Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus

Abstract

Recent studies suggest that stress-induced atrophy and loss of hippocampal neurons may contribute to the pathophysiology of depression. The aim of this study was to investigate the effect of antidepressants on hippocampal neurogenesis in the adult rat, using the thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. Our studies demonstrate that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the dentate gyrus and hilus of the hippocampus. Administration of several different classes of antidepressant, but not non-antidepressant, agents was found to increase BrdU-labeled cell number, indicating that this is a common and selective action of antidepressants. In addition, upregulation of the number of BrdU-labeled cells is observed after chronic, but not acute, treatment, consistent with the time course for the therapeutic action of antidepressants. Additional studies demonstrated that antidepressant treatment increases the proliferation of hippocampal cells and that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal-or glial-specific markers. These findings raise the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic actions of antidepressant treatment.Key words: proliferation; granule cell; fluoxetine; tranylcypromine; reboxetine; depression Depression is a devastating illness that is estimated to affect 12-17% of the population at some point during the lifetime of an individual (Kessler et al., 1994). Antidepressants are commonly prescribed for depression and other affective disorders, although the molecular and cellular mechanisms by which these agents exert their therapeutic effects are not well understood. Preclinical and clinical research has focused on the interactions between stress and depression and their effects on the hippocampus, among other brain regions (Duman et al., 1999;McEwen, 1999). For example, the hippocampus has been shown to undergo morphological changes in response to stress, including atrophy and loss of CA3 pyramidal neurons after exposure to physical or psychosocial stress (Watanabe et al., 1992c;Stein-Behrens et al., 1994;Margarinos et al., 1996;McEwen, 1999). In addition, brain-imaging studies demonstrate that hippocampal volume is decreased in patients with stress-related psychiatric illnesses, including depression and posttraumatic stress disorder (Sapolsky, 1996;Sheline et al., 1996).The hippocampus is one of only a few brain regions where production of neurons occurs throughout the lifetime of animals, including humans (Eriksson et al., 1998). Hippocampal neurogenesis can be influenced by several environmental factors and stimuli (Kuhn et al., 1996;Kempermann et al., 1997;Gould et al., 1999a;van Praag et al., 1999b). Importantly, it has been shown that stressful experiences, including both ph...

Patterns of gene expression in the limbic system of suicides with and without major depression

“…This supports recent findings indicating an important role of the hippocampus in depression and in the antidepressant response to pharmacotherapy. 52,53 Also, altered size and impaired function of the hippocampus have been found in a number of recent clinical imaging studies of major depression (for a meta-analysis see Campbell 54 ). Furthermore, expression changes in genes implicated in the second messenger systems, such as kinases, phosphatases and the adenylate cyclase 8 gene (ADCY8) were observed in the hippocampus, supporting previous evidence of synaptic plasticity alterations in mood disorders 55,56 and in antidepressant response beyond the neurotransmitter and receptor level.…”

Expression of BDNF and trkB in the hippocampus of a rat genetic model of vulnerability (Roman low‐avoidance) and resistance (Roman high‐avoidance) to stress‐induced depression

“…Under baseline conditions, BDNF and its receptor trkB are densely expressed in the hippocampal formation (Conner et al., 1997; Phillips et al., 1991; Quartu et al., 1999, 2013; Webster, Herman, Kleinman, & Weickert, 2006; Yan, Radeke, et al., 1997; Yan, Rosenfeld, et al., 1997), one of the key regions implicated in depression‐linked maladaptive neuronal plasticity (Dias, Banerjee, Duman, & Vaidya, 2003; Malberg, Eisch, Nestler, & Duman, 2000; Vaidya, Siuciak, Du, & Duman, 1999). Accordingly, the hippocampal volume is reduced in patients with post‐traumatic stress disorder (Angelucci, Brene, & Mathe, 2005), and with depression associated with the BDNF Met polymorphism, which is known to be less active than its normal variant (Autry & Monteggia, 2012).…”

Differential effects of TRPV1 receptor ligands against nicotine-induced depression-like behaviors

“…The effects of such antidepressants have recently been characterized by their ability to cause neurogenesis in the hippocampus [19,20]. Brain cannabinoid (CB) receptors, typically CB1 (CB type 1) receptors, can be considered one of the potent "antidepressant" targets of NC, based on their contribution to neurogenesis in the hippocampus via endogenous ligands [21,22] and the NC-altered levels of endogenous CB1 ligands in the brain including the hippocampus [23].…”