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models with the benefit that they can be given over longer periods
of time compared with EPO. Carbamylated EPO (Cepo) is an
EPO-derivative that lacks hematopoietic activity and has been
demonstrated to be neuroprotective (
6
).
The trophic hypothesis of depression states that deficits in
trophic support and signaling could contribute to neuronal atro-
phy, dysfunction, and behavioral depression, while antidepres-
sants are able to elevate trophic signaling and alleviate these
abnormalities (
8
). The trophic actions of EPO in brain suggested
it might have antidepressant properties and this has been sup-
ported by initial studies in rodents (
9
). EPO is induced in brain
by an antidepressant treatment and EPO can produce antide-
pressant-like behavioral responses in mouse and rat models (
9
).
These results are consistent with human studies showing that
EPO improves mood (
10
).
Major depressive disorders are a heterogeneous group of ill-
nesses that vary in symptomology and likely in etiology. Because
the pathophysiological basis for depression is not known, re-creating
the disease in animal models is not possible. In this chapter we
present three rodent behavioral models that are relevant to
depression research in different ways and that are each amenable
to testing with EPO or related compounds.
The forced-swim test (FST) has been widely used as screening
test for antidepressant activity due to its ease of use, high through-
put and relatively good predictive validity. The FST does not
reproduce the pathophysiology of depression but induces changes
that are sensitive to therapeutic agents in a manner predictive of
their effects in humans (
11-13
). Stress exposure is an important
component of many depression models and this test includes
acute or sub-chronic stress. In the FST, a rat or mouse is placed
in a cylinder with enough water so that it cannot touch the bot-
tom with its hindpaws. A normal animal will show an immediate
burst of activity, try to escape, and then eventually adopt an
“immobile” posture, where it will make only those movements
necessary to keep its head above water. The development of
immobility may be facilitated by prior exposure to the test (
13
).
Immobility is quantified during the test and classical antidepres-
sants such as the monoamine oxidase inhibitors, tricyclics, and
atypical antidepressants all decrease the duration of immobility in
rats and mice in a dose-dependent manner (
11, 12, 14
).
Neurotrophic factors have also been demonstrated to decrease
immobility in the FST similarly to antidepressants (
15, 16
). In
rats it is possible to separately quantify the predominant active
behavior as either swimming or climbing which are associated
with predominantly serotonergic and noradrenergic mechanisms,
respectively, allowing the FST to detect this distinction (
17, 18
).
1.2 Models
of Depression
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