Elsevier

Brain Research

Volume 933, Issue 2, 19 April 2002, Pages 130-138
Brain Research

Research report
Chronic treatment with supraphysiological levels of corticosterone enhances d-MDMA-induced dopaminergic neurotoxicity in the C57BL/6J female mouse

https://doi.org/10.1016/S0006-8993(02)02310-7Get rights and content

Abstract

Chronic stress and extended periods of elevated circulating glucocorticoids have been reported to exacerbate excitotoxicity-induced hippocampal neuronal injury in rat. Despite continued interest in the effects of protracted exposure to stress or glucocorticoids, there has been little examination of how other types of neurotoxicity may be exacerbated or blocked, by stress. Here we examined the effects of chronic supraphysiologic levels of corticosterone on d-3,4-methylenedioxymethamphetamine (d-MDMA)-induced striatal dopaminergic neurotoxicity in the female C57BL/6J mouse. Corticosterone (5 mg, 15 mg or placebo) pellets were implanted to continuously elevate circulating glucocorticoids and create a model of the ultimate effect of chronic activation of the hypothalamic–pituitary–adrenal axis. After 7 days, a neurotoxic regimen of d-MDMA was administered (20 mg/kg s.c. every 2 h×4); thymus, spleen, striatum and hippocampus were collected 72 h later. Significant involution of thymus and spleen confirmed the bioavailability of the corticosterone at both dosages. d-MDMA increased the striatal levels of the astrocyte-localized protein glial fibrillary acidic protein (GFAP, a marker of gliosis); both dosages of corticosterone exacerbated this increase but only the 15 mg pellet exacerbated the decrease in tyrosine hydroxylase protein. Corticosterone alone or in combination with d-MDMA produced no neural injury in hippocampus, as measured by GFAP. Our work indicates corticosterone was able to increase the vulnerability of the striatum, but not the hippocampus to d-MDMA. An examination of other mouse strains and models of neurotoxic injury would be useful in determining the general validity of the glucocorticoid neuroendangerment hypothesis.

Introduction

The hypothalamic–pituitary–adrenal (HPA) axis is one of the major body systems activated in response to stress or homeostatic disturbance. Consequently, chronic stress could be viewed as a state in which the HPA axis is activated for extended periods and, as such, it would engender a prolonged elevation in levels of circulating glucocorticoids. Such extended exposure to elevated glucocorticoids levels is suspected to have detrimental effects on a number of body systems including the nervous system [15], [16], [17]. For example, repeated exposure to certain stressors or to exogenous corticosterone exacerbates the excitotoxic neuronal death induced in hippocampus by the neurotoxicant kainic acid [27], [28], [29]. Despite the continued interest in chronic stress and its consequences for brain integrity and function, there has been little examination of whether or how prolonged stress can exacerbate the neurotoxic response of brain areas other than the hippocampus.

The striatum and prefrontal cortex are among the non-hippocampal brain regions considered to be vulnerable to the effects of chronic stress, however; this vulnerability has been infrequently considered in the context of the toxicological actions of exogenous agents [1], [7], [9]. Many investigations have shown that acute stress procedures can affect various aspects of dopamine neurotransmission. Consequently, chronic stress has been examined most often for the role it may play in disease states believed to affect dopamine neurotransmission. For example, aberrant function of the HPA axis has been hypothesized to underlie the pathophysiology of disorders such as depression and drug abuse [6]. There has been, as well, great interest in how chronic stress or persistent exposure to glucocorticoids may alter the pharmacological actions of agents targeting dopamine neurotransmission. The paucity of data related to chronic stress and neurotoxicity in striatum may be related to the lack of convenient or reliable models of dopaminergic neurotoxicity. For example, 6-hydroxydopamine reliably produces striatal damage but it cannot be given systemically; the requirement for intracerebral injection of this compound may introduce variables such as altered blood–brain barrier function, etc., that can make interpretation of the data difficult. In other models (e.g., 3-nitroproprionic acid) the compound can be administered systemically but the degree of striatal damage often is inconsistent [26].

The discovery that several substituted amphetamines cause striatal dopaminergic neurotoxicity in the mouse may now provide an in vivo model for examination of the interaction between chronic stress and neurotoxicity in this brain area [25], [14]. Thus, we elected to study the impact of chronic stress, as mimicked by the implantation of sustained release corticosterone pellets, on dopaminergic neurotoxicity induced by d-3,4-methylenedioxymethamphetamine (MDMA). MDMA produces marked damage to striatal dopaminergic nerve terminals as evidenced by decreases in dopamine, its metabolites, and tyrosine hydroxylase (TH) protein as well as by an increase in glial fibrillary acidic protein (GFAP), an astrocyte protein that serves as a marker of injury-induced gliosis. Our data indicate that supraphysiological levels of corticosterone increase MDMA-induced striatal dopaminergic neurotoxicity. Although hippocampus is not a brain area targeted by MDMA it is considered to be vulnerable to insult by high levels of corticosterone and thus was also chosen for evaluation. No hippocampal gliosis or alterations in serotonin or norepinephrine content occurred in response to either corticosterone alone or in combination with MDMA. These results suggest that high circulating levels of corticosterone, such as those experienced during chronic stress, may enhance the neurotoxicity of agents targeting the striatum.

Section snippets

Materials

The following drugs and chemicals were kindly provided by or obtained from the sources indicated: high-performance liquid chromatography (HPLC) standards (Sigma, St. Louis, MO, USA); d-MDMA (Research Technology Branch, National Institute on Drug Abuse, Rockville, MD, USA). Reagents used for HPLC were of HPLC-grade (ESA, Chelmsford, MA, USA). Twenty-one-day release pellets containing placebo, 5 mg or 15 mg of corticosterone were obtained from Innovative Research of America (Sarasota, FL, USA).

Animals

Effect of corticosterone pellets and d-MDMA treatment on immune organs

Thymus and spleen weights were chosen as endpoints to evaluate the bioeffectiveness of the sustained release corticosterone. This strategy served to avoid the repeated blood collection necessary to obtain corticosterone levels during the experiment. Thymus weight and/or size especially serves as an established biomarker of the bioactivity of glucocorticoids (see Ref. [2] for a discussion). As expected, implantation of the corticosterone pellets caused a marked involution of the thymus as

Discussion

Our data indicate that supraphysiological levels of corticosterone can enhance the striatal dopaminergic neurotoxicity engendered by treatment with d-MDMA. In agreement with our previous findings [25], d-MDMA reduced the striatal content of TH protein, DA and its metabolites. These decreases in markers of DA terminal integrity were accompanied by marked astrogliosis, as indicated by a robust elevation in GFAP. Treatment with corticosterone enhanced this striatal neurotoxicity. These findings

Acknowledgements

The authors gratefully acknowledge Fang X. Ma, Monica Graziani, Mary Ann Hammer, Brenda Billig and Christopher Felton for their expert technical assistance.

References (37)

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