Elevated plasma corticosterone level and depressive behavior in experimental temporal lobe epilepsy
Introduction
Depression is one of the most common co-morbidities of epilepsy, including temporal lobe epilepsy (TLE), and has a high negative impact on the quality of life in epilepsy patients (Hermann et al., 2000, Kanner and Balabanov, 2002, Kondziella et al., 2007). While psychosocial factors may contribute to depression in epilepsy, there is growing evidence that this condition has a neurobiological basis (Kanner, 2005, Kondziella et al., 2007). Nevertheless, mechanisms that underlie depression in epilepsy are poorly understood, and its effective therapies are lacking.
Validation of animal models of co-morbidity between TLE and depression is instrumental for understanding mechanisms of this condition and for the development of its rational therapies. In the pursuit of such an animal model, we previously established that LiCl and pilocarpine status epilepticus (SE) in rats, along with chronic epilepsy, led to behavioral (despair and anhedonia) and biochemical (deficit of the raphe-hippocampal serotonergic transmission) hallmarks of depression (Mazarati et al., 2008). However, since depression in epilepsy is a multifactorial disorder (Kanner, 2003, Kondziella et al., 2007), the model validation process should include the identification of other contributing physiological, biochemical and endocrine factors.
One core feature of major depression is chronic stress (Chaouloff, 2000, El Yacoubi et al., 2003, Yu et al., 2008) which is manifested as the paucity of the negative feedback inhibition within the hypothalamo–pituitary–adrenocortical (HPA) axis: under conditions of chronic stress, cortisol fails to inhibit the production of corticotropin releasing hormone (CRH) and of adrenocorticotropic hormone (ACTH), thus resulting in a high sustained level of circulating cortisol (Herman and Cullinan, 1997). The laboratory diagnosis of depression involves the dexamethasone (DEX)/CRH test, which is purposed to reveal the described HPA dysregulation: the test is considered positive, that is diagnostic of depression, if DEX fails to decrease the level of plasma cortisol, and if exogenously administered CRH leads to the exacerbated increase of the plasma stress hormone (Watson et al., 2006).
While the described dysregulation of the HPA axis has been established in major depression, the role of this neuroendocrine impairment in depression associated with epilepsy has not been sufficiently examined. Nevertheless, several reports suggested that epilepsy may be indeed accompanied by chronic, interictal hyperactivity of the HPA axis evident as the increased content of plasma cortisol (Gallagher, 1987) and positive DEX/CRH test (Zobel et al., 2004); the latter study suggested that such chronic HPA dysfunction may be a factor contributing to depression in TLE.
In animal epilepsy models, several reports showed ictal or early postictal HPA hyperactivity (Daniels et al., 1990, Lai et al., 2006, Szafarczyk et al., 1986); however, the interictal state of the HPA axis has not been examined, and thus it is not known whether chronic experimental epilepsy is accompanied by the depressive endocrine abnormalities.
The present study continues our efforts in the validating an animal model of co-morbidity between TLE and depression and focuses on the establishing of endocrine hallmark of depression in the post-SE model. Specifically, we examined whether chronic epilepsy in rats is accompanied by the interictal hyperactivity of the HPA axis, and if it does, whether the extent of such dysregulation correlates with the severity of depressive behavior.
Section snippets
Experimental subjects
The experiments were performed in male Wistar rats (Charles River, Wilmington, MA), 45–55 days old at the beginning of the study, in accordance with the policies of the National Institutes of Health.
Study design is outlined in Fig. 1.
Status epilepticus and spontaneous seizure monitoring
SE was induced by LiCl (128 mg/kg, dissolved in deionized water, injected intraperitoneally, i.p. at a volume of 1 ml/kg) and pilocarpine (40 mg/kg, dissolved in 0.9% NaCl, injected subcutaneously, s.c. at a volume of 1 ml/kg; both from Sigma, St. Louis, MO) (
Spontaneous seizures and hippocampal afterdischarge properties
Out of 16 animals which had developed SE and were used for further studies, spontaneous seizures were observed in 10 rats. The animals exhibited both focal and generalized seizures. For both types of seizures combined, weekly minimal/maximal/median count was 1/8/3.5. No rats exhibited seizures consisting of exclusively a single pattern (i.e. only focal or only generalized). At the same time, post-SE animals, both with and without documented recurrent seizures, showed a statistically similar
Discussion
The main finding of this study is that SE led to hyperactivity of the HPA axis, which was evident as the increased basal plasma CORT level and a positive DEX/CRH test. This endocrine abnormality was observed both in animals with documented clinical seizures during the interictal period, and in those post-SE rats, in which clinical seizures were not detected. Furthermore, the endocrine response to CRH positively correlated with the severity of depressive behavior.
While several studies showed the
Acknowledgments
This work was supported by the National Institutes of Health research grants NS059505 (AM) and NS046516 (RS).
References (34)
- et al.
The pilocarpine model of seizures
- et al.
Neurocircuitry of stress: central control of the hypothalamo–pituitary–adrenocortical axis
Trends. Neurosci.
(1997) - et al.
Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor
Behav. Brain Res.
(2006) Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms, and treatment
Biol. Psychiatry
(2003)- et al.
Effect of neonatal isolation on outcome following neonatal seizures in rats—the role of corticosterone
Epilepsy Res.
(2006) - et al.
Kindling epileptogenesis in immature rats leads to persistent depressive behavior
Epilepsy Behav.
(2007) The kindling phenomenon
- et al.
The Flinders Sensitive Line rat: a selectively bred putative animal model of depression
Neurosci. Biobehav. Rev.
(2005) Modification of seizure activity by electrical stimulation: II. Motor seizures. Electroencephalogr
Clin. Neurophysiol.
(1972)- et al.
Plasma corticosterone, dexamethasone (DEX) suppression and DEX/CRH tests in a rat model of genetic vulnerability to depression
Psychoneuroendocrinology
(2007)
Plasma ACTH and corticosterone responses to limbic kindling in the rat
Exp. Neurol.
The DEX/CRH test—is it better than the DST?
Psychoneuroendocrinology
Neuronal actions of glucocorticoids: focus on depression
J. Steroid. Biochem. Mol. Biol.
High-frequency oscillations after status epilepticus: epileptogenesis and seizure genesis
Epilepsia
Serotonin, stress and corticoids
J. Psychopharmacol.
Rapid loss of dendritic spines after stress involves derangement of spine dynamics by corticotropin-releasing hormone
J. Neurosci.
The effect of intrahippocampal injection of kainic acid on corticosterone release in rats
Neurochem. Res.
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