Model Organisms in Drug Discovery

noise, 120 dB alone, 74+120 dB at postpartum day 4, 78+120 dB at
postpartum day 8, 82+120 dB at postpartum day 12, and 90+120 dB at
postpartum day 20) each repeated in pseudorandom order six times for a total
of 36 trials. The maximum response to the stimulus (V max) is averaged for each
trial type. The percentage inhibition of the animal’s response to the startle
stimulus is calculated for each prepulse intensity and then graphed. This test is
being used increasingly as a model of human schizophrenia and a test for
antipsychotic drugs.
Tail suspension
The tail-suspension and forced-swim assays are the two mainstay assays for
the discovery and validation of novel antidepressants. The knock-out of the
noradrenalin transporter, one target of the antidepressant Welbutrin,
demonstrates an increased struggle time in the tail-suspension assay (Xu
et al., 2000). The tail-suspension assay has been automated, giving it added
objectivity and making it appropriate for high-throughput analysis. Both of
these assays measure the efforts of the subject to extricate itself from an
inescapable situation, i.e. they measure a tendency toward ‘giving up’.
Compounds known to reduce depressive symptoms in patients reduce the
immobility time in tail suspension, therefore gene knock-outs that result in
decreased time spent being immobile, in the absence of any general increase in
activity levels (as measured in assays such as the open field), point to excellent
opportunities for the discovery of novel therapeutics for the treatment of
depression. In this particular set-up (PHM-300 Tail Suspension Test Cubicle)
a mouse is suspended by its tail for 6 min, and in response the mouse will
struggle to escape from this position. Extended struggle is taken as
antidepressive behavior, whereas curtailed struggle is interpreted as depressive.
Circadian rhythms
HIGH-THROUGHPUT BIOLOGY 269
Changes in sleep patterns can be detected by examining activity continuously
over a period of days and nights. We use an infrared beam system that
monitors the horizontal locomotor activity of individual mice in their home
cage environment for 3 days and nights. This allows us to obtain an accurate
indication of their sleep–wake cycle as well as overall locomotor activity rates.
Changes in the normal circadian rhythm or an increase or decrease in the
periods of activity during the normal sleep cycle can indicate genes controlling
sleep and can be supportive of therapeutic potential for other conditions, such
as depression or schizophrenia, in which normal sleep patterns are disrupted.