A neurotoxic regimen of MDMA suppresses behavioral, thermal and neurochemical responses to subsequent MDMA administration (original) (raw)
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British Journal of Pharmacology, 2006
13,4-Methylenedioxymethamphetamine (MDMA or ‘ecstasy’) decreases the 5-HT concentration, [3H]-paroxetine binding and tryptophan hydroxylase activity in rat forebrain, which has been interpreted as indicating 5-HT neurodegeneration. This has been questioned, particularly the 5-HT loss, as MDMA can also inhibit tryptophan hydroxylase. We have now evaluated the validity of these parameters as a reflection of neurotoxicity.2Male DA rats were administered MDMA (12.5 mg kg−1, i.p.) and killed up to 32 weeks later. 5-HT content and [3H]-paroxetine binding were measured in the cortex, hippocampus and striatum. Parallel groups of treated animals were administered NSD-1015 for determination of in vivo tryptophan hydroxylase activity and 5-HT turnover rate constant.3Tissue 5-HT content and [3H]-paroxetine binding were reduced in the cortex (26–53%) and hippocampus (25–74%) at all time points (1, 2, 4, 8 and 32 weeks). Hydroxylase activity was similarly reduced up to 8 weeks, but had recovered at 32 weeks. The striatal 5-HT concentration and [3H]-paroxetine binding recovered by week 4 and hydroxylase activity after week 1. In all regions, the reduction in 5-HT concentration did not result in an altered 5-HT synthesis rate constant.4Administering MDMA to animals when housed at 4°C prevented the reduction in [3H]-paroxetine binding and hydroxylase activity observed in rats housed at 22°C, but not the reduction in 5-HT concentration.5These data indicate that MDMA produces long-term damage to serotoninergic neurones, but this does not produce a compensatory increase in 5-HT synthesis in remaining terminals. It also highlights the fact that measurement of tissue 5-HT concentration may overestimate neurotoxic damage.3,4-Methylenedioxymethamphetamine (MDMA or ‘ecstasy’) decreases the 5-HT concentration, [3H]-paroxetine binding and tryptophan hydroxylase activity in rat forebrain, which has been interpreted as indicating 5-HT neurodegeneration. This has been questioned, particularly the 5-HT loss, as MDMA can also inhibit tryptophan hydroxylase. We have now evaluated the validity of these parameters as a reflection of neurotoxicity.Male DA rats were administered MDMA (12.5 mg kg−1, i.p.) and killed up to 32 weeks later. 5-HT content and [3H]-paroxetine binding were measured in the cortex, hippocampus and striatum. Parallel groups of treated animals were administered NSD-1015 for determination of in vivo tryptophan hydroxylase activity and 5-HT turnover rate constant.Tissue 5-HT content and [3H]-paroxetine binding were reduced in the cortex (26–53%) and hippocampus (25–74%) at all time points (1, 2, 4, 8 and 32 weeks). Hydroxylase activity was similarly reduced up to 8 weeks, but had recovered at 32 weeks. The striatal 5-HT concentration and [3H]-paroxetine binding recovered by week 4 and hydroxylase activity after week 1. In all regions, the reduction in 5-HT concentration did not result in an altered 5-HT synthesis rate constant.Administering MDMA to animals when housed at 4°C prevented the reduction in [3H]-paroxetine binding and hydroxylase activity observed in rats housed at 22°C, but not the reduction in 5-HT concentration.These data indicate that MDMA produces long-term damage to serotoninergic neurones, but this does not produce a compensatory increase in 5-HT synthesis in remaining terminals. It also highlights the fact that measurement of tissue 5-HT concentration may overestimate neurotoxic damage.British Journal of Pharmacology (2006) 148, 778–785. doi:10.1038/sj.bjp.0706783
Behavioural analysis of the acute and chronic effects of MDMA treatment in the rat
Psychopharmacology, 1999
Rationale: A variety of animal models have shown MDMA (3,4-methylenedioxymethamphetamine) to be a selective 5-HT neurotoxin, though little is known of the long-term behavioural effects of the pathophysiology. The widespread recreational use of MDMA thus raises concerns over the long-term functional sequelae in humans. Objective: This study was designed to explore both the acute-and post-treatment consequences of a 3day neurotoxic exposure to MDMA in the rat, using a variety of behavioural paradigms. Methods: Following training to pretreatment performance criteria, animals were treated twice daily with ascending doses of MDMA (10, 15, 20 mg/kg) over 3 days. Body temperature, locomotor activity, skilled paw-reaching ability and performance of the delayed non-match to place (DNMTP) procedure was assessed daily during this period and on an intermittent schedule over the following 16 days. Finally, post mortem biochemical analyses of [ 3 H] citalopram binding and monoamine levels were performed. Results: During the MDMA treatment period, an acute 5-HT-like syndrome was observed which showed evidence of tolerance. Once drug treatment ceased the syndrome abated completely. During the post-treatment phase, a selective, delay-dependent, deficit in DNMTP performance developed. Post-mortem analysis confirmed reductions in markers of 5-HT function, in cortex, hippocampus and striatum. Conclusions: These results confirm that acutely MDMA exposure elicits a classical 5-HT syndrome. In the long-term, exposure results in 5-HT neurotoxicity and a lasting cognitive impairment. These results have significant implications for the prediction that use of MDMA in humans could have deleterious long-term neuropsychological/psychiatric consequences.
