As we discuss below, inhibition of specific phosphodiesterases may thus represent a new strategy for developing novel agents for the treatment of depression. One way in which CREB can mediate antidepressant induccd neural plasticity is by regulating target genes that, are essential for maintaining synaptic function and cell survival, most notably BDNF.7-10,135 Several studies have shown that chronic administration of different types of antidepressant, increases the expression of BDNF in limbic brain areas, particularly the hippocampus, and blocks the
Inhibitors,research,lifescience,medical stress-induced downregulation of BDNF in the hippocampus.7-10,135 The possibility that increased expression of BDNF may contribute to the therapeutic effects of antidepressants is supported by the rodent, behavioral studies in which direct, infusion of BDNF into the rat. midbrain showed efficacy in the learned-helplessness Inhibitors,research,lifescience,medical and forced-swim “depression behavioral models.”7-10,135 Although the human
postmortem studies are quite limited and subject, to numerous methodological confounds, they have revealed increased BDNF levels in hippocampal regions in subjects treated with antidepressant medications at the time of death, compared with Inhibitors,research,lifescience,medical unmedicated subjects.139 As discussed above, BDNF is known to play a major role in regulating structural plasticity. Do antidepressants, via effects on this major Belnacasan molecular weight growth factor, actually bring about
structural changes in the brain? Because the dendrite is the dynamic compartment of neuronal cell body processes that, forms synapses with other neurons, these changes Inhibitors,research,lifescience,medical in its spine density could dramatically alter neurotransmission, synaptic function, and ultimately, neural plasticity.7-10,135 In this context, an important, studv demonstrated that chronic administration of tianeptine (an Inhibitors,research,lifescience,medical antidepressant that, facilitates serotonin reuptake) blocked stress-induced dendritic remodeling of hippocampal CA3 pyramidal neurons.139 However, precluding the generalizability to all antidepressants is the observation that chronic fluoxetine and fluvoxamine treatment (more traditional antidepressants that inhibit serotonin reuptake) had no influence on dendritic remodeling.140 More recently, the influence of chronic no antidepressant treatment, on neurogenesis of hippocampal neurons has been examined.7,135 Chronic, but not. acute, antidepressant treatment was found to increase the number of new cells in the dentate gyrus granule cell layer. Furthermore, these effects were observed with different classes of antidepressants, but, not with several other psychotropic medications investigated.7,135 A very recent, detailed study investigated the effects of tianeptine in the chronic psychosocial stress model of depression in adult, male tree shrews.