Antidepressant action: to the nucleus and beyond

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After decades of effort, the field of depression research is far from understanding how antidepressant drugs mediate their clinical effects. The time lag of 2–6 weeks of therapy that is necessary to obtain antidepressant efficacy indicates a requirement for long-term regulation of molecules activated by drug treatment. The focus of antidepressant research has thus expanded from examining acute monoamine-mediated mechanisms to include long-term transcriptional regulators such as cAMP response element-binding protein (CREB) and trophic factors such as brain-derived nerve growth factor and insulin-like growth factor. In addition, the recent discovery of antidepressant-induced neurogenesis provides another avenue by which antidepressants might exert their effects. Current efforts are aimed at understanding how CREB and trophic factor signaling pathways are coupled to neurogenic effects and how alterations in behavioral, molecular and cellular endpoints are related to the alleviation of the symptoms of depression.

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What is the mechanism of action of antidepressant drugs?

Depression is a clinically and biologically heterogeneous disease. It is one of the most prevalent and costly psychiatric disorders worldwide, with 10–30% of women and 7–15% of men likely to suffer from depression in their life-time [1]. Despite the prevalence and societal cost of depression of an estimated US$50 billion [2], currently used antidepressants do not improve symptoms in all patients. This is, at least in part, the consequence of our limited understanding of the mechanisms of

Antidepressant drugs: beyond neurotransmitters to activation of second messenger pathways and transcriptional regulators

The monoamine hypothesis of depression postulates that a functional deficiency of 5-hydroxytryptamine [5-HT (serotonin)] or noradrenaline in the brain is key to the pathology and/or behavioral manifestations associated with depression 5, 6. In support of this theory, the majority of antidepressant drugs used clinically produce acute increases in the levels of 5-HT and noradrenaline. This in turn causes the activation of seven-transmembrane domain receptors that are coupled to heterotrimeric G

Genetic models of CREB activity

Because antidepressant drugs can activate CREB, recent studies have examined whether manipulation of CREB activity and/or levels of CREB can recapitulate some effects of antidepressants. To date, the function of CREB has been investigated using animal models or viral-vector-mediated gene overexpression (Table 1). Given that the majority of studies have reported increased CREB and/or CREB phosphorylation after chronic antidepressant treatment, the hypothesis of many of these studies was that

Brain-derived nerve growth factor

Plasticity in the nervous system is subserved by a variety of neurotrophins and growth factors. One well-characterized neurotrophic factor involved in activity-dependent neuronal plasticity, survival and differentiation of peripheral and central neurons is brain-derived nerve growth factor (BDNF) 29, 30, 31. Several studies suggest that BDNF is a target of antidepressant action. Robust increases in the levels of BDNF mRNA in cortical and hippocampal regions have been reported following chronic

Genetic models of BDNF action

Mice that lack BDNF display severe neuronal deficits and early postnatal death [31]. However, studies examining mice that lack only one allele of the gene encoding BDNF (BDNF+/−) have identified alterations in learning [46] and synaptic plasticity 47, 48. Some lines of BDNF+/− mice display a reduction in BDNF protein levels but without any accompanying changes in baseline behavior in models such as the FST [49]. Other lines of BDNF+/− mice display altered synaptic responses, but a specific

Insulin like growth factor

Recent studies in rats have identified another neurotrophic factor, insulin-like growth factor (IGF-1), in antidepressant action and neurogenesis. Both systemic and central administration of IGF-1 increase cell proliferation in the adult hippocampus, and IGF-1 has been shown to selectively increase maturation of neurons 53, 54. Central administration of IGF-1 produces antidepressant-like effects in the forced swim tests in rats, which indicates that IGF-1 and IGF-1-induced signal transduction

Antidepressant-induced neurogenesis

Reduced hippocampal cell volume has been observed in depressed humans in both magnetic resonance imaging (MRI) and post-mortem studies, compared with normal individuals 59, 60. Furthermore, antidepressant treatment has been shown to reverse or prevent this decrease in hippocampal volume [61]. Multiple classes of antidepressant drugs increase both cell proliferation and neurogenesis in the dentate gyrus of the adult hippocampus (Table 2), and this requires a chronic, and not an acute,

Conclusions and future directions

Although the field of antidepressant pharmacology has progressed rapidly during the past 10 years, there are many unanswered questions about the function and mechanism by which antidepressants exert their therapeutic effects. Recent research has moved beyond neurotransmitters to understanding the role of second messengers and their targets such as phosphorylated CREB and BDNF. Advanced genetic techniques have enabled the development of various rodent models, which permit evaluation of

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