Psychopharmacology, 2006
Rationale: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug. In animals, high-dose administration of MDMA produces deficits in serotonin (5-HT) neurons (e.g., depletion of forebrain 5-HT) that have been interpreted as neurotoxicity. Whether such 5-HT deficits reflect neuronal damage is a matter of ongoing debate. Objective: The present paper reviews four specific issues related to the hypothesis of MDMA neurotoxicity in rats: (1) the effects of MDMA on monoamine neurons, (2) the use of "interspecies scaling" to adjust MDMA doses across species, (3) the effects of MDMA on established markers of neuronal damage, and (4) functional impairments associated with MDMA-induced 5-HT depletions. Results: MDMA is a substrate for monoamine transporters, and stimulated release of 5-HT, NE, and DA mediates effects of the drug. MDMA produces neurochemical, endocrine, and behavioral actions in rats and humans at equivalent doses (e.g., 1-2 mg/kg), suggesting that there is no reason to adjust doses between these species. Typical doses of MDMA causing long-term 5-HT depletions in rats (e.g., 10-20 mg/kg) do not reliably increase markers of neurotoxic damage such as cell death, silver staining, or reactive gliosis. MDMA-induced 5-HT depletions are accompanied by a number of functional consequences including reductions in evoked 5-HT release and changes in hormone secretion. Perhaps more importantly, administration of MDMA to rats induces persistent anxiety-like behaviors in the absence of measurable 5-HT deficits. Conclusions: MDMA-induced 5-HT depletions are not necessarily synonymous with neurotoxic damage. However, doses of MDMA which do not cause longterm 5-HT depletions can have protracted effects on behavior, suggesting even moderate doses of the drug may pose risks.
Pharmacology Biochemistry and Behavior, 1989
PHARMACOL BIOCHEM BEHAV 33(3) 641-648, 1989.--The behavioral effect of single administration of +--3,4-methylenedioxymethamphetamine (MDMA) on rats performing on the differential-reinforcement-of-low-rate 72-second schedule (DRL 72-sec) was compared before and after a period of repeated administration of MDMA known to deplete 5-hydroxytryptamine (5-HT) levels in the brain. Single administration of MDMA decreased reinforcement rate (1, 2, 4, 6 mg/kg) and increased response rate (4,6 mg/kg) of rats performing on the DRL 72-sec schedule. This effect is typical of amphetamines and other psychomotor stimulants. Four weeks after repeated administration of MDMA (6 mg/kg twice daily for 4 days) there was an increase in sensitivity to the effect of single administration of MDMA. Doses of 2, 4 and 6 mg/kg of MDMA resulted in increases in response rate that were significantly greater after repeated MDMA administration than before. Doses of 0.5, 2, and 6 mg/kg of MDMA resulted in decreases of reinforcement rate that were significantly greater after repeated MDMA administration than before. Repeated administration of MDMA resulted in long-term depletion of serotonin levels by 30-50% in the amygdala, neostriatum, hippocampus and the frontal cortex. Norepinephrine and dopamine (DA) levels were not significantly different from control in any of the brain regions analyzed. The behavioral and neurochemical results suggest that serotonergic neurons normally exert an inhibitory action upon the psychomotor stimulant effects of MDMA. Since the psychomotor stimulant effects of amphetamines appear to be mediated primarily by the dopamine system, these results provide evidence that 5-HT and DA may represent opposing systems in the DRL schedule-controlled behavior.
European Journal of Pharmacology, 1987
(±)3,4-Methylenedioxymethamphetamine (MDMA) was administered to rats as a single 40 mg/kg injection s.c. or 40 mg/kg s.c. every second day for 4 injections. Sixteen days following the last injection rats were killed. MDMA produced significant depletions of 5-HT and its metabolite 5-HIAA in the hippocampus and the frontal cortex. 5-HT was depleted to 30% of control value in the hippocampus following a single dose. 5-HT levels were not affected in the hypothalamus, suggesting differential effects on brain 5-HT systems. DA levels in the hypothalamus were significantly increased while NE levels in the frontal cortex were decreased to 73% of control following 4 doses of MDMA. MDMA, therefore, produces long-term depletions in 5-HT which suggests that it may act as a neurotoxin at 5-HT neurons in the brain of rats.
