INDUCTION OF DEPRESSION BY EXPOSURE TO DAMP ...

egions (Uzbay, 2008; Kasper and McEwen, 2008; Boldrini et al., 2009). Supporting the
link between antidepressant effects and neurogenesis, an experiment demonstrated that
the effects of antidepressants were nullified when neurogenesis was blocked by
irradiation of hippocampi in mouse model (Santarelli et al., 2003).
Several mechanisms inducing neural atrophy have been elucidated. A well-
supported pathway leading to neural atrophy is a phenomenon termed excitotoxicity.
This phenomenon occurs when neurons receive excessive stimulation, resulting in
neuronal damage and cell death. As reviewed by Forder and Tymianski, excitotoxicity
studies have primarily focused on activation of voltage-gated calcium channels and
glutamate-sensitive channels, such as N-methyl-d-aspartate (NMDA) receptors on
neurons (Forder and Tymianski, 2009). Binding of the NMDA receptor opens its channel
to the influx of calcium ions. The calcium ions bind and activate the intracellular protein
calmodulin. In neurons, calmodulin then activates neuronal nitric oxide synthase
(nNOS). While the free radical nitric oxide (NO) acts as a neurotransmitter, high levels
are toxic to cells. In addition, the influx of calcium results in the production of oxygen
free radicals, such as superoxide. NO reacts with superoxide to create peroxynitrite
(ONOO-). Peroxynitrite is a very toxic chemical that oxidizes lipids, proteins, and DNA.
Peroxynitrite also interferes with important phosphorylation events. Beyond NMDA
receptors, other receptors may also be involved with producing reactive oxygen species
and the resulting toxicity (Forder and Tymianski, 2009).
Several lines of evidence support the NO toxicity hypothesis. One line of
evidence is that several NMDA receptor antagonists have anti-depressant activities and
lessen hippocampal dendrite atrophy in animal screenings and human studies (Oliveira et
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