3,4‐Methylenedioxymethamphetamine increases interleukin‐1β levels and activates microglia in rat brain: studies on the relationship with acute hyperthermia and 5‐HT depletion

Orío, Laura; O’Shea, Esther; Sánchez, Verónica; Pradillo, Jesús M.; Escobedo, Isabel; Camarero, Jorge; Moro, Marı́a A.; Green, A. Richard; Colado, M. Isabel

doi:10.1111/j.1471-4159.2004.02443.x

Cited by 72 publications

(73 citation statements)

References 53 publications

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“…This effect is not surprising because it is also observed in normal experimental room conditions when the body temperature is monitored throughout the day and mainly when rats are maintained without manipulation during some time (Orio et al 2004). The exposure to binge plasma ethanol concentrations induced a more pronounced decrease in rectal temperature than that observed in rats exposed to air.…”

Section: Discussionmentioning

confidence: 70%

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Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain

et al. 2006

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Rationale Ecstasy abuse commonly occurs in hot, overcrowded environments in combination with alcohol. Around 90% of ecstasy users take ethanol; over 70% of these users also often drink alcohol at hazardous levels. Objectives We wished to examine whether binge ethanol administration enhanced the long-lasting 5-HT neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats maintained at high ambient temperature and the role of acetaldehyde. Materials and methods Rats were treated with a 4-day ethanol regimen leading to plasma ethanol levels of around 450 mg/dl. On day 5, rats were placed at 30°C and administered MDMA (5 mg/kg). Rectal temperature and hydroxyl radical formation were measured immediately before and up to 6 h after MDMA. 5-HT concentration and 5-HT transporter density were determined 7 days later. A group of rats received cyanamide (50 mg/kg) on days 1 and 3 of the 4-day-ethanol inhalation. Results In ethanol treated rats, MDMA produced a hyperthermic response similar to that observed in controls but enhanced the loss of 5-HT concentration and 5-HT transporter density in the hippocampus. Cyanamide elevated the plasma acetaldehyde concentration fivefold to sevenfold, reduced the MDMA-induced hyperthermia and increased the neuronal damage with neurotoxicity also appearing in the cortex. MDMA increased hydroxyl radical production in the hippocampus, the effect being more marked in rats pre-exposed to ethanol.Conclusions Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity by a mechanism not related to changes in acute hyperthermia but probably involving hydroxyl radical formation. The magnitude of this effect is more pronounced after increasing plasma acetaldehyde levels by aldehyde dehydrogenase inhibition.

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Section: Discussionmentioning

confidence: 70%

“…This hyperthermic response being a key factor in the long-term 5-HT neurotoxicity (Sanchez et al 2001;Orio et al 2004). However, the changes induced by ethanol in MDMA neurotoxicity do not seem to be related to an effect on the MDMA-induced hyperthermia.…”

Section: Discussionmentioning

confidence: 99%

Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain

et al. 2006

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“…The previously reported failure to detect a loss of SERT protein in Western blot analyses is not the sole reason why some have questioned the 5-HT neurotoxic potential of substituted amphetamines. In particular, the fact that MDMA and structurally related drugs (PCA, FEN) do not typically produce signs of glial activation in the context of selective 5-HT deficits (Rowland et al, 1993;O'Callaghan and Miller, 1994;Pubill et al, 2003;Wang et al, 2004Wang et al, , 2005Rothman et al, 2004;Thomas et al, 2004; but see Wilson et al, 1993;Aguirre et al, 1999;Orio et al, 2004) has led some of these investigators to reconsider the notion that substituted amphetamines produce neurotoxic effects. When considering these data, however, it is important to bear in mind that the effects of established 5-HT neurotoxins (5,7-DHT and 5,6-DHT) on glial responses have also been largely negative, particularly in brain regions removed from the site of intracerebral toxin injection (Stagaard et al, 1987;Hardin et al, 1994;Rowland et al, 1993;Bendotti et al, 1994;Dugar et al, 1998; but see Frankfurt et al, 1991;Dugar et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Loss of Serotonin Transporter Protein after MDMA and Other Ring-Substituted Amphetamines

Xie

Tong

McLane

et al. 2006

Neuropsychopharmacol

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We studied in vivo expression of the serotonin transporter (SERT) protein after 3,4-methylenedioxymethamphetamine (MDMA), p-chloroamphetamine (PCA), or fenfluramine (FEN) treatments, and compared the effects of substituted amphetamines to those of 5,7-dihydroxytryptamine (5,7-DHT), an established serotonin (5-HT) neurotoxin. All drug treatments produced lasting reductions in 5-HT, 5-HIAA, and [ 3 H]paroxetine binding, but no significant change in the density of a 70 kDa band initially thought to correspond to the SERT protein. Additional Western blot studies, however, showed that the 70 kDa band did not correspond to the SERT protein, and that a diffuse band at 63-68 kDa, one that had the anticipated regional brain distribution of SERT protein (midbrain4 striatum4neocortex4cerebellum), was reduced after 5,7-DHT and was absent in SERT-null animals, was decreased after MDMA, PCA, or FEN treatments. In situ immunocytochemical (ICC) studies with the same two SERT antisera used in Western blot studies showed loss of SERT-immunoreactive (IR) axons after 5,7-DHT and MDMA treatments. In the same animals, tryptophan hydroxylase (TPH)-IR axon density was comparably reduced, indicating that serotonergic deficits after substituted amphetamines differ from those in SERT-null animals, which have normal TPH levels but, in the absence of SERT, develop apparent neuroadaptive changes in 5-HT metabolism. Together, these results suggest that lasting serotonergic deficits after MDMA and related drugs are unlikely to represent neuroadaptive metabolic responses to changes in SERT trafficking, and favor the view that substituted amphetamines have the potential to produce a distal axotomy of brain 5-HT neurons.

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“…METH abusers who participated in this study denied any history of use of other illicit drugs, including MDMA, which has been reported to cause microglial reaction in both rats and mice (Orio et al, 2004;Thomas et al, 2004a,b;Zhang et al, 2006). These individuals had no previous history of hospitalization for any other psychiatric illnesses, such as affective disorders and schizophrenia, disorders reported to be associated with increased microglial density in the brain (Wierzba-Bobrowicz et al, 2005;Rajkowska and Miguel-Hidalgo, 2007).…”

Section: Discussionmentioning

confidence: 97%

Methamphetamine Causes Microglial Activation in the Brains of Human Abusers

Sekine

Ouchi²,

Sugihara³

et al. 2008

J. Neurosci.

346

260

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Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, and education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, [ C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ([ C](R)-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of [ C](R)-PK11195 in brain regions with dopaminergic and/or serotonergic innervation. The mean levels of [11 C](R)-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (Ͼ250% higher; p Ͻ 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices ( p Ͻ 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence.

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3,4‐Methylenedioxymethamphetamine increases interleukin‐1β levels and activates microglia in rat brain: studies on the relationship with acute hyperthermia and 5‐HT depletion

Cited by 72 publications

References 53 publications

Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain

Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain

Loss of Serotonin Transporter Protein after MDMA and Other Ring-Substituted Amphetamines

Methamphetamine Causes Microglial Activation in the Brains of Human Abusers

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