This is consistent with another report demonstrating that decreased neurogenesis is not correlated with behavior in the learned helplessness model of depression.50 INK1197 Together these studies indicate that neurogenesis is not required for baseline response. However, it is possible that intact neurons are sufficient to sustain baseline response and that more long-term inhibition of neurogenesis would be required to influence activity. The cAMP-CREB cascade and depression Neural plasticity upon antidepressant treatment is likely to involve Inhibitors,research,lifescience,medical adaptations of multiple intracellular signaling cascades and even interactions of these pathways. One of the pathways

that is regulated by antidepressant treatment and has been demonstrated to contribute to the actions of chronic antidepressant responses is the cAMP-CREB cascade, the subject of this section. However, it is likely that other signaling

pathways are also regulated Inhibitors,research,lifescience,medical by – and play a role in – the actions of antidepressants. For reviews covering other signal transduction pathways, see reference 51 and 52. Antidepressant treatment upregulates the cAMP CREB cascade Several studies have investigated the influence of antidepressant treatment on the cAM’P-CREB pathway (Figure 3).53,54 Inhibitors,research,lifescience,medical This work demonstrates that chronic antidepressant treatment upregulates the cAMP second-messenger cascade at several different levels. This includes increased coupling of the stimulatory G protein to adenylyl cyclase, increased levels of cAMP-dependent protein kinase (PKA), and increased levels of CREB as well as phospho-CREB.55-57 Upregulation of these components of the cAMP-CREB Inhibitors,research,lifescience,medical signaling pathway is Inhibitors,research,lifescience,medical dependent, on chronic antidepressant treatment, consistent with the time course for the therapeutic action of antidepressants. In addition, upregulation of the cAMP-CREB cascade

is observed in response to chronic administration of different classes of antidepressants, indicating that this is a common target of antidepressant treatment. In addition to phosphorylation by PKA, CREB is also phosphorylated by Ca2+-dependent kinases, already such as Ca2+/calmodulin-dependent protein kinase, and by mitogen-activated protein kinase pathways (Figure 3). In this way, CREB can serve as a target for multiple signal transduction pathways and neurotransmitter receptors that activate these cascades. Activation of the cAMP-CREB cascade produces an antidepressant response Direct, evidence for cAMP-CREB signaling in the action of antidepressant treatment has been tested by pharmacological, viral vector, and mutant mouse approaches. First, drugs that block the breakdown of cAMP produce an antidepressant response in behavioral models of depression.