Research ReportQuetiapine reverses the suppression of hippocampal neurogenesis caused by repeated restraint stress
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.
References (53)
- et al.
Antipsychotic drugs clozapine and olanzapine upregulate bcl-2 mRNA and protein in rat frontal cortex and hippocampus
Brain Res.
(2004) - et al.
Anterior hippocampal volume reductions predict frontal lobe dysfunction in first episode schizophrenia
Schizophr. Res.
(1995) - et al.
Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus
Neuroscience
(1994) - et al.
CREB: a major mediator of neuronal neurotrophin responses
Neuron
(1997) - et al.
Neurogenesis in adulthood: a possible role in learning
Trends Cogn. Sci.
(1999) - et al.
Neuroprotective effects of olanzapine on methamphetamine-induced neurotoxicity are associated with an inhibition of hyperthermia and prevention of Bcl-2 decrease in rats
Brain Res.
(2004) - et al.
Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus
Neuron
(1996) - et al.
Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat
Biol. Psychiatry
(2004) - et al.
Magnetic resonance imaging of brain in people at high risk of developing schizophrenia
Lancet
(1999) - et al.
Post-stress changes in BDNF and Bcl-2 immunoreactivities in hippocampal neurons: effect of chronic administration of olanzapine
Brain Res.
(2004)
Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate
Brain Res.
Regional specificity of hippocampal volume reductions in first-episode schizophrenia
NeuroImage
The adult rat hippocampus contains primordial neural stem cells
Mol. Cell. Neurosci.
7-Nitroindazole upregulates phosphorylated cAMP response element binding protein, polysialylated-neural cell adhesion molecule and tryptophan hydroxylase expression in the adult rat hippocampus
Brain Res.
Body weight gain and diurnal differences of corticosterone changes in response to acute and chronic stress in rats
Psychoneuroendocrinology
Cognitive performance in schizophrenia: relationship to regional brain volumes and psychiatric symptoms
Psychiatry Res.
Thalamic and amygdala–hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis
Biol. Psychiatry
Memory traces of trace memories: neurogenesis, synaptogenesis and awareness
Trends Neurosci.
The relationship between volumetric brain changes and cognitive function: a family study on schizophrenia
Biol. Psychiatry
Schizophrenia: from phenomenology to neurobiology
Neurosci. Biobehav. Rev.
Quetiapine attenuates the immobilization stress-induced decrease of brain-derived neurotrophic factor expression in rat hippocampus
Neurosci. Lett.
The effect of chronic restraint stress on spatial learning and memory: relation to oxidant stress
Int. J. Neurosci.
Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression
Mol. Psychiatry
Volumes of brain structures in twins discordant for schizophrenia
Arch. Gen. Psychiatry
Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs
J. Neurosci. Res.
Toward a molecular definition of long-term memory storage
Proc. Natl. Acad. Sci. U. S. A.
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2019, Psychiatry ResearchCitation Excerpt :On the other hand, in the ventral area, hippocampal cell proliferation and immature neurons were negatively affected by psychosocial stress, but little effect has been observed under QTP treatment. Previous studies indicated that chronic administration with QTP blocked the suppression of cell proliferation, differentiation, and survival of the hippocampus induced by repeated restraint stress (Luo et al., 2005; Xu et al., 2006). Although the present results are not consistent with these previous data, this inconsistency may be attributed to the separate analysis of dorsal and ventral hippocampal subregion.
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These authors contributed equally to this work and are listed alphabetically.