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Regulation of cortical and hippocampal 5-HT1A receptor function by corticosterone in GR+/− mice

https://doi.org/10.1016/j.psyneuen.2009.08.015Get rights and content

Summary

Our objective in the present study was to examine 5-HT1A receptor function in prefrontal cortex and hippocampus of GR+/− mice, which appear to be an appropriate murine model of depression. 5-HT1A receptor function was determined by measuring [35S]GTPγS binding stimulated by the 5-HT1A receptor agonist 8-OH-DPAT (1 μM), an indication of the capacity of the receptor to activate G proteins. 5-HT1A receptor expression was determined by measuring the binding of [3H]8-OH-DPAT (2 nM). We observed no effect of the constitutive reduction in GR on 5-HT1A receptor-stimulated [35S]GTPγS binding or 5-HT1A receptor binding sites. Corticosterone treatment (10 mg/kg, sc once daily for 21 days) of wild-type mice resulted in a decrease in 5-HT1A receptor function in prefrontal cortex [8-OH-DPAT-stimulated [35S]GTPγS binding (% above basal), vehicle-treated: 39 ± 4.9; corticosterone-treated: 17 ± 2.8], but not in hippocampus. The constitutive reduction in GR expression prevented the down-regulation of 5-HT1A receptor function in frontal cortex by chronic corticosterone administration. In contrast, corticosterone treatment of GR+/− mice resulted in an increase in 5-HT1A receptor function in hippocampus which reached statistical significance in CA2/3 region [8-OH-DPAT-stimulated [35S]GTPγS binding (% above basal), vehicle-treated: 41 ± 9.7; corticosterone-treated: 94 ± 23]. These changes seem to be evoked by a combined effect of high corticosterone levels and GR deficiency. Although GR+/− mice do not exhibit changes in baseline corticosterone, the constitutive deficiency in GR appears to have unmasked regulatory effects of elevated corticosterone in the maintenance of 5-HT1A receptor function in prefrontal cortex and hippocampus.

Introduction

Neurotransmitter and hormonal responses associated with acute stress are adaptive in short-term in that they are necessary to promote homeostasis. However, repeated exposure to stress over time may lead to pathophysiological changes due to chronic elevations in glucocorticoid levels. The deleterious effects of prolonged exposure to elevated glucocorticoid levels, which include neurochemical and morphological changes in forebrain structures, are associated with cognitive deficits and affective disorders, specifically major depression (Herman et al., 2003, Sapolsky, 2003, McEwen, 2007).

Hyperactivity of the hypothalamic–pituitary–adrenal (HPA) system and elevated plasma cortisol levels associated with major depressive disorder may be due to diminished glucocorticoid receptor (GR) function or expression, and as a consequence, deficient feedback regulation of cortisol (Holsboer, 2000, Pariante, 2006). GR-heterozygous (GR+/−) mice, with a 50% reduction in GR expression, are indistinguishable from wild-type control mice at baseline, but exhibit increased sensitivity to stress and dysregulation of the HPA axis. GR+/− mice display increased helplessness after stress exposure, a behavioral correlate of depression in mice, and increased stress-induced plasma corticosterone levels (Ridder et al., 2005). GR+/− mice also exhibit abnormal responses in the dexamethasone suppression test and dexamethasone/corticotropin-releasing hormone test (DEX/CRH test), similar to what is observed clinically in severely depressed patients (Ridder et al., 2005). Consistent with the neurotrophin hypothesis of depression, GR+/− mice exhibit a down-regulation of brain-derived neurotrophic factor (BDNF) protein in hippocampus (Ridder et al., 2005).

As GR+/− mice appear to be an appropriate murine model of depression (Ridder et al., 2005), our objective in the present study was to examine serotonin (5-hydroxytryptamine, 5-HT) 5-HT1A receptor function in GR+/− mice. 5-HT1A receptors are present in high density in cortical and limbic areas, where they are post-synaptic to serotonergic neurons. The distribution of 5-HT1A receptors in brain is consistent with a role for this 5-HT receptor in cognitive or integrative functions, as well as in emotional states. We have found that 5-HT1A receptor function in hippocampus, but not in frontal cortical areas, is attenuated in BDNF+/− mice and mice with a forebrain-specific reduction in BDNF (Hensler et al., 2003, Hensler et al., 2007). As hippocampal BDNF protein levels are also diminished in GR+/− mice, we hypothesized that hippocampal 5-HT1A receptor function would be attenuated in GR+/− mice. Moreover, we were interested in examining the effect of chronic corticosterone treatment, a means to mimic chronic stress, on 5-HT1A receptor function and expression. 5-HT1A receptor function was determined by measuring 5-HT1A receptor agonist 8-OH-DPAT-stimulated [35S]GTPγS binding to G proteins, an indication of the capacity of the receptor to activate G proteins. 5-HT1A receptor expression was determined by measuring the binding of the agonist radioligand [3H]8-OH-DPAT to 5-HT1A receptor sites. As cortical and limbic structures play a key role in the integration and association of stressful stimuli with previous experiences, and therefore are brain regions of particular interest when examining the long-term effects of repeated exposure to stress, we focused our attention in the current study on prefrontal cortex and dorsal hippocampus.

Section snippets

Mice

GR-heterozygous mice (GR+/−) were generated as previously described to obtain F1 hybrid mice with the same background as used in behavioral and neurochemical studies (Ridder et al., 2005, Schulte-Herbrüggen et al., 2007, Trajkovska et al., 2009). Male GR+/− mice and wild-type littermate controls were 4–5 months old at the beginning of experiments. Mice were housed individually under a reverse phase 12:12 h light/dark cycle, with ad libitum access to food and water. German animal welfare

Differences in 5-HT1A receptor function: wild-type versus GR+/− mice

[35S]GTPγS binding stimulated by the 5-HT1A receptor agonist 8-OH-DPAT was assessed in the dorsal hippocampus (Fig. 1, panels A–C). In CA1, dentate gyrus and CA2/3 regions we found no significant main effect of genotype (CA1: F1,22 = 1.71, p = 0.20; CA2/3: F1,22 = 1.35, p = 0.26; dentate gyrus: F1,22 = 1.83, p = 0.19). There was also no difference between wild-type and GR+/− mice in the number of 5-HT1A receptor binding sites as measured by the binding of [3H]8-OH-DPAT [main effect of genotype, CA1: F1,22 = 

Discussion

In the present study we found no effect of the constitutive reduction in GR on 5-HT1A receptor function or binding sites in hippocampus or in prefrontal cortex. The lack of effect of genotype on 5-HT1A receptor-stimulated [35S]GTPγS binding in hippocampus was somewhat unexpected given the reduction in hippocampal BDNF in GR+/− mice (Ridder et al., 2005) and our previous findings of reduced hippocampal 5-HT1A receptor-stimulated [35S]GTPγS binding in mice deficient in BDNF (Hensler et al., 2003,

Role of funding source

Funding for this study was provided by NARSAD (JGH) and NIMH grant MH 071488 (JGH). NARSAD and NIMH had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication. This work was also supported by grants from the Deutsche Forschungsgemeinschaft (SFB636/B3 and GA 427/9-1 to P.G.). MAV received a scholarship from the GK791 of the University of Heidelberg.

Conflict of interest

None.

Acknowledgements

The authors gratefully acknowledge the excellent technical assistance of Mrs. Teresa Burke, Mrs. Christiane Brandwein, Mrs. Natascha Pfeiffer and Mr. Christof Dormann.

References (18)

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