Research reportChronic treatment with supraphysiological levels of corticosterone enhances d-MDMA-induced dopaminergic neurotoxicity in the C57BL/6J female mouse
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)
- et al.
Effects of a cold environment or age on methamphetamine-induced dopamine release in the caudate putamen of female rats
Pharmacol. Biochem. Behav.
(1993) - et al.
Rapid and transient inhibition of mitochondrial function following methamphetamine or 3,4-methylenedioxymethamphetamine administration
Eur. J. Pharmacol.
(2000) - et al.
Dopaminergic activity in transgenic mice underexpressing glucocorticoid receptors: effect of anitidepressants
Neuroscience
(2001) - et al.
[3H]Corticosterone binding in the caudate-putamen
Brain Res.
(1983) - et al.
Oxidative stress: free radical production in neural degeneration
Pharmacol. Ther.
(1994) - et al.
Dexamethasone induces limited apoptosis and extensive sublethal damage to specific subregions of the striatum and hippocampus: implications for mood disorders
Neuroscience
(2001) - et al.
Restraint as a stressor in mice: against the dopaminergic neurotoxicity of d-MDMA, low body weight mitigates restraint-induced hypothermia and consequent neuroprotection
Brain Res.
(2000) - et al.
Differences between rats and mice in MDMA(methylenedioxymethamphetamine) neurotoxicity
Eur. J. Pharmacol.
(1988) The neurobiology of stress: from serendipity to clinical relevance
Brain Res.
(2000)Effects of adverse experiences for brain structure and function
Biol. Psychiatry
(2000)
Glucocorticoids may alter antioxidant enzyme capacity in the brain: baseline studies
Brain Res.
Glucocorticoids may alter antioxidant enzyme capacity in the brain: kainic acid studies
Brain Res.
Quantification of glial fibrillary acidic protein: comparison of slot-immunobinding assays with a novel sandwich ELISA
Neurotoxicol. Teratol.
Major strain differences in response to chronic systemic administration of the mitochondrial toxin 3-nitroproprionic acid in rats: implications for neuroprotection studies
Neuroscience
Glucocorticoids, stress and exacerbation of excitotoxic neuron death
Semin. Neurosci.
Seizure-induced neuronal death is associated with induction of c-Jun N-terminal kinase and is dependent on genetic background
Brain Res.
Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are independently mediated by 5-HT2 receptors
Brain Res.
Measurement of protein using bicinchoninic acid
Anal. Biochem.
Cited by (34)
Chronic alcohol causes alteration of lipidome profiling in brain
2019, Toxicology LettersCitation Excerpt :To the best of our knowledge, this is the first report showing that chronic alcohol exposure significantly alters the lipidomic profile of PFC and striatum, which may underlie the potential pathogenesis of alcohol-related neurotoxicity and neuroplasticity. Alcoholics with cognitive impairment often accompany with deficiency in both white matter and gray matter brain structure (Johnson et al., 2002). The correlation between the degree of brain atrophy and the rate of amount of consumed alcohol have been widely known; however, the exact neuropathological mechanism still remains unclear.
Impact of neuroimmune activation induced by alcohol or drug abuse on adolescent brain development
2019, International Journal of Developmental NeuroscienceThe profile of mephedrone on human monoamine transporters differs from 3,4-methylenedioxymethamphetamine primarily by lower potency at the vesicular monoamine transporter
2015, European Journal of PharmacologyCitation Excerpt :By contrast, the majority of studies did not find neurotoxic loss of parameters of serotoninergic or dopaminergic nerve terminals after binge-type dosing schedule of MMC in rats (Baumann et al., 2012; den Hollander et al., 2013; Motbey et al., 2012; Shortall et al., 2012) or mice (Angoa-Perez et al., 2011; den Hollander et al., 2013). Finally, MMC did not activate glia or increase glial fibrillary acidic protein (Angoa-Perez et al., 2011; den Hollander et al., 2013), whereas the latter marker of neurodegeneration was increased by MDMA (Johnson et al., 2002; Miller and O׳Callaghan, 1995). A connection between longterm neurotoxicity of amphetamine-related drugs and interaction with mechanisms regulating the intraneuronal neurotransmitter concentrations has been established.
'Ecstasy' enhances noise-induced hearing loss
2013, Hearing ResearchEffects of developmental stress and lead (Pb) on corticosterone after chronic and acute stress, brain monoamines, and blood Pb levels in rats
2011, International Journal of Developmental Neuroscience