IN VIVO MODEL OF
Depression is defined as disorders of mood rather than
disturbances of thought or cognition; it may range from a
very mild condition, bordering on normality, to severe
(psychotic) depression accompanied by hallucinations and
Worldwide, depression is a major cause of disability and
misery, apathy and pessimism
low self-esteem: feelings of guilt, inadequacy and ugliness
indecisiveness, loss of motivation
retardation of thought and action
loss of libido
sleep disturbance and loss of appetite
o Unipolar depression
o Bipolar depression 3
THEORIES OF DEPRESSION
1. Monoamine theory:
• Monoamine hypothesis, proposed by Schildkraut in 1965,
which states that depression is caused by a functional
deficit of monoamine transmitters at certain sites in the
brain, while mania results from a functional excess i.e.
2. Neuroendocrine mechanism:
• Increase cortisol, growth hormone concentration is
reduced and prolactin is increased.
• But these changes are nonspecific.
• Depression is associated with neuronal loss in the
hippocampus and prefrontal cortex.
• Antidepressant therapies of different kinds act by
inhibiting or actually reversing this loss by stimulating
ANIMAL MODELS OF DEPRESSION
Despair swim test
Tail suspension test in mice
Learned helplessness in rats
Muricide behaviour in rats
Potentiation of norepinephrine toxicity
Reserpine induced hypothermia
DESPAIR SWIM TEST
Mice or rats forced to swim in a restricted space from which they
cannot escape are induced to a characteristic behavior of
Rats placed in the cylinders for the first time
Initially-They are highly active
After 2-3 min-Starting of immobility or floating
After 5-6 min-Remain immobile
Test drugs or standard are administered one hour prior to
Duration of immobility is measured in controls and animals
treated with various doses of a test drug or standard.
TAIL SUSPENSION TEST IN MICE
The immobility displayed by rodents when subjected to an
unavoidable and inescapable stress has been reflect
depressive disorders in humans.
Male Balb/cJ mice weighing 20–25 g are used
Animals are treated with the test compounds or the
vehicle by i.p. injection 30 min prior to testing.
Mice are suspended on the edge of a shelf 58 cm above a
table top by adhesive tape placed approximately 1 cm
from the tip of the tail.
The duration of immobility is recorded for a period of 5
The percentage of animals showing the passive behavior is
counted and compared with vehicle treated controls.
Using various doses, ED50 values can be calculated.
LEARNED HELPLESSNESS IN RATS
Animals exposed to inescapable and unavoidable electric
shocks in one situation later fail to escape shock in a
different situation when escape is possible
Learned helplessness is produced in male Sprague-
Dawley rats (300 g) by exposure to electric shock (0.7 mA)
for 1 h on a schedule of 10 s of shock/min.
The platform is not available during training.
After giving test drug,the shock is initiated (0.4 mA)
Shock is terminated in 10 s if the animal has not escaped
onto the platform by this time.
If an escape response occurred, the animal is allowed to
remain on the platform for the duration of 10 s, then
returned to the grid floor.
Ten such trials with an interval of 20 s are given.
A drug is considered to be effective, if the learned
helplessness is reduced and the number of failures to
escape is decreased.
MURICIDE BEHAVIOUR IN RATS
A selective inhibition of mouse-killing behavior in rats by
Male SD rats (300–350 g) are isolated for 6 weeks in
One mouse is placed into the rat’s cage. About 10 to 30% of
rats kill the mouse by biting the animal through the cervical
Only rats consistently killing mice within 5 min after
presentation are used for the test.
Drugs are injected i.p. to the rats before the test.
Mice are presented 30, 60 and 120 min after drug
Failure to kill a mouse within 5 min is considered inhibition
of muricidal behavior.
The ED50 is calculated(dose which inhibits mouse killing
in 50% of the rats.)
Injections of 5,7-dihydroxytryptamine into the lateral
hypothalamus increased mouse-killing behavior in rats
POTENTIATION OF NOREPINEPHRINE TOXICITY
Antidepressants block the re-uptake of biogenic amines into
nervous tissue. In this way, the toxic effects of
norepinephrine are potentiated.
Male NMRI mice (22–25 g) are randomly assigned to test
groups of 10 subjects.
The test drug, the standard or the vehicle are given orally 1
h prior to the s.c. injection of the sublethal dose of 3 mg/kg
The mortality rate is assessed 48 h post-dosing. ED50,or
dose which causes death of 50% of the treated subjects,is
RESERPINE INDUCED HYPOTHERMIA
Depletion of biogenic amines (noradrenaline, 5-
hydroxytryptamine, dopamine) in the brain induces not
only catalepsy and ptosis but also hypothermia in rodents.
The decrease of body temperature induced by reserpine is
antagonized by antidepressants, MAO-inhibitors and
Groups of male NMRI mice (19–21 g body weight)are
On the day before testing, they are dosed with 2 mg/kg
Eighteen hours after reserpine administration, the animals
are placed into individual cages.
The initial rectal temperature is determined by insertion of
an electronic thermometer
Following administration of the test compound (either i.p.
or p.o.), the rectal temperature is measured again at 60
min intervals for 7 h.
Rectal temperature is recorded every hour.
The difference in temperature from vehicle controls is
calculated for each time and the maximal difference is