Short communicationRegulation of cortical and hippocampal 5-HT1A receptor function by corticosterone in GR+/− mice
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)
- et al.
Serotonin-1A receptor imaging in recurrent depression: replication and literature review
Nucl. Med. Biol.
(2007) - et al.
Regulation of 5-HT1A receptor function in inducible BDNF knock-out mice following administration of corticosterone
Biol. Psychiatry
(2007) - et al.
Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo–pituitary–adrenocortical responsiveness
Front. Neuroendocrinol.
(2003) The corticosteroid receptor hypothesis of depression
Neuropsychopharmacology
(2000)- et al.
Effects of adrenalectomy and Type I or Type II glucocorticoid receptor activation on 5-HT1A and 5-HT2 receptor binding and 5-HT transporter mRNA expression in rat brain
Brain Res.
(1994) - et al.
Elevated basal trough levels of corticosterone suppress hippocampal 5-hydroxytryptamine1A receptor expression in adrenally intact rats: implications for the pathogenesis of depression
Neuroscience
(1997) - et al.
Differential regulation of neurotrophins and serotonergic function in mice with genetically reduced glucocorticoid receptor expression
Exp. Neurol.
(2007) - et al.
Therapy insight: is there an imbalanced response of mineralocorticoid and glucocorticoid receptors in depression?
Nat. Clin. Pract. Endocrinol. Metab.
(2007) - et al.
The Mouse Brain in Stereotaxic Coordinates
(1997)
Cited by (9)
Corticosterone impairs gap junctions in the prefrontal cortical and hippocampal astrocytes via different mechanisms
2018, NeuropharmacologyCitation Excerpt :The prefrontal cortex was more sensitive to oxidative stress than the hippocampus following chronic isolation stress (Zlatkovic et al., 2014). CORT treatment (10 mg/kg, once daily for 21 days) of wild-type mice resulted in a decrease in 5-HT1A receptor function in prefrontal cortex, but not in hippocampus (Hensler et al., 2010). In monkeys exposed to adult social stress, GR expression but not MR was diminished in hippocampal CA1, whereas MR but not GR was diminished in cell layer III of ventrolateral prefrontal cortex (Patel et al., 2008).
Enhanced novelty-induced corticosterone spike and upregulated serotonin 5-HT<inf>1A</inf> and cannabinoid CB<inf>1</inf> receptors in adolescent BTBR mice
2014, PsychoneuroendocrinologyCitation Excerpt :This HPA axis suppression is likely mediated via inhibitory metabotrophic Gαi/o coupled serotonin 5-HT1A and CB1 receptors. When direct HPA axis feedback by circulating CORT via GRs is impaired, 5-HT1A and CB1 receptors may be up-regulated in compensation (Lanfumey et al., 2008; Pompili et al., 2010; Hensler et al., 2010). We hypothesized that this type of compensation may occur to a greater extent during adolescence, particularly if the HPA stress-response is exaggerated.
Cortisol-mediated downregulation of the serotonin 1A receptor subtype in the Gulf toadfish, Opsanus beta
2013, Comparative Biochemistry and Physiology - A Molecular and Integrative PhysiologyCitation Excerpt :While fish that were crowded and experienced cortisol levels of 200 ng mL− 1 did not show a downregulation in 5-HT1A receptor mRNA expression, it appears that the cortisol levels experienced by oil-injected controls (400 ng mL− 1) were enough to elicit the downregulation in transcription. An increase in 5-HT1A receptor protein binding has been measured in GR-deficient mice (Hensler et al., 2010) and an increase in 5-HT1A receptor Bmax has also been measured in adrenalectomized mice (Martire et al., 1989; Burnet et al., 1992; Zhong and Ciaranello, 1995) and mice with a hypofunctioning HPA axis (Burnet et al., 1992). However, it appears that treatment with RU486 does not completely abolish the effects of elevated cortisol, as indicated by the significant difference between the Bmax of the RU486-treated and unstressed groups.
Effects of sugar rich diet on brain serotonin, hyperphagia and anxiety in animal model of both genders
2016, Pakistan Journal of Pharmaceutical Sciences