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Moreover, emerging evidence suggests that BDNF playsdifferent and perhaps opposing roles in the brain stresssystemincludingthehippocampusandhypothalamus–pituitary–adrenocortical axis, and the brain reward systemincluding the nucleus accumbens and the ventral tegmentalarea (Bertonet al, 2006; Eischet al, 2003). It is clear thatspecific circuits and brain regions are undoubtedly involvedin the pathophysiology of mood disorders; defining theeffects of altering-specific signaling pathways, in specificbrain regions of rodents, will allow for translational studiesof similar brain regions/functions in humans (ie studies ofhuman endophenotypes).Bcl-2 is a Therapeutic Target for the Actions ofLithium and VPAOne of the major downstream targets of the ERK MAPKcascades is arguably one of the most important neuropro-tective proteins, bcl-2. Bcl-2 is expressed in the rodent andmammalian nervous system and is localized to the outermitochondrialmembrane,endoplasmicreticulum,andnuclear membrane. It is now clear that bcl-2 is a proteinthat inhibits both apoptotic and necrotic cell death inducedby diverse stimuli (Adams and Cory, 1998; Bruckheimeret al, 1998; Merry and Korsmeyer, 1997, and referencestherein). Several cellular mechanisms are likely involved inmediating bcl-2’s protective effects, including sequesteringthe proforms of caspases, inhibiting the effects of caspaseactivation,antioxidanteffects,enhancingmitochondrialcalciumuptake,andattenuatingthereleaseofcalciumand cytochromecfrom mitochondria (reviewed in Adamsand Cory, 1998; Bruckheimeret al, 1998; Li and Yuan, 1999;Sadoul, 1998). The role for bcl-2 in protecting neurons fromcell death is now supported by abundant evidence; bcl-2 hasbeen shown to protect neurons from a variety of insultsinvitroincluding growth factor deprivation, glucocorticoids,ionizing radiation, and oxidant stressors such as hydrogenperoxide,tert-butylhydroperoxide, reactive oxygen species,andbuthioninesulfoxamine(AdamsandCory,1998;Bruckheimeret al, 1998). In addition to these potentinvitroeffects, bcl-2 also prevents cell death in numerousstudiesin vivo.In the absence of pharmacological means of increasingCNS bcl-2 expression (until recently), all the studies havehitherto utilized transgenic mouse models or viral vector-mediated delivery of the bcl-2 gene into the CNS. In thesemodels, bcl-2 overexpression has been shown to preventmotor neuron death induced by facial nerve axotomy andsciatic nerve axotomy, to save retinal ganglion cells fromaxotomy-induced death, to protect cells from the deleter-ious effects of MPTP or focal ischemia, and to protectphotoreceptor cells from two forms of inherited retinaldegeneration; interestingly, neurons that survive ischemiclesions or traumatic brain injuryin vivoshow upregulationof bcl-2 (Bonfantiet al, 1996; Chenet al, 1997; Lawrenceet al, 1996; Merry and Korsmeyer, 1997; Raghupathiet al,1998; Sadoul, 1998; Yanget al, 1998, and references therein).