A neurotoxic regimen of MDMA suppresses behavioral, thermal and neurochemical responses to subsequent MDMA administration

Shankaran, Mahalakshmi; Gudelsky, Gary A.

doi:10.1007/s002130051143

Cited by 107 publications

(132 citation statements)

References 30 publications

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“…It was demonstrated that the increase in the extracellular concentration of ACh in the PFC elicited by MDMA was attenuated in rats previously exposed to a neurotoxic regimen of MDMA in much the same manner as has been reported for the MDMA induced increase in 5-HT release (Shankaran and Gudelsky, 1999;Shankaran et al, 2001). In contrast, physical (i.e., tail pinch) or psychological (i.e., intruder rat) stressors evoked a similar increase in ACh release in the PFC of control animals and animals previously exposed to a neurotoxic regimen of MDMA (Nair and Gudelsky, 2006b).…”

Section: Long Term Effects Of Repeated Mdma Administrationsupporting

confidence: 62%

“…However, following a neurotoxic regimen of MDMA, the ability of a subsequent injection of MDMA to elicit the 5-HT behavioral syndrome has been shown to be greatly diminished (Shankaran and Gudelsky, 1999;Shankaran et al, 2001). Series et al (1995) and Baumann et al (1998) also have demonstrated that the acute behavioral effects of fenfluramine are diminished following treatment with 5-HT depleting regimens of p-choloramphetamine, fenfluramine or MDMA.…”

Section: Long Term Effects Of Repeated Mdma Administrationmentioning

confidence: 99%

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Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

Gudelsky

Yamamoto

2008

Pharmacology Biochemistry and Behavior

122

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Abstract3,4-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.

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Section: Long Term Effects Of Repeated Mdma Administrationsupporting

confidence: 62%

Section: Long Term Effects Of Repeated Mdma Administrationmentioning

confidence: 99%

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

Gudelsky

Yamamoto

2008

Pharmacology Biochemistry and Behavior

122

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“…A gradually diminishing temperature dysregulation in rat dams was also seen by [76]. The development of thermal tolerance is not unique to females or to pregnancy as a blunted temperature dysregulation also occurs in adolescents [118] and adults [25,142]. The mechanism(s) responsible for tolerance, especially at different ages, is presently unclear as, in addition to the activation of uncoupling proteins by norepinephrine and thyroid hormones [103], dopamine, serotonin, and several cytokines mediate the core temperature response to MDMA [58].…”

mentioning

confidence: 89%

“…A locomotor sensitization two weeks after an escalating MDMA regimen was reported [127,128]. In contrast, the serotonin syndrome and pyrexia was substantially reduced one week after a rat MDMA binge [142].Intermittent MDMA exposure every five days beginning on PD 35 (adolescence) lead to a reduction in the temperature dysregulation and headweaving stereotopy by PD 60 [118]. Prior embryonic experience modified the behavioral response to a second MDMA treatment in newly hatched chickens [13].…”

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confidence: 99%

A developmental comparison of the neurobehavioral effects of ecstasy (MDMA)

Piper

2007

Neurotoxicology and Teratology

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The entactogen ±3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug among college, high school, and, occasionally, middle school students. Preclinical research examining the acute and long-term effects of MDMA has predominately been conducted in reproductively mature subjects but there has been increasing interest in adolescent and in utero exposure. This review examines the acute and long-term responses to MDMA during perinatal, adolescent, and adult periods. The ability of MDMA to alter core body temperature emerges gradually during ontogeny while a reduction in body weight is evident at all ages. Learning and workingmemory are also altered independent of the developmental stage of exposure. Current evidence suggests adults are more sensitive to the long-term serotonin depletions following MDMA but younger ages also exhibit substantial and rapid neuroplasticity. Sexually dimorphic MDMA responses have been identified for the acute hyperthermic and motoric effects of MDMA with pubescent males being especially susceptible. Several physiological, behavioral, and neurochemical MDMA issues requiring further study are also outlined. Keywords±3; 4-methylenedioxymethamphetamine; Adolescence; Anxiety; Depression; Learning; SerotoninThe phenylethylamine ±3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug best known as ecstasy. MDMA has several other street names including Adam, baby slits, chocolate chips, clarity, doctor, essence, kleenex, and roll [77]. Although ecstasy has some similarities with both stimulants and hallucinogens, MDMA is an entactogen. Entactogen means "touching within" based on the drug's subjective effects [110]. MDMA also causes long term changes in several markers of the integrity of the serotonin (5-HT) neurotransmitter system [58]. There have been several excellent recent reviews on MDMA toxicology, pharmacokinetics, pharmacodynamics, and neurobehavioral consequences [30,37,113,157], but none have systematically addressed the intricate effects of MDMA during development.Ecstasy use is not restricted to limited subpopulations, that is fans of techno music and "raves" [173] or male homosexuals [73,81], as MDMA has expanded into the general population [124,148,170] and especially young people [52,78,170,172]. Over one hundred pregnant women in Toronto called a substance abuse helpline between 1998 and 2000 to inquire Corresponding Author: Brian J. Piper, Neuroscience and Behavior Program, University of Massachusetts, Amherst, MA 01003-7710, Tel: (413) 545-0996, bpiper@nsm.umass.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers...

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“…Although it could be argued that the development of compensatory mechanisms diminishes the clinical importance of MDMA-induced neurotoxicity, an alternative view is that MDMA-induced lesions produce a brain milieu of diminished functional reserve that may become clinically apparent under various forms of stress. One method that has proved useful for unmasking such 'subclinical' deficits in animals treated with neurotoxic doses of MDMA has been the use of pharmacological challenge (Poland et al, 1997;Virden and Baker, 1999;Shankaran and Gudelsky, 1999;Gardani et al, 2005). The foregoing studies demonstrate that animals with MDMA-induced lesions that exhibit normal behaviors or physiology at baseline have abnormal thermal, behavioral and circadian responses to pharmacological challenges with drugs that influence these 5-HTmediated functional domains.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Catecholamine Depletion by Alpha-Methyl-Para-Tyrosine on Measures of Cognitive Performance and Sleep in Abstinent MDMA Users

McCann¹,