Elsevier

Brain Research

Volume 1063, Issue 1, 23 November 2005, Pages 32-39
Brain Research

Research Report
Quetiapine reverses the suppression of hippocampal neurogenesis caused by repeated restraint stress

https://doi.org/10.1016/j.brainres.2005.09.043Get rights and content

Abstract

Quetiapine is an atypical antipsychotic effective in treating the positive, negative, and cognitive symptoms of patients with schizophrenia. Our previous study has shown that chronic administration of quetiapine attenuates the decrease in levels of brain-derived neurotrophic factor (BDNF) in the hippocampi of rats subjected to chronic-restraint stress. In the present study, we investigated the effects of quetiapine on hippocampal neurogenesis that had been compromised in stressed rats. Newborn cells in the hippocampus were labeled by bromodeoxyuridine (BrdU), and immature neurons were detected immunohistochemically using an antibody against phosphorylated cAMP response element-binding protein (pCREB). The restrained rats (4 h/day for 7 days) showed lower levels of hippocampal neurogenesis indicated by decreased numbers of BrdU-labeled and pCREB-positive cells. Post-stress administration of quetiapine (10 mg/kg) for 7 or 21 days reversed the stress-induced suppression of hippocampal neurogenesis, evidenced in the numbers of BrdU-labeled and pCREB-positive cells that are comparable to those in non-stressed rats but higher than those in the vehicle-treated rats. The results may help us understand the therapeutic effects of quetiapine on cognitive deficits in patients with schizophrenia and depression, in which the structure and functions of the hippocampus are implicated.

Introduction

Antipsychotic drugs are divided into two groups, typical and atypical. Typical antipsychotics, for example, haloperidol, ameliorate only the positive symptoms, whereas atypical antipsychotics, represented by clozapine, are effective in treating the positive, negative, and cognitive symptoms [22]. Both typical and atypical antipsychotics can bind to dopamine receptors, and the blockade of D2 receptors in the mesolimbic region is thought to be the mechanism responsible for the reversal of positive symptoms by antipsychotics [49]. The mechanisms underlying the therapeutic effects of atypical antipsychotics on negative and cognitive symptoms of schizophrenia, however, remain to be elucidated.

The hippocampus, a brain region playing pivotal roles in learning and memory, has been the subject of numerous studies addressing the pathophysiology of schizophrenia. For instance, the majority of in vivo imaging studies show hippocampal volume reductions in patients with schizophrenia as compared to healthy volunteers [29], [30], [50]. Furthermore, volume reductions have been reported in first-episode patients [8], [39], [46] and in some healthy biological relatives of schizophrenia probands [3], [24], [36]. Furthermore, hippocampal size has been associated with the neurocognition in schizophrenia [8], [35], [42]. These observations suggest that hippocampus is one of the targets implicated in schizophrenia.

An assumption raised from these clinical studies is that atypical antipsychotics may be beneficial to the affected hippocampus of patients with schizophrenia, thus improving their cognitive deficits. In line with this hypothesis, previous animal studies have shown that chronic administration of olanzapine, an atypical antipsychotic, up-regulates the expression of brain-derived neurotrophic factor (BDNF) and bcl-2 mRNA in rat hippocampus [4], [5]. Moreover, chronic olanzapine increased cell proliferation in hippocampus [23] and accelerated the recovery of reduced levels of BDNF and Bcl-2 following chronic-restraint stress [25]. Similarly, quetiapine, another atypical antipsychotic, attenuated the decrease in hippocampal levels of BDNF caused by chronic-restraint stress [51] and increased BDNF mRNA levels in the rat hippocampus [15]. In the present study, we wanted to find out if quetiapine has beneficial effects on the recovery of the hippocampus of the rat exposed to repeated restraint stress, which suppresses hippocampal cell proliferation [33], [52]. We measured the number of newborn cells taking up bromodeoxyuridine (BrdU) in hippocampal dentate gyri of normal controls and stressed rats and monitored the post-stress time course of this number at the 7th and 21st day following the last session of restraint stress. During these periods, the rats administered quetiapine solution or the same volume of vehicle. In addition, we observed the concurrent changes in the number of cells expressing phosphorylated cAMP response element-binding protein (pCREB) in the hippocampus. pCREB has been shown to be colocalized with polysialylated-neural cell adhesion molecule (PSA-NCAM) in immature neurons of the hippocampus [27] and linked to learning, neuronal survival, and synaptic plasticity [6], [14], [20].

Section snippets

Animal groups and drug administration

All of the procedures involving animals were in accordance with the guidelines established by the Canadian Council on Animal Care and approved by the University of Saskatchewan Animal Care Committee.

A total of 30 adult male Sprague–Dawley rats (Charles River Laboratories, St. Constant, PQ), weighing 200–225 g on arrival, were used in this study. They were group housed and maintained on a 12:12 h light/dark cycle with food and water freely available. After 10 days of acclimatization, the rats

Repeated restraint stress decreased the numbers of BrdU-labeled and pCREB-positive cells in the hippocampus

In accordance with previous descriptions [13], [27], [52], both BrdU- and pCREB-positive cells localize in SGZ. The representative photographs showing the distribution of BrdU-labeled cells in SGZ of rats from the groups NS (image A) and Str (image B) are displayed in the upper panel of Fig. 1. Most of BrdU-labeled cells (as indicated by arrows) appear in pairs or clusters. Under a higher magnification (400×), the individual cells in the clusters were clearly visualized (image C taken from a

Discussion

Consistent with previous studies [2], [11], [33], [52], in the present study, repeated restraint stress decreased hippocampal cell proliferation, as indicated by the reduced number of BrdU-labeled cells in the group Str relative to the group NS (Fig. 1). It has been demonstrated that both acute and chronic-restraint stress increase the levels of corticosterone in rats [1], [34], [44], which diminishes the proliferation of granule cell precursors [9]. In addition to corticosterone, stress

Acknowledgments

This work was supported by Saskatchewan Health Research Foundation, CIHR, Canadian Psychiatric Research Foundation, Royal University Hospital Foundation, and Schizophrenia Society of Saskatchewan. The authors are grateful to Gabriel Stegeman for her excellent technical assistance. We thank Drs. Sergey Fedoroff and Augusto V. Juorio for their helpful comments during the preparation of the manuscript.

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