Elsevier

Psychoneuroendocrinology

Volume 32, Issue 7, August 2007, Pages 834-842
Psychoneuroendocrinology

The acceleration of amygdala kindling epileptogenesis by chronic low-dose corticosterone involves both mineralocorticoid and glucocorticoid receptors

https://doi.org/10.1016/j.psyneuen.2007.05.011Get rights and content

Summary

We have previously demonstrated that low-dose corticosterone (CS) administration, used as a model of the effect of chronic stress, accelerates epileptogenesis in the electrical amygdala kindling rat model of temporal lobe epilepsy (TLE). This current study examined the relative contributions to this effect of mineralocorticoid (MR) and glucocorticoid (GR) subtypes of glucocorticoid receptors. Female non-epileptic wistar rats 10–13 weeks of age were implanted with a bipolar electrode into the left amygdala. Five treatment groups were subjected to rapid amygdala kindling: water-control (n=9), CS treated (6 mg/100 ml added to drinking water; n=9), CS+spironolactone (MR antagonist, 50 mg/kg sc; n=9), CS+mifepristone (GR antagonist, 25 mg/kg sc; n=9), and CS+both antagonists (n=7). Rats were injected with vehicle or the relevant antagonist twice daily for the entire kindling period. Experimental groups differed significantly in the number of stimulations required to reach the ‘fully kindled state’ (Racine, 1972) ANOVA, F(4,38)=2.73, p=0.04). Amygdala kindling was accelerated in the CS-treated group compared with water controls (mean stimulations for full kindling: 45.2 vs. 86.5, p<0.01). This acceleration was inhibited by both the MR and GR antagonist treatments (mean stimulations: 69.6 and 70.4, p=0.04 and 0.04 vs. CS group, respectively), with the kindling rates in these groups not significantly different from water-treated subjects (p=0.26 and 0.29, respectively). The kindling rates in the MR and GR antagonist treatment groups did not significantly differ from each other (p=0.93), nor from the combined treatment group (mean stimulations: 62.8, p=0.59 and 0.54, respectively). This study demonstrates that activation of both high-affinity (MR) and low-affinity (GR) glucocorticoid receptors are involved in mediating CS-induced acceleration of amygdala kindling epileptogenesis.

Introduction

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy in adults and is a disorder with high levels of disability, treatment-resistance and psychiatric comorbidity (Engel et al., 1997). The etiology and pathogenesis of this disease is poorly understood, but there are several good reasons to suggest that stress and stress processes may play a significant role. First, there are well-established morphological and functional effects of stress on the mesial temporal lobe, particularly the hippocampus and amygdala, the key structures implicated in MTLE (Gould et al., 1990; Woolley et al., 1990; Sapolsky, 1992; McEwen, 1999; McEwen and Chattarji, 2004). Further, stress and/or glucocorticoid exposure potentiate the effects of concurrent neurological insults in the hippocampus, such as ischemia and hypoglycemia (Sapolsky, 1996; Reagan and McEwen, 1997) and seizures themselves (Lai et al., 2006), exposures which may be relevant to the evolution of MTLE. Second, there are several lines of evidence directly implicating stress and physiological stress response mediators (glucocorticoids (GCs), corticotropin releasing hormone (CRH), neuropeptide Y amongst others) in the regulation of hippocampal electrophysiology (Joels, 1997; Pavlides et al., 2002), seizures and epileptogenesis (Baram and Hatalski, 1998; Karst et al., 1999). Third, various forms of psychopathology, especially depression and psychosis, occur in MTLE at elevated rates and contribute greatly to the disability and impaired quality of life associated with the disorder (Lambert and Robertson, 1999; Harden, 2002; Kanner and Balabanov, 2002). In the past, these have been thought to be a consequence of the epilepsy, via psychological or biological mechanisms, but there is increasing evidence to suggest either a ‘common causation’ model or reverse causation, especially given the considerable evidence implicating the mesial temporal lobe in affective disorder and psychosis in non-epileptic populations. In addition there is good reason to hypothesize that the depressed state itself may contribute to the emergence or acceleration of the course of MTLE in those with a pre-existing vulnerability to the disorder (Dominian et al., 1963; Hesdorffer et al., 2000). Finally, it should be noted that the mesial temporal lobe is itself a crucial site for the regulation of the stress response (Herman and Cullinan, 1997; Herman and Spencer, 1998; Herman et al., 2003).

Few published studies directly address the possibility that stress may affect epileptogenesis. We have previously demonstrated that low-dose corticosterone (CS) administration (3 mg/100 ml in drinking water) results in acceleration of electrical amygdala kindling epileptogenesis in rats (Taher et al., 2005), a result consistent with that found in adrenalectomized rats (Edwards et al., 1999). Also, Karst et al. (1999) showed that a much higher dose of CS enhances hippocampal electrical kindling in young rats, although the pharmacological dose of CS used in that study is unlikely to equate to the physiological alterations seen in chronic stress and depression. However, no studies have investigated directly the neurochemical mechanisms by which CS accelerates epileptogenesis in the electrical amygdala kindling model of epileptogenesis.

High-affinity mineralocorticoid (MR) and low-affinity glucocorticoid (GR) receptors are the two binding sites which mediate the majority of biological actions of GCs in vivo (de Kloet et al., 1998), and evidence exists to suggest roles for both in epileptogenesis. A third, non-genomic membrane-associated GC receptor has also been suggested to mediate CS actions (Takahashi et al., 2002), but to date this has not been implicated in seizures or epileptogenesis. Maximal binding of CS to MR in the hippocampus has been shown to increase convulsion susceptibility in kainic acid, strychnine and pentylenetetrazol models of induced seizures, effects reversible by the MR antagonist, spironolactone (Roberts and Keith, 1994a, Roberts and Keith, 1994b; Talmi et al., 1995). Studies which found adrenalectomy (absence of GCs) to protect against kindling epileptogenesis (when compared to low-dose CS-replaced adrenalectomized rats) also implicate a high-affinity, MR-mediated mechanism in the acceleration of epileptogenesis by GCs (Cottrell et al., 1984; Karst et al., 1997). However, the findings of acceleration of epileptogenesis by supplementation with CS at high dose (Karst et al., 1999), when GR would be activated, suggests a role also for this glucocorticoid receptor subtype.

To further investigate the mechanism of acceleration of epileptogenesis by GCs, the present study examined the effect of glucocorticoid receptor antagonists acting at both MR and GR, alone and in combination, on low-dose CS-induced acceleration of epileptogenesis in the rapid amygdala kindling (RAK) model of MTLE.

Section snippets

Animals

Female non-epileptic Wistar rats were obtained from our breeding colonies at the Ludwig Institute of Cancer Research/Department of Surgery Royal Melbourne Hospital Biological Research Facility (BRF) and the Department of Medicine (Royal Melbourne Hospital)/Department of Dentistry BRF. Rats were housed in the Department of Medicine (Royal Melbourne Hospital) BRF at 20 °C on a 12 h light/dark cycle (lights on at 06:00 h). Female ovariectomized rats were used in this study to keep consistency with

CS dose received

The mean (±SEM) fluid intake for all CS-treated rats was 30.3±1.2 ml/day during the treatment period, equating to an average of 7.3±0.4 mg/kg/day of CS. This average intake did not differ between treatment groups (CS+vehicle: 33.2±3.1 ml/day, CS+Spiro: 30.8±2.1 ml/day, CS+Mif: 28.2±2.6 ml/day, CS+Both: 29.0±2.9 ml/day; F(3,29)=0.67, p=0.58), suggesting that CS dosing was not affected by antagonist treatment. Also, no preference was observed for CS or water (30.1±1.3 ml/day CS, 29.0±1.9 ml/day water; t

Discussion

The main results of this study firstly confirmed that low-dose CS administration accelerates electrical amygdala kindling epileptogenesis in female rats, this time using the rapid amygdala kindling protocol. This supports the view that chronically elevated CS exposure, such as is seen in stress or depression, may accelerate limbic epileptogenesis. The second important finding was the demonstration that antagonism of both MR and GR inhibited the acceleration of epileptogenesis by GCs,

Role of funding source

The study was supported in part by a Project Grant from the National Health and Medical Research Council (NH&MRC) of Australia (Project Grant #400088, O’Brien, Morris, Salzberg, Rees, Velakoulis) and an Independent Investigator Grant from The National Alliance for Research on Schizophrenia and Depression (NARSAD). GK was supported by a Melbourne International Research Scholarship. None of the organizations which donated funds to this project had any further role in the study design, collation

Conflict of interest

All authors (GK, AC, TOB, MS, NJ, SR, MM) individually disclose that they have no conflicts of interest, financial or otherwise, associated with this research.

Acknowledgment

We are grateful for the generous donation of EEG equipment by Compumedics™, Australia.

References (63)

  • M. Joels

    Steroid hormones and excitability in the mammalian brain. Front

    Neuroendocrinology

    (1997)
  • M. Joels et al.

    Mineralocorticoid and glucocorticoid receptors in the brain. Implications for ion permeability and transmitter systems

    Prog. Neurobiol.

    (1994)
  • M.A. Kling et al.

    Facilitation of cocaine kindling by glucocorticoids in rats

    Brain Res.

    (1993)
  • H.N. Koenig et al.

    The glucocorticoid receptor antagonist mifepristone reduces ethanol intake in rats under limited access conditions

    Psychoneuroendocrinology

    (2004)
  • H.J. Krugers et al.

    Down-regulation of the hypothalamo-pituitary-adrenal axis reduces brain damage and number of seizures following hypoxia/ischaemia in rats

    Brain Res.

    (1995)
  • M.C. Lai et al.

    Effect of neonatal isolation on outcome following neonatal seizures in rats--the role of corticosterone

    Epilepsy Res.

    (2006)
  • D.L. McCullers et al.

    Mifepristone protects CA1 hippocampal neurons following traumatic brain injury in rat

    Neuroscience

    (2002)
  • B.S. McEwen et al.

    Molecular mechanisms of neuroplasticity and pharmacological implications: the example of tianeptine

    Eur. Neuropsychopharmacol.

    (2004)
  • C.A. Mejias-Aponte et al.

    Sex differences in models of temporal lobe epilepsy: role of testosterone

    Brain Res.

    (2002)
  • R.J. Racine

    Modification of seizure activity by electrical stimulation. II. Motor seizure

    Electroencephalogr. Clin. Neurophysiol.

    (1972)
  • L.P. Reagan et al.

    Controversies surrounding glucocorticoid-mediated cell death in the hippocampus

    J. Chem. Neuroanat.

    (1997)
  • A.J. Roberts et al.

    Sensitivity of the circadian rhythm of kainic acid-induced convulsion susceptibility to manipulations of corticosterone levels and mineralocorticoid receptor binding

    Neuropharmacology

    (1994)
  • C. Schwarzer et al.

    Somatostatin, neuropeptide Y, neurokinin B and cholecystokinin immunoreactivity in two chronic models of temporal lobe epilepsy

    Neuroscience

    (1995)
  • D.E. Semler et al.

    The effects of chronic ingestion of spironolactone on serum thyrotropin and thyroid hormones in the male rat

    Toxicol. Appl. Pharmacol.

    (1989)
  • M. Talmi et al.

    Synergistic action of corticosterone on kainic acid-induced electrophysiological alterations in the hippocampus

    Brain Res.

    (1995)
  • H.M. van Praag

    Can stress cause depression?

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2004)
  • E. van Riel et al.

    Chronic unpredictable stress causes attenuation of serotonin responses in cornu ammonis 1 pyramidal neurons

    Neuroscience

    (2003)
  • G. Weiss et al.

    The effect of adrenalectomy on the circadian variation in the rate of kindled seizure development

    Brain Res.

    (1993)
  • G.K. Weiss et al.

    Amygdala kindling rate is altered in rats with a deficit in the responsiveness of the hypothalamo-pituitary-adrenal axis

    Neurosci. Lett.

    (1993)
  • C.S. Woolley et al.

    Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons

    Brain Res.

    (1990)
  • C.W. Breuner et al.

    Seasonal regulation of membrane and intracellular corticosteroid receptors in the house sparrow brain

    J. Neuroendocrinol.

    (2001)
  • Cited by (83)

    • The impact of early-life environment on absence epilepsy and neuropsychiatric comorbidities

      2022, IBRO Neuroscience Reports
      Citation Excerpt :

      HPA-related stress hormones can affect excitatory and inhibitory processes in the brain structures that are critically involved in seizure generation. Early-life stress might provoke vulnerability to seizure generation and epileptogenesis via altering glucocorticoids level (Kumar et al., 2007), HPA-axis (Joëls, 2009), membrane receptors, for instance, GABA (Reddy, 2013), NMDA and AMPA (Olney et al., 1991; Rogawski, 2013), neurogenesis (McCabe et al., 2001), brain structures connectivity (Nephew et al., 2017; Wang and Meng, 2016), monoaminergic brain systems (Matthews et al., 2001), dendritic spine morphology (Wang et al., 2013; Wong and Guo, 2013), and ion channels (Jones et al., 2011; Russo et al., 2016). Ion channels are a class of gene products that influence neuronal and network excitability.

    View all citing articles on Scopus
    1

    Co-first authors.

    View full text