Brain Research, 1998
The effect of MDMA 3,4-methylenedioxymethamphetamine , a psychotropic amphetamine derivative, treatment on the rate of Ž. w 14 x serotonin 5-hydroxytryptamine; 5-HT synthesis in the rat brain was studied by autoradiography using a-C-methyl-L-tryptophan Ž. Ž. method. Three different treatment protocols were compared to the control saline treated rats: 1 rats treated twice with 10 mgrkg every Ž. Ž. 12 h 20 mgrkg total and injected tracer for the synthesis measurements 15 h later; 2 rats treated with four injections of 5 mgrkg every Ž. Ž. 12 h 20 mgrkg total and injected tracer for the synthesis measurement 17 h after the last dose; and 3 rats given eight injections of 5 Ž. mgrkg every 12 h for four days 40 mgrkg and used in the synthesis study 14 days after the last dose. Results showed a significant decrease in the rate of synthesis in the majority of cerebral structures examined in the 10 mgrkg group. In contrast the group receiving Ž. Ž. the same total amount 20 mgrkg of MDMA but over two days 4 = 5 mgrkg showed a significant increase in 5-HT synthesis in Ž. comparison to controls. The 5-HT synthesis rates measured 14 days after the last dose four days, 8 = 5 mgrkg were significantly reduced. The findings suggest that MDMA can produce either an increase or a decrease in the 5-HT synthesis a short time after a total dose of 20 mgrkg depending on the dose fractionation. However, 14 days after total dose of 40 mgrkg given over four days the synthesis rate was significantly reduced in many brain structures. The latter suggests a possible effect of the MDMA neurotoxicity on the serotonergic neurons, in addition to a possible influence on 5-HT synthesis via a feedback mechanism.
Pharmacology Biochemistry and Behavior, 2008
3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative and a popular drug of abuse that exhibits mild hallucinogenic and rewarding properties and engenders feelings of connectedness and openness. The unique psychopharmacological profile of this drug of abuse most likely is derived from the property of MDMA to promote the release of dopamine and serotonin (5-HT) in multiple brain regions. The present review highlights primarily data from studies employing in vivo microdialysis that detail the actions of MDMA on the release of these neurotransmitters. Data from in vivo microdialysis experiments indicate that MDMA, like most amphetamine derivatives, increases the release of dopamine in the striatum, n. accumbens and prefrontal cortex. However, the release of dopamine evoked by MDMA in each of these brain regions appears to be modulated by concomitantly released 5-HT and the subsequent activation of 5-HT2A/C or 5-HT2B/C receptors. In addition to its stimulatory effect on the release of monoamines, MDMA also enhances the release of acetylcholine in the striatum, hippocampus and prefrontal cortex, and this cholinergic response appears to be secondary to the activation of histaminergic, dopaminergic and/or serotonergic receptors. Beyond the acute stimulatory effect of MDMA on neurotransmitter release, MDMA also increases the extracellular concentration of energy substrates, e.g., glucose and lactate in the brain. In contrast to the acute stimulatory actions of MDMA on the release of monoamines and acetylcholine, the repeated administration of high doses of MDMA is thought to result in a selective neurotoxicity to 5-HT axon terminals in the rat. Additional studies are reviewed that focus on the alterations in neurotransmitter responses to pharmacological and physiological stimuli that accompany MDMA-induced 5-HT neurotoxicity.
European Journal of Neuroscience, 2002
The respective in¯uences of the corticotropic axis and sympathetic activity on 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) immediate effects on body temperature and long-term neurotoxicity, as assessed by decreases in hippocampal and striatal [ 3 H]5-hydroxytryptamine ([ 3 H]5-HT) reuptake, [ 3 H]paroxetine binding at 5-HT transporters (5-HTT), and 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels, were examined in Fischer 344 rats. On each of the two injections of MDMA (5 or 10 mg/kg s.c. once a day for 2 consecutive days) body temperature rapidly increased in a dose-dependent manner. Six days after the last injection of 10 mg/kg MDMA, [ 3 H]5-HT reuptake, [ 3 H]paroxetine binding and 5-HT and 5-HIAA levels were decreased in the hippocampus and, to a lower extent, in striatum. Prior adrenalectomy (1 week beforehand), which weakened the immediate hyperthermic effect of MDMA, prevented the long-term MDMA-elicited reduction in hippocampal and striatal [ 3 H]paroxetine binding. Supplementation of adrenalectomised Fischer 344 rats with corticosterone almost reinstated the immediate hyperthermic effect of MDMA and restored MDMA-elicited reduction in hippocampal and striatal [ 3 H]paroxetine binding. In a ®nal set of experiments, Fischer 344 rats were pretreated (30 min before each of the two injections of 10 mg/kg MDMA) with the ganglionic blocker chlorisondamine (2.5 mg/kg). This pretreatment markedly reduced the amplitudes of the immediate hyperthermia and long-term declines in hippocampal [ 3 H]5-HT reuptake and [ 3 H]paroxetine binding at 5-HTT, and in hippocampal and striatal 5-HT and 5-HIAA levels. These results suggest that sympathetic activity (possibly through its control of body temperature), but not corticotropic activity, plays a key role in MDMA-elicited neurotoxicity in Fischer 344 rats.
Psychopharmacology, 2004
Rationale 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) administration to rats produces acute hyperthermia and long-term neurotoxic damage to 5-hydroxytryptamine (serotonin, 5-HT) neurones. Objective We wished to examine MDMA-induced hyperthermia in rats housed at normal (19°C) and high (30°C) room temperatures and investigate the effect of a prior neurotoxic lesion. Methods Rectal temperature was measured after administration of single or repeated doses of MDMA to rats housed at 19°C and 30°C. Results MDMA (5 mg/kg IP) produced a sustained hyperthermic response in rats housed at 30°C, but not in rats housed at 19°C. A prior (5 weeks earlier) neurotoxic dose of MDMA (12.5 mg/kg IP) resulted in MDMA (5 mg/kg) producing a greater hyperthermic response in rats housed at 30°C than in non-pre-treated animals. Repeated MDMA administration (binge dosing; 2, 4 or 6 mg/kg ×3) produced dose-dependent hyperthermia in rats housed at 19°C, with MDMA (2 mg/kg ×3) having little effect. However, this dose produced significant hyperthermia (≥2°C above control values)in rats housed at 30°C following the third dose. A prior neurotoxic dose of MDMA resulted in MDMA (2 mg/kg ×3) producing marked hyperthermia (>1°C) after the first dose and severe hyperthermia (≥2°C) after the third dose. Conclusions MDMA administration to rats housed at 30°C produces a more severe hyperthermic response than that seen in rats housed at 19°C. A prior neurotoxic dose enhances the response further in animals housed at 30°C. Binge dosing produces a higher final peak response than a similar non-divided dose. This effect is more marked in animals housed at high room temperature. These data may have implications for recreational users of MDMA in hot environments, particularly those who may have damaged serotoninergic neurones because of prior heavy or frequent use of the drug.
…, 2003
Rationale: There is some uncertainty whether the acute hyperthermia caused by MDMA (ecstasy) plays a significant role in determining the long-term neurotoxic effects on brain 5-HT systems and associated changes in mood and behaviour. Objective: The present study assessed whether long-term behavioural and cognitive changes seen in MDMA-treated rats are affected by hyperthermia at the time of drug administration. Method: Male Wistar rats were treated with MDMA (45 mg/ kg i.p. over 4 h on 2 consecutive days) or vehicle at either a high ambient temperature (28C) or a low ambient temperature (16C). Eight to 18 weeks later, rats were tested in behavioural measures of anxiety (social interaction and emergence tests), a test of cognition (object recognition test) and the forced swim test of depression. At the conclusion of behavioural testing the rats were killed and their brains analysed using HPLC. Results: MDMA treatment caused a clear and consistent hyperthermia at 28C and hypothermia at 16C. Months later, rats pre-treated with MDMA at either 16 or 28C displayed increased anxiety in the social interaction and emergence tests and reduced escape attempts and in-creased immobility in the forced swim test. MDMA pretreatment was also associated with poorer memory on the object recognition test, but only in rats given the drug at 28C. Rats pre-treated with MDMA showed loss of 5-HT in the hippocampus, striatum, amygdala and cortex, regardless of body temperature at the time of dosing. However, 5-HIAA loss in the amygdala and hippocampus was greater in rats pre-treated at 28C. Dopamine in the striatum was also depleted in rats given MDMA. Conclusions: These results indicate that hyperthermia at the time of dosing with MDMA is not necessary to produce subsequent 5-HT depletion and anxiety in rats. They also extend previous findings of long-term effects of brief exposure to MDMA in rats to include apparent "depressive" symptoms in the forced swim model.