ,models anhedonia (major
symptom of depression).
 This model reproduce a condition of decreased
sensitivity to usually pleasurable stimuli.

20.  Adult wistar rat of either sex (200 to 250
grams) are placed in a compartment with
steel mesh grid floor.
 Repeated shocks (15 sec duration,0.8mA
every min) -serves as stress to animals.
 Rats are exposed for 1 hour without any
escape route.

22.  Escape response:- After chronic exposure to
cue (buzzer or light signal) preceeds 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.

24.  Failure to exhibit escape response by an animal
is said to be indicative of its depressive state.
 Antidepressant reduce escape failure.
 This classic paradigm has a variable score of 30
to 80%.

25.  Rats socially deprived for 15 days exhibit
depressive behavior.
 Reduction in spontaneous locomotor activity,
exploratory behavior rearing and stereotype.
 Animals are subjected to behavior testing on an
arbitrary scale for sleep , reduced response to
external stimuli , ambulatory behavior,
stereotype and posture.

26.  PRINCIPLE:- Modification of the behavior
despair test, mice are rendered immobile by
suspending from tail to induce behavior
despair.
 Mouse( 20 to 30gm ,either sex)is hung on a
wire in a upside down posture such that its
nostril touches the water surface

27.  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

28. This test is reliable and rapid screening method for
potential antidepressant.

29.  Any pharmacological agents which reverse
this typical effect of resrpine may have
antidepressant activity.
 Simple and reliable method to screen the
tricyclics, MAO inhibitors.

30.  Used for early screening of potential
antidepressant drugs with the mechanism
action similar to tricyclic antidepressants.
 Reserpin in a dose of 2.5 -5.0mg/kg induces
ptosis, hypothermia, catalepsy.

31.  PRINCIPLE:-
• Amphetamine- sympathomimetic agent,
promoting neuroexocytosis or displacement
of transmitter from axonal terminal .
• Screening method to detect adaptive changes
in dopaminergic and noradrenergic system
after AD treatment.

32.  Rats (male wistar 250 to 300g) are housed in a controlled
environment – test drug for 2 weeks.
 90 min after the last treatment D-amphetamine (5-10mg/kg ip )
and 30min later they are housed singly.
 Typical stereotypic effects (sniffing, body and head movement ,
biting, licking etc).
 Most of the antidepressant including TCA, MAOI potentiate
amphetamine effects seen as increased locomotor activity.

33.  Apomorphine - dopamine agonist dose
16mg/kg , i.p., induces hypothermia,
stereotype and climbing behavior.
 Differentiates between neuroleptics and
antidepressant as the former blocks
stereotype and climbing behavior but not
hypothermia.

34.  Animals used :-Female rats of Holtzman
strain exhibit compulsive mouse killing
behavior irrespective of their satiety status.
 Agents reducing muricidal behavior exhibit
antidepressant action.

35.  A major problem in the search for new
antidepressant drug is the lack of animal model
that resemble depressive illness in human
models and are selectively insensitive to
stimulate effective antidepressant treatment.
 Novel antidepressant like mianserin shows little
or no antidepressant effect on laboratory
animals.

36.  Tripathi KD .In :Essential of Medical,
Pharmacology JAYPEE publisher New
Delhi.8th edition.
 Gupta S K. In: Drugs screening methods
JAYPEE publisher New Delhi.3rd edition.