Blockade of CRF1 or V1b receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression

Abstract

Repeated exposure to stress is known to induce structural remodelling and reduction of neurogenesis in the dentate gyrus. Corticotrophin-releasing factor (CRF) and vasopressin (AVP) are key regulators of the stress response via activation of CRF 1 and V 1b receptors, respectively. The blockade of these receptors has been proposed as an innovative approach for the treatment of affective disorders. The present study aimed at determining whether the CRF 1 receptor antagonist SSR125543A, the V 1b receptor antagonist SSR149415, and the clinically effective antidepressant fluoxetine may influence newborn cell proliferation and differentiation in the dentate gyrus of mice subjected to the chronic mild stress (CMS) procedure, a model of depression with predictive validity. Repeated administration of SSR125543A (30 mg/kg i.p.), SSR149415 (30 mg/kg i.p.), and fluoxetine (10 mg/kg i.p.) for 28 days, starting 3 weeks after the beginning of the stress procedure, significantly reversed the reduction of cell proliferation produced by CMS, an effect which was paralleled by a marked improvement of the physical state of the coat of stressed mice. Moreover, mice subjected to stress exhibited a 53% reduction of granule cell neurogenesis 30 days after the end of the 7-week stress period, an effect which was prevented by all drug treatments. Collectively, these results point to an important role of CRF and AVP in the regulation of dentate neurogenesis, and suggest that CRF 1 and V 1b receptor antagonists may affect plasticity changes in the hippocampal formation, as do clinically effective antidepressants. Keywords: depression; hippocampus; vasopressin; corticotrophin Despite extensive investigation, the mechanisms by which antidepressants exert their therapeutic effects are far from being fully understood. The dentate gyrus of the hippocampal formation is a brain region, which has focused much attention with respect to the effects of stress and the action of antidepressants. It is one of the few brain regions where adult neurogenesis has been documented in different species, including humans.1 Neurogenesis is defined by the proliferation of progenitor cells, giving rise to cells that migrate into the granule cell layers, and ultimately differentiate into neurons.2,3 Among the regulatory factors of neurogenesis, stressful events have been identified as potent inhibitors of dentate cell proliferation. [4][5][6][7][8] Chronic antidepressant treatment was reported to increase the rate of neurogenesis in adult brain. 9,10 Together, these findings led to the proposal that suppression of hippocampal neurogenesis in response to stress could be part of the structural remodelling occurring under pathological conditions and, accordingly, that restoration of this form of neural plasticity could be involved in the therapeutic effects of antidepressant treatment. [11][12][13] The precise mechanisms by which stress exerts these deleterious effects on hippocampal neurogenesis are unclear. However, this reduction appears to be mediated partly via st...

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

“…An exciting area of research has been the use of CRH receptor antagonists as antidepressants. Administration of CRH-R1 antagonist reduces chronic stress [108] and induces neurogenesis [93] in a manner similar to that of the antidepressant fluoxetine suggesting that CRH-R1 antagonists have the potential to become a novel class of antidepressants.…”

“…SSRIs or NRIs increase serotonin and/or NE levels, allowing these neurotransmitters to stimulate the cAMP cascade or the Ca 2+ cascade, leading to an increase in CREB and BDNF [92]. Studies indicate that the CRH receptor antagonist reverses the decrease in neurogenesis observed in stressed mice [93]. This suggests the involvement of multiple receptor systems and signal transduction cascades in neurogenesis.…”

“…In rats that were given the antidepressants venlafaxine or fluoxetine, 33 proteins were modulated by drug treatment including proteins involved in neurogenesis, outgrowth, maintenance of neuronal process, and neural regeneration/axonal guidance systems [101]. Very little information is available about signal transduction cascades involved in adult neurogenesis, although some studies have implicated the cAMP-CREB cascade in this process [93]. It is quite likely that additional signaling pathways and cellular networks are involved and they need to be explored further.…”

Disruption of the Prepulse Inhibition of the Startle Reflex in Vasopressin V1b Receptor Knockout Mice: Reversal by Antipsychotic Drugs

“…V1bR KO mice have also been reported to exhibit markedly reduced aggressive behavior (Wersinger et al, 2002). Moreover, it has been reported that a selective V1bR antagonist produced anxiolytic-and antidepressantlike effects in rodents Serradeil-Le Gal et al, 2002) and reversed stress-induced suppression of neurogenesis in a mouse model of depression (Alonso et al, 2004). V1bR is widely distributed in the central nervous system including the cerebral cortex, hippocampus, and hypothalamus (Lolait et al, 1995;Vaccari et al, 1998), suggesting that V1bR regulates the HPA system and plays a potential role in stress-related behavior.…”

Hippocampal Cytogenesis Correlates to Escitalopram-Mediated Recovery in a Chronic Mild Stress Rat Model of Depression

“…Furthermore, studies have demonstrated that chronic treatment with antidepressants reverses stress-induced inhibition of neurogenesis in the hippocampal formation (van der Hart et al, 2002;Malberg and Duman, 2003;Alonso et al, 2004;Fuchs et al, 2004;Czeh et al, 2001).…”