Mapping Toxicant-Induced Nervous System Damage With a Cupric Silver Stain: A Quantitative Analysis of Neural Degeneration Induced by 3,4- Methylenedioxymethamphetamine

Kf, Jensen; Olin, Jeanene K.; Haykal-Coates, Najwa; O’Callaghan, James P.; Db, Miller; Js, de Olmos

doi:10.1037/e495922006-008

Cited by 33 publications

(38 citation statements)

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“…The lack of GFAP response and inconsistencies in silver staining following a 5-HT-depleting regimen of MDMA have led to debate as to whether MDMA is neurotoxic to 5-HT axon terminals (Commins et al, 1987, Jensen et al, 1993, Pubill et al, 2003. In the present study, the lack of an increase in the number of C-tau positive astrocytes in response to MDMA and PMA also could be viewed as indirect evidence that these amphetamine analogs are not neurotoxic.…”

Section: Discussionmentioning

confidence: 42%

“…Additionally, studies have indicated a lack of Fluoro-Jade-B positive neurons in the hippocampus and striatum following administration of MDMA, although a limited number of degenerating neurons have been noted in other brain regions (Schmued, 2003). Furthermore, although some investigators have reported silver staining of degenerating axon terminals in the brains of rats treated with MDMA (Commins et al, 1987, Molliver et al, 1990, others have reported inconsistent results or patterns of staining that are not in agreement with other indicators of altered 5-HT innervation (Jensen et al, 1993). Given the mixed data regarding loss of 5-HT nerve terminals following administration of MDMA, investigation of additional markers of CNS injury are warranted.…”

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confidence: 88%

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The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain

et al. 2007

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The present study quantified the cleaved form of the microtubule associated protein tau (cleaved MAP-tau, C-tau), a previously demonstrated marker of CNS toxicity, following the administration of monoamine-depleting regimens of the psychostimulant drugs amphetamine (AMPH), methamphetamine (METH), ±3,4-methylenedioxymethamphetamine (MDMA), or paramethoxyamphetamine (PMA) in an attempt to further characterize psychostimulant-induced toxicity. A dopamine (DA)-depleting regimen of AMPH produced an increase in C-tau immunoreactivity in the striatum, while a DA-and serotonin (5-HT)-depleting regimen of METH produced an increase in the number of C-tau immunoreactive cells in the striatum and CA2/CA3 and dentate gyrus regions of the hippocampus. MDMA and PMA, two psychostimulant drugs that produce selective 5-HT depletion in the striatum, had no effect on C-tau immunoreactivity in the striatum or hippocampus. Furthermore, 5,7-dihydroxytryptamine (5,7-DHT), an established 5-HT selective neurotoxin, did not produce an increase in C-tau immunoreactivity. Dual fluorescent immunocytochemistry with antibodies to GFAP and C-tau indicated that C-tau immunoreactivity was present in astrocytes, not neurons, suggesting that increased C-tau may be an alternative indicator of reactive gliosis. The present results are consistent with previous findings that the DA-depleting psychostimulants AMPH and METH produce reactive gliosis whereas the 5-HT-depleting drugs MDMA and PMA, as well as the known 5-HT selective neurotoxin 5,7-DHT, do not produce an appreciable glial response. Keywords methamphetamine; 3,4-methylenedioxymethamphetamine; amphetamine; paramethoxyamphetamine; 5,7-dihydroxytryptamine; toxicity Methamphetamine (METH) and ±3,4-methylenedioxymethamphetamine (MDMA) are substituted phenylethylamines whose popularity among young adults continues to be a public

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Section: Discussionmentioning

confidence: 42%

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confidence: 88%

The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain

et al. 2007

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“…These procedures have been used for the identification of apoptotic neurons during the early postnatal period (22) as well as for neurotoxicity evaluations (23,24). To date, silver degeneration stains have been applied mostly in adult neurotoxicity studies (25,26), but their potential for adding to the understanding of developmental neurotoxicity is beginning to be explored. For example, silver degeneration stains have been used recently to show that ethanol and other drugs that antagonize the N -methyl-D-aspartate receptor (the major excitatory receptor in the brain) dramatically increase the rate of apoptosis during the early postnatal period in rat pups (27,28).…”

Section: Stains For Neurons and Myelinmentioning

confidence: 99%

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. II: neuropathology.

Garman¹,

Fix²,

Jortner³

et al. 2001

Environ Health Perspect

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Neuropathologic assessment of chemically induced developmental alterations in the nervous system for regulatory purposes is a multifactorial, complex process. This calls for careful qualitative and quantitative morphologic study of numerous brains at several developmental stages in rats. Quantitative evaluation may include such basic methods as determination of brain weight and dimensions as well as the progressively more complex approaches of linear, areal, or stereologic measurement of brain sections. Histologic evaluation employs routine stains (such as hematoxylin and eosin), which can be complemented by a variety of special and immunohistochemical procedures. These brain studies are augmented by morphologic assessment of selected peripheral nervous system structures. Studies of this nature require a high level of technical skill as well as special training on the part of the pathologist. The pathologist should have knowledge of normal microscopic neuroanatomy/neuronal circuitry and an understanding of basic principles of developmental neurobiology, such as familiarity with the patterns of physiologic or programmed cell de

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“…As a result, MDMA doses as high as 100 mg/kg have been administered to rats (Jensen et al, 1993). The limitations of this dosing method have been reviewed (de la Torre and Farre, 2004), and an alternative approach, "effects scaling," has been suggested (Baumann et al, 2007).…”

mentioning

confidence: 99%

MDMA (3,4-Methylenedioxymethamphetamine)-Mediated Distortion of Somatosensory Signal Transmission and Neurotransmitter Efflux in the Ventral Posterior Medial Thalamus

Starr

Page

Waterhouse³

2008

J Pharmacol Exp Ther

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MDMA (3,4-methylenedioxymethamphetamine, Ecstasy) is reported to enhance tactile sensory perception, an effect that is believed to contribute to its popularity as a recreational drug. To date, no literature exists that addresses the neurophysiological mechanisms underlying the effects of MDMA on somatosensation. However, MDMA interactions with the serotonin transporter protein (SERT) are well known. The rat trigeminal somatosensory system has been studied extensively and receives serotonergic afferents from the dorsal raphe nucleus. Given that these fibers express SERT, they should be vulnerable to MDMA-induced effects. We found that short-term lowdose MDMA administration (3 mg/kg i.p.) led to a significant increase in 5-hydroxytryptamine (5-HT) efflux in the ventral posterior medial (VPM) thalamus, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We further evaluated the potential for MDMA to modulate whisker-evoked discharge (WED) of individual neurons in this region. After surgically implanting stainless steel 8-wire multichannel electrode bundles, we recorded spike train activity from single cells of halothane-anesthetized rats while mechanically activating the whisker pathway. We found that short-term low-dose MDMA (3 mg/kg i.p.) increased the spontaneous firing rate but reduced the magnitude and duration of WED in individual VPM thalamic neurons. It is noteworthy that the time course of drug action on neuronal firing patterns was generally consistent with increased 5-HT efflux as shown from our microdialysis studies. Based on these results, we propose the working hypothesis that MDMA may "distort" rather than enhance tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits.

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Mapping Toxicant-Induced Nervous System Damage With a Cupric Silver Stain: A Quantitative Analysis of Neural Degeneration Induced by 3,4- Methylenedioxymethamphetamine

Cited by 33 publications

References 0 publications

The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain

The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. II: neuropathology.

MDMA (3,4-Methylenedioxymethamphetamine)-Mediated Distortion of Somatosensory Signal Transmission and Neurotransmitter Efflux in the Ventral Posterior Medial Thalamus

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