Antidepressants Restore Hypothalamic-Pituitary-Adrenal Feedback Function in Aged, Cognitively-Impaired Rats

Rowe, Wayne B.; Steverman, Allen; Walker, Mathieu; Sharma, Shakti; Barden, Nicholas; Meaney, Michael J.

doi:10.1016/s0197-4580(97)00103-6

Cited by 26 publications

(20 citation statements)

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“…Many but not all studies show increased levels of glucocorticoids in aging rats and humans (89,125,132,144,149). The reasons for these differences are likely to relate to individual differences in brain aging and in the differences in the distribution of aging, impaired individuals in populations of animals and human subjects (89).…”

Section: The Hippocampus and Hpa Regulationmentioning

confidence: 99%

“…It is this last aspect of HPA regulation that is the most intriguing, namely, that the role of the hippocampus may be as an adrenal steroidprimed modulator of neural activity that is involved in regulating hypothalamic output of CRF and vasopressin. In other words, ''shutoff'' of the HPA stress response may be due to steroid-modulated neural input, e.g., increasing inhibitory input to the PVN (53), rather than due exclusively to rapid and delayed steroid feedback at the level of the PVN neuron or pituitary corticotroph.Many but not all studies show increased levels of glucocorticoids in aging rats and humans (89,125,132,144,149). The reasons for these differences are likely to relate to individual differences in brain aging and in the differences in the distribution of aging, impaired individuals in populations of animals and human subjects (89).…”

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Stress and the Aging Hippocampus

McEwen

1999

Frontiers in Neuroendocrinology

208

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The ''glucocorticoid cascade hypothesis'' of hippocampal aging has stimulated a great deal of research into the neuroendocrine aspects of aging and the role of glucocorticoids, in particular. Besides strengthening the methods for investigating the aging brain, this research has revealed that the interactions between glucocorticoids and hippocampal neurons are far more complicated than originally envisioned and involve the participation of neurotransmitter systems, particularly the excitatory amino acids, as well as calcium ions and neurotrophins. New information has provided insights into the role of early experience in determining individual differences in brain and body aging by setting the reactivity of the hypothalamopituitary-adrenal axis and the autonomic nervous system. As a result of this research and advances in neuroscience and the study of aging, we now have a far more sophisticated view of the interactions among genes, early development, and environmental influences, as well as a greater appreciation of events at the cellular and molecular levels which protect neurons, and a greater appreciation of pathways of neuronal damage and destruction. While documenting the ultimate vulnerability of the brain to stressful challenges and to the aging process, the net result of this research has highlighted the resilience of the brain and offered new hope for treatment strategies for promoting the health of the aging brain. KEY WORDS: stress; hippocampal aging; glucocorticoid cascade hypothesis. 1999 Academic Press INTRODUCTIONThe hippocampus is a particularly vulnerable and sensitive region of the brain that is also very important for declarative and spatial learning and memory (36). Hippocampal neurons are vulnerable to seizures, strokes, and head trauma, as well as responding to stressful experiences (27,92,130). At the same time they show remarkable plasticity, involving long-term synaptic potentiation and depression, dendritic remodeling, synaptic turnover, and neurogenesis in the case of the dentate gyrus (Fig 1) (17,27,92).The work of aus der Muhlen and Ockenfels (3) first drew attention to potentially toxic actions of adrenal steroids. The reported darkly stained neurons in the hippocampus of guinea pigs exposed to high levels of glucocorticoids, an observation that has been confirmed and extended to repeated stress in subsequent studies (41,100), although there are still some doubts as to whether ''dark neurons'' may be artifacts of tissue trauma (18). In 1968, we discovered receptors for adrenal steroids in hippocampus (95), and it is now known that two types of adrenal steroid receptors exist in the hippocampus and other brain regions and mediate a variety of adrenal steroid effects on excitability, neurochemistry, and structure (27). Landfield (68) and then Sapolsky (127,128) provided evidence for a role of adrenal steroids in neuronal aging in the hippocampus, leading to the formulation of the ''glucocorticoid cascade hypothesis '' (130). This hypothesis states that glucocorticoids participate in a ...

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Section: The Hippocampus and Hpa Regulationmentioning

confidence: 99%

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confidence: 99%

Stress and the Aging Hippocampus

McEwen

1999

Frontiers in Neuroendocrinology

208

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“…Furthermore, depressed patients show incomplete suppression of cortisol by dexamethasone, which indicates impaired negative feedback function most likely due to impaired corticosteroid receptor signaling [26,27], a deficit that may be induced by the proinflammatory cytokine IL-1 [28]. Treatment with antidepressants appears to restore negative feedback deficits by increasing corticoid receptor sensitivity [29]. Hypothalamo-pituitary-adrenocortical axis activation could thus play a role in mediating the depressive response following increased immune activation.…”

Section: Introductionmentioning

confidence: 99%

Interferon-α-induced depressive symptoms are related to changes in the cytokine network but not to cortisol

Wichers

Kenis

Koek

et al. 2007

Journal of Psychosomatic Research

109

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“…Animal studies have shown that antidepressants may restore HPA axis feedback deficiency (Rowe et al 1997). Subsequently, it has been hypothesized that antidepressant treatment might exert its action through direct effects on the HPA axis, particularly by enhancing cellular corticosteroid receptors, leading to a normalization of defective glucocorticoid feedback inhibition (Barden et al 1995;Pepin et al 1989).…”

Section: Introductionmentioning

confidence: 99%

Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response

et al. 2005

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Rationale: A dysregulation of the hypothalamicpituitary-adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity. Objective: The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV). Methods: Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/S-CIT treatment. Results: The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p<0.0001) of the degree of symptom improvement following 16 weeks on drug (i.e., decrease in HAM-D 21 total score). The model demonstrated that the interaction of CSF S-CIT concentrations and clinical improvement was the most powerful predictor of AUC cortisol responsiveness. Conclusion: The present study shows that decreased AUC cortisol was highly associated with S-CIT concentrations in plasma and CSF. Therefore, our data suggest that the CSF or plasma S-CIT concentrations rather than the R/S-CIT dose should be considered as an indicator of the selective serotonergic reuptake inhibitors (SSRIs) effect on HPA axis responsiveness as measured by AUC cortisol response.

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Antidepressants Restore Hypothalamic-Pituitary-Adrenal Feedback Function in Aged, Cognitively-Impaired Rats

Cited by 26 publications

References 50 publications

Stress and the Aging Hippocampus

Stress and the Aging Hippocampus

Interferon-α-induced depressive symptoms are related to changes in the cytokine network but not to cortisol

Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response

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