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Uploaded byKashikant Yadav
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Screening of depressents by Kashikant Yadav

This document discusses depression, including its causes, symptoms, and treatment options. It describes several animal models used in screening for potential antidepressant drugs, including the water wheel model, forced swim test, and learned helplessness test. These models evaluate behaviors like escape attempts, mobility, and reactions to inescapable shocks. The document also outlines in vivo and in vitro assays, such as those measuring neurotransmitter uptake inhibition and receptor binding, used to assess drug effects at the pharmacological level.

Health & Medicine◦
1 PRESENTED BY: KASHIKANT YADAV KARNATAKA COLLEGE OF PHARMACY Email: ykashikant@gmail.com
Depression
Depression  is a mental health disorder persistently low mood feeling of sadness loss of interest
Causes of depression  genetics  biological - changes in neurotransmitter levels  environmental  psychological and social (psychosocial)
Symptoms of depression Depressed mood Loss of interest or pleasure Significant weight or appetite alteration Insomnia or hyposomnia Psychomotor agitation or retardation Fatigue or loss of energy Feelings of worthlessness Diminished ability to think or concentrate or indecisiveness; and Suicidal ideation.
Depression The biogenic amine hypothesis proposes Reduction in NE Reduction in level of 5HT
Antidepressant drugs  RIMAO-A: Moclobemide, clorgyline  TCAs: Imipramine, Amitryptyline,  SSRIs: Fluoxetine, Sertraline, Citalopram, Escitalopram  SSNRIs: Duloxetine  ATYPICAL ANTIDEPRESSANT: Buspropion, Venalafexine, Trazodone
Screening Method’s Principles  To see the relationship between the Clinical efficacy of known antidepressants and their effects on various pharmacological test models.
In vivo methods  Water Wheel Model  Learned Helplessness Test  Tail Suspension Test  Reserpine Induced Hypothermia  Amphetamine Potentiation  Resident Intruder Paradigm  Muricidal Behavior in Rats
In vitro assays  Assays based on inhibition of amine uptake  Assays based on binding to the receptors Though complicated but these are precise and accurate
Water Wheel 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 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 a float.
Water Wheel Model
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.
Water Wheel Model
Forced Swim Test
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.
Forced Swim Test
Learned Helplessness Test
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. This forms the first phase of the animal model where animal is exposed to `inescapable shock treatment` 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
Learned Helplessness Test First Phase
Learned Helplessness Test Second Phase After chronic exposure a cue(buzzer or light signal)precedes the shock. This is termed as the escape response. Simultaneously a door open for a safe chamber, which is unelectrified. The animal is allowed to escape towards it and avoid the noxious stimulus.
Learned Helplessness Test Second Phase
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.
Tail suspension test
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 Pretreatment with antidepressant drug reduces immobility time. A computerized system with 16 channels are used to measure the time of activity, time of immobility of the animal in real time.
Tail suspension test
Amphetamine potentiation test
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 90mins after the last dose of the test drug, D-amphetamine(5- 10mg/kg,ip)is injected and 30mins later they are placed singly into cages with photocells to record their activity. The rat receives the test drug(antidepressants drugs) in their home cage usually for 2 weeks Most antidepressants including TCA,MAOI potentiate amphetamine effects seen as increased locomotor activity.
Assays based on inhibition of amine uptake (Norepinephrine/Dopamine/Serotonin) Isolate hypothalamus/ corpora striata / hypothalamus or whole brain minus cerebellum. Homogenize with 0.32 M sucrose solution. The homogenate is centrifuged The supernatant is incubated with 3H-norepinephrine /Dopamine / serotonin in Krebs-Henseleit bicarbonate buffer and appropriate drug concentration (or the vehicle) at 37 °C and then centrifuge. The supernatant fluid is aspirated and the pellets dissolved adding 1 ml of solubilizer (Triton X-100 + 50% ethanol, 1 : 4).
Take the count for radioactivity by liquid scintillography IC50 are derived & compared with standards.
Basic procedure of receptor binding Assay Isolate the cells with receptors Add radioactive ligand for that receptor in presence or absence of test drugs Count the receptor ligand binding by liquid scintillography.
References •Kessler, R.C., et al., Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry, 2005. 62(6): p. 593- 602. •Murray, C.J. and Lopez, A.D. (1997) Alternative projections of mortalityand disability by cause 1990–2020: Global Burden of Disease Study. Lancet349, 1498–1504 •Hua-Cheng YAN, Xiong CAO, Manas Das, Xin-Hong ZHU, Tian-Ming GAO. 2010. "Behavioral animal models of depression" Neurosci Bull August 1, 2010, 26(4): 327-337 •Hasler, G. et al. (2004) Discovering endophenotypes for major depression. Neuropsychopharmacology 29, 1765–1781
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