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1Confidential
Preclinical Tests For Depression
2Confidential
Forced Swim Test
• When rats or mice are forced to swim in a deep cylinder with tepid water they become nearly immobile and cease trying to escape.
• Immobility is thought to reflect a state of “behavioral despair” and is reduced when rats and mice are treated with a wide variety of antidepressants.
• Rodent models of depression are mainly based on predictive validity, objectivity of measured response and their high reliability and reproducibility.
3Confidential
Ketamine Shows a Prolonged Effect in the Rat FS test
• Single injection of ketamine (10 mg/kg ip) after habituation session produces a long-lasting antidepressant-like effects in SD rats in the FS test
24 hours 3 days 7 days
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VehicleKetamine (10 mg/kg)
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24 hours 3 days 7 days
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VehicleKetamine (10 mg/kg)
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*
24 hours 3 days 7 days
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ing
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VehicleKetamine (10 mg/kg)
*
~ *p<0.05
~p<0.1
4Confidential
Effects of SSRI and Tricyclic Antidepressants
• The FS test in rats can differentiate between SSRI and Tricyclic-like antidepressants by their differential effects on climbing and swimming behaviors.
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VehicleFluoxetine 20 mg/lgDesipramine 20 mg/kg
Immobility Swimming Climbing
* *
*
*
5Confidential
Immobility Swimming Climbing
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VehicleDesipramine 20 mg/kgDOV21947 20 mg/kg
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Effects of Double and Triple Reuptake Inhibitors
• The triple uptake inhibitor DOV21947 and the 5-HT and NE reuptake inhibitor venlafaxine decreases immobility in the rat FS test.
Immobility Swimming Climbing
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VehicleVenlafaxine 80 mg/kg
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6Confidential
Sertraline Decreases Time Immobile in Balb/cJ Mice
Time (min)
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e Im
mo
bile (
sec)
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VehicleSertraline (20 mg/kg)
Vehicle Sertraline
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tal T
ime Im
mo
bile (
sec)
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*
7Confidential
Differential Strain Responses to Sertraline in the FS Test
C57BL/6J DBA/2J
To
tal T
ime Im
mo
bile (
sec)
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VehicleSertraline 5 mg/kg Sertraline 10 mg/kgSertraline 20 mg/kg
*
*
8Confidential
Tail Suspension in A/J mice
• Mice that are suspended by their tails become motionless.
• Clinically active typical and atypical antidepressants reduces this immobility
Tim
e Im
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bile (
sec)
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500VehicleBuproprion 20 mg/kgDesipramine 20 mg/kgFluoxetine 20 mg/kg
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9Confidential
Marble Burying
• Marble burying is normally used as a model for both anxiety and obsessivecompulsive disorder.
• Mice are placed individually in clean mouse cages containing approximately 6-cmof hard wood bedding and twenty black marbles placed in spaced rows of 5 for 30min. Distance traveled during the test is captured by overhead cameras andquantified using Video Tracker Software (ViewPoint Life Sciences, France). Aftertermination of the test the mice are removed from the cage and the number ofburied marbles is counted. A marble is considered buried if it is pushed at leasttwo thirds into the bedding.
• This test can be used to investigate pharmacological mechanisms throughagonist/antagonists studies. It is also a useful test for yielding surrogatepharmacokinetic information on the duration of action of a drug.
• Mice pretreated antidepressants of various classes show less marble buryingability compared to the control mice
10Confidential
Desipramine Decreases Marble BuryingM
arb
les B
uri
ed
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VehicleDesipramine 5 mg/kg Desipramine 10 mg/kg Desipramine 20 mg/kg
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*
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tal D
ista
nce T
ravele
d
(cm
/30m
in)
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Vehicle Desipramine 5 mg/kgDesipramine 10 mg/kgDesipramine 20 mg/kg
*
**
11Confidential
Bupropion Decreases Marble BuryingM
arb
les B
uri
ed
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VehicleBupropion 5 mg/kg Bupropion 10 mg/kg Bupropion 20 mg/kg
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*
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tal D
ista
nce T
ravele
d
(c
m/3
0m
in)
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Vehicle Bupropion 5 mg/kgBupropion 10 mg/kgBupropion 20 mg/kg
*
12Confidential
Paroxetine Decreases Marble BuryingM
arb
les B
uri
ed
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VehicleParoxetine 5 mg/kg
*
To
tal
Dis
tan
ce
Tra
vele
d(c
m / 3
0m
in)
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20000
VehicleParoxetine 5 mg/kg
13Confidential
Venlafaxine Decreases Marble BuryingM
arb
les B
uri
ed
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VehicleVenlafaxine 10 mg/kg Venlafaxine 20 mg/kg
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*
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rav
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(cm
/ 3
0m
in)
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VehicleVenlafaxine 10 mg/kg Venlafaxine 20 mg/kg
14Confidential
Novelty Suppressed Feeding
• NSF measures a rodent’s aversion to eating in a novel environment.
• Chronic administration of imipramine decreases the latency to eat but does not impact home cage food consumption
Fo
od
co
ns
um
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on
(g
)
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12VehicleImipramine 60 mg/kg/day
Late
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o e
at
(sec)
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VehicleImipramine 60 mg/kg/day
*
15Confidential
Differential Reinforcement of Low Rate – 72 second schedule
• Differential reinforcement of low rates of responding (DRL) is an operant test that requires behavioral suppression: the withholding of a response for a period of time such as 72 seconds (‘DRL72s’).
• DRL72s has predictive validity for antidepressant drugs. Administration of different classes of antidepressant (tricyclics, MAOIs, SSRIs) results in a decrease in response rate and an increase in reinforcement rate.
• Non-antidepressant drugs have different profiles of effects, such as, psychostimulants, which increase lever-presses and decrease reinforcers earned.
16Confidential
Tricyclic antidepressants increase the reinforcement rate and decrease the response rate
Imipramine Dose (mg/kg)
Perc
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Reinforcement RateResponse Rate
0.0 3.0 10.0 17.0 30.0
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Desipramine Dose (mg/kg)P
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aselin
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Reinforcement RateResponse Rate
0.0 3.0 10.0 17.0 30.0
* * *
* * *
*
17Confidential
Berton et al., 2006; Donahue et al., 2014).
Chronic Social Defeat Stress (CSDS)
• Closely mimics the dynamic range of reactions that an individual can show in response to physical and psychological stressors.• Ranges from the development of a major depressive disorder, post-traumatic stress disorder or resiliency to these disease states.• Individual responses to stressors are particularly useful in modeling aspects of anxiety disorders such as PTSD with high construct, face, discriminative and predictive validity
18Confidential
Schematic of CSDS Test
Control Defeat
Social Interaction
Control group
goes through 24
hr sensory
contact with
same strain
mouse
Aggressor PhysicalContact 5-10 min
Experimental
SensoryContact 24 hrs
New aggressor for 10 days
19Confidential
CSDS – Control and Defeat PhenotypeS
oc
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tio
n S
co
re
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ControlDefeat - Susceptible
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)
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ControlDefeat - Susceptible
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ControlDefeat - Susceptible
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20Confidential
Effects of Imipramine on Social Deficits in Defeated Mice
• Oral administration of imipramine for 2 weeks attenuated social deficits in defeated mice.
• Acute administration of imipramine does not show efficacy in this model
Acute Chronic
So
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l In
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Rati
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Control - VehicleDefeat - VehicleDefeat - Imipramine 20 mg/kg
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21Confidential
Ketamine Attenuates Social Deficits in Defeated Mice
So
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tera
cti
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Sco
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2.4 Control - VehicleDefeat - Vehicle Defeat - Ketamine (10 mg/kg)
*
22Confidential
Sexual Dysfunction in Rats
23Confidential
Normal distribution of ejaculation frequency during 30min exposure to receptive female
‘rapid’ ejaculation(n=12)
‘normal’ ejaculation(n=12)
Ejaculation frequency5.04.03.02.01.00.0
Num
ber
of
anim
als
40
30
20
10
0
Std. Dev = 1.29
Mean = 2.7
N = 99.00
‘delayed’ ejaculation(n=12)
24Confidential
Chronic Administration of Paroxetine Causes Sexual Dysfunction
Day 1 Day 7 Day 14T
ota
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um
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of
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cu
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SalineParoxetine 5 mg/kgParoxetine 5 mg/kg
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Late
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or
1st E
jacu
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(sec)
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SalineParoxetine 5 mg/kgParoxetine 10 mg/kg
* *
*
*
25Confidential
Effects of Bupropion on Sexual Function
Day 1 Day 7 Day 14
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VehicleBuproprion 15 mg/kg
*
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lati
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VehicleBuproprion 15 mg/kg
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