Chlormethiazole, dizocilpine and haloperidol prevent the degeneration of serotonergic nerve terminals induced by administration of MDMA ('Ecstasy') to rats

Hewitt, Kim; Green, A.R.

doi:10.1016/0028-3908(94)90134-1

Cited by 78 publications

(73 citation statements)

References 29 publications

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“…[ 3 H]-Paroxetine binding was measured by the method described in detail by Hewitt and Green (1994). The animals were killed, the brain rapidly removed and dissected on ice within 2 min.…”

Section: Measurement Of Monoamines and Their Metabolites In Cerebral mentioning

confidence: 99%

“…The degeneration is reflected by a substantial decrease in the concentration of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), a reduction in the density of 5-HT uptake sites labelled with [ 3 H]-paroxetine (Sharkey et al 1991;Hewitt and Green 1994;Colado et al 1997a;Sanchez et al 2001) and a decrease in the immunoreactivity of fine 5-HT axons in the neocortex, hippocampus and striatum (O'Hearn et al 1988).…”

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confidence: 99%

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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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“…[ 3 H]-Paroxetine binding was measured by the method described in detail by Hewitt and Green (1994). The animals were killed, the brain rapidly removed and dissected on ice within 2 min.…”

Section: Measurement Of Monoamines and Their Metabolites In Cerebral mentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2006

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“…[ 3 H]-Paroxetine binding was measured by the method described in detail by Hewitt & Green (1994). The animals were killed, the brain rapidly removed and dissected on ice within 2 min.…”

Section: Measurement Of Monoamines and Their Metabolites In Cerebral mentioning

confidence: 99%

“…The second action of MDMA in the brain of experimental animals is to produce a long lasting neurotoxic loss of 5-HT nerve terminals in several areas of the brain, an e ect demonstrated both histologically (O'Hearn et al, 1988;Molliver et al, 1990) and biochemically (Battaglia et al, 1987;Sharkey et al, 1991;Hewitt & Green, 1994). The mechanisms involved in producing this neurodegeneration are not fully understood at present, but recent data have given substantial evidence to support the contention that increased free radical production is involved (see Colado et al, 1997b).…”

Section: Introductionmentioning

confidence: 99%

“…In addition Stone et al (1988) reported that the dopamine uptake inhibitor GBR 12909 was neuroprotective. Finally, both Schmidt et al (1990b) and Hewitt & Green (1994) have shown that acute administration of the dopamine antagonist haloperidol together with MDMA provides e ective protection against neurotoxic damage. It is acknowledged that none of these studies demonstrate authoritatively the involvement of dopamine in the MDMAinduced neurodegeneration because none of the compounds used in these investigations (haloperidol, 6-OHDA, a-methyl p-tyrosine) selectively alter dopamine function.…”

Section: Introductionmentioning

confidence: 99%

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Studies on the role of dopamine in the degeneration of 5‐HT nerve endings in the brain of Dark Agouti rats following 3,4‐methylenedioxymethamphetamine (MDMA or ‘ecstasy’) administration

Colado

O’Shea

Granados

et al. 1999

British J Pharmacology

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1 We investigated whether dopamine plays a role in the neurodegeneration of 5-hydroxytryptamine (5-HT) nerve endings occurring in Dark Agouti rat brain after 3,4-methylenedioxymethamphetamine (MDMA or`ecstasy') administration. 2 Haloperidol (2 mg kg 71 i.p.) injected 5 min prior and 55 min post MDMA (15 mg kg 71 i.p.) abolished the acute MDMA-induced hyperthermia and attenuated the neurotoxic loss of 5-HT 7 days later. When the rectal temperature of MDMA+haloperidol treated rats was kept elevated, this protective e ect was marginal. 3 MDMA (15 mg kg 71 ) increased the dopamine concentration in the dialysate from a striatal microdialysis probe by 800%. L-DOPA (25 mg kg 71 i.p., plus benserazide, 6.25 mg kg 71 i.p.) injected 2 h after MDMA (15 mg kg 71 ) enhanced the increase in dopamine in the dialysate, but subsequent neurodegeneration was unaltered. L-DOPA (25 mg kg 71 ) injected before a sub-toxic dose of MDMA (5 mg kg 71 ) failed to induce neurodegeneration. 4 The MDMA-induced increase in free radical formation in the hippocampus (indicated by increased 2,3-and 2,5-dihydroxybenzoic acid in a microdialysis probe perfused with salicylic acid) was unaltered by L-DOPA. 5 The neuroprotective drug clomethiazole (50 mg kg 71 i.p.) did not in¯uence the MDMA-induced increase in extracellular dopamine. 6 These data suggest that previous observations on the protective e ect of haloperidol and potentiating e ect of L-DOPA on MDMA-induced neurodegeneration may have resulted from e ects on MDMA-induced hyperthermia. 7 The increased extracellular dopamine concentration following MDMA may result from e ects of MDMA on dopamine re-uptake, monoamine oxidase and 5-HT release rather than aǹ amphetamine-like' action on dopamine release, thus explaining why the drug does not induce degeneration of dopamine nerve endings.

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Combined phentermine/fenfluramine administration enhances depletion of serotonin from central terminal fields

Lew

Weisenberg

Vosmer

et al. 1997

Synapse

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Administration of phentermine (Phen) together with (+/-) fenfluramine (Fen) enhances the weight reduction that is observed with either drug alone; consequently, these anorectic agents are commonly prescribed together for weight reduction. Repeated administration of Fen is known to cause long-term depletion of axonal serotonin (5-HT) and loss of 5-HT transporters, and is therefore considered neurotoxic. We now report that combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg, and 20 mg/kg/3.125 mg/kg) can enhance the neurotoxic effect of Fen (3.125 mg/kg) and Phen (5 mg/kg and 20 mg/kg) on central 5-HT systems. Rats were repeatedly treated once each hour for a total of four injections with saline, Phen (5 mg/kg and 20 mg/kg), Fen (3.125 mg/kg and 12.5 mg/kg), or combined Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg), and sacrificed either 7 or 28 days after cessation of treatment. Combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg) caused significantly greater reductions of 5-HT levels in the striatum, nucleus accumbens/olfactory tubercle, hypothalamus, amygdala, frontal parietal cortex, and hippocampus than either drug alone. Combined Phen/Fen at the higher drug-dose combination (20 mg/kg/3.125 mg/kg) was observed to reduce the density of 5-HT transporters in rat striatum at both 7 and 28 days after cessation of treatment. In addition, combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg) caused greater weight loss than that observed with either compound alone. Collectively, the present data demonstrate that combined Phen/Fen administration enhances the neurotoxicity of Phen or Fen on 5-HT neurons.

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Chlormethiazole, dizocilpine and haloperidol prevent the degeneration of serotonergic nerve terminals induced by administration of MDMA ('Ecstasy') to rats

Cited by 78 publications

References 29 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

Studies on the role of dopamine in the degeneration of 5‐HT nerve endings in the brain of Dark Agouti rats following 3,4‐methylenedioxymethamphetamine (MDMA or ‘ecstasy’) administration

Combined phentermine/fenfluramine administration enhances depletion of serotonin from central terminal fields

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