A Neurogenic Theory of Depression Gains Momentum

Thomas, Rosanne M.; Peterson, Daniel A.

doi:10.1124/mi.3.8.441

Cited by 17 publications

(13 citation statements)

References 27 publications

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“…Moreover, chronic alcohol reduces hippocampal neurogenesis (Nixon and Crews, 2002) but the behavioral effects of antidepressant medications may require hippocampal neurogenesis (Santarelli et al, 2003). These and other findings have led to emerging theories that implicate a CREB-BDNF-neurogenesis pathway in both the etiology of depression and antidepressant efficacy Malberg et al, 2000;Thomas and Peterson, 2003). Overall, CREB and BDNF activity in the dentate gyrus appear to be important mediators of antidepressant efficacy and raise the hypothesis that decreases in p-CREB, such as those that occur after chronic alcohol, have the potential to induce behavioral despair and reductions in neurogenesis as seen in the present study.…”

Section: Discussionmentioning

confidence: 99%

Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice

Stevenson

Schroeder

Nixon

et al. 2008

Neuropsychopharmacol

132

102

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Alcoholism and depression show high degrees of comorbidity. Clinical evidence also indicates that depression that emerges during abstinence from chronic alcohol use has a greater negative impact on relapse than pre-existing depression. Although no single neurobiological mechanism can account for the behavioral pathologies associated with these devastating disorders, converging evidence suggests that aspects of both alcoholism and depression are linked to reductions in hippocampal neurogenesis. Here, we report results from a novel preclinical behavioral model showing that abstinence from voluntary alcohol drinking leads to the emergence of depressionlike behavior and reductions in neurogenesis. C57BL/6J mice were allowed to self-administer ethanol (10% v/v) vs H 2 O in the home cage for 28 days. Alcohol was then removed for 1 or 14 days, and mice were tested in the forced swim test to measure depression-like behavior. After 14 days, but not 1 day of abstinence from alcohol drinking, mice showed a significant increase in depression-like behavior. The significant increase in depression-like behavior during abstinence was associated with a reduction in proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) immunoreactivity in the dentate gyrus of the hippocampus indicating that both the number of proliferating neural progenitor cells (NPC) and immature neurons were reduced, respectively. The number of NPCs that were labeled with bromo-deoxyuridine (BrdU) at the beginning of alcohol exposure was not altered indicating that survival of NPCs is not linked to abstinence-induced depression. Chronic treatment (14 days) with the antidepressant desipramine during abstinence prevented both the emergence of depression-like behavior and the reduction in hippocampal neurogenesis indicating that abstinence-induced depression is associated with structural plasticity in the hippocampus. Overall, the results of this study support the conclusion that profound functional (ie behavioral) and structural changes occur during abstinence from alcohol use and suggest that antidepressant treatment may alleviate some of these pathological neurobehavioral adaptations.

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Section: Discussionmentioning

confidence: 99%

Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice

Stevenson

Schroeder

Nixon

et al. 2008

Neuropsychopharmacol

132

102

View full text Add to dashboard Cite

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“…The rationale for this view is that stress diminishes neurogenesis, and clinical depression is often associated with stress (Jacobs et al, 2000a,b). It has even been concluded that neurogenesis is a "requirement" for certain antidepressant behavioral effects (Santarelli et al, 2003), but it is still unknown whether diminished neurogenesis could be a cause, a consequence, or a correlate of depression (Gage, 2000;Thomas and Peterson, 2003). It is an important finding that an acute episode of psychosocial stress did not alter proliferation or immediate survival, as evidenced by IdU/CldU administration in experiment 1, but it did alter short-and long-term survival as shown in experiments 2 and 3.…”

Section: Discussionmentioning

confidence: 99%

Acute Psychosocial Stress Reduces Cell Survival in Adult Hippocampal Neurogenesis without Altering Proliferation

Thomas¹,

Hotsenpiller²,

Peterson³

2007

J. Neurosci.

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213

143

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Factors modulating neurogenesis may contribute to the pathophysiology of affective disorders such as major depression. Environmental stressors in animal models have been proposed to alter neurogenesis, suggesting a mechanism for this contribution. The effect of an acute psychosocial stressor on either proliferation or survival (immediate, short term, and long term) was examined along with subsequent neuronal differentiation in the hippocampus of adult male Sprague Dawley rats. Subjects were exposed to a widely used social dominance paradigm that elicits behavioral and physiological responses to an acute psychosocial stressor. This social dominance paradigm may mimic human relational stress more realistically than laboratory stressors and provides a socially relevant model. We found that exposure to an acute psychosocial stressor at the time of cell generation resulted in a decreased number of newly generated cells in the hippocampus. By using sequential thymidine analog administration to provide temporal discrimination of DNA replication, we showed that short-term survival but not initial proliferation or immediate survival was altered in response to stress. Furthermore, we determined that stress experienced subsequent to proliferation also diminished long-term survival of cells. Thus, an acute episode of a social stress produces long-lasting effects on the incorporation of new hippocampal neurons by reducing their survival.

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“…Recent reports indicate an association between depression and hippocampal atrophy which may partially result from excessive programmed cell death (Lee et al, 2002 ;Thomas and Peterson, 2003). Both TNF-a and IL-1b were found to be potent proapoptotic factors of the nervous cells (Downen et al, 1999 ;Ma et al, 2002Ma et al, -2003.…”

Section: Discussionmentioning

confidence: 96%

Amitriptyline and nortriptyline inhibit interleukin-1 release by rat mixed glial and microglial cell cultures

Obuchowicz¹,

Kowalski

Łabuzek³

et al. 2005

Int. J. Neuropsychopharm.

100

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Pro-inflammatory cytokines, such as interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha have been suggested to be involved in the pathophysiology of depression and in the mechanism of action of antidepressant drugs. Until now the effect of antidepressants on cytokines has been examined only in plasma, blood mononuclear cells and spleen, which reflect the activity of peripheral cytokine network. The aim of this study was to evaluate the effect of amitriptyline and its metabolite nortriptyline on the release of IL-1beta and TNF-alpha by lipopolysaccharide (LPS)-activated rat mixed glial and microglial cell cultures. LPS stimulated the release of both cytokines. The exposure of mixed glial culture to amitriptyline and nortriptyline led to a decrease in both IL-1beta and TNF-alpha release. Moreover, amitriptyline reduced LPS-stimulated IL-1beta release by microglial cultures. Although amitriptyline reduced secretion of both cytokines, the drug did not affect IL-1beta and TNF-alpha mRNAs in mixed cell cultures. Our study has shown for the first time that amitriptyline and nortriptyline administered at concentrations which may be achieved in plasma and brain structures during treatment, inhibit the secretion of IL-1beta and TNF-alpha in rat mixed glial and microglial cell cultures. The obtained results support the previous observations that antidepressants are able to reduce peripheral release of pro-inflammatory cytokines and suggest that the cytokine network may be involved in the central mechanism of action of amitriptyline and nortriptyline.

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A Neurogenic Theory of Depression Gains Momentum

Cited by 17 publications

References 27 publications

Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice

Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice

Acute Psychosocial Stress Reduces Cell Survival in Adult Hippocampal Neurogenesis without Altering Proliferation

Amitriptyline and nortriptyline inhibit interleukin-1 release by rat mixed glial and microglial cell cultures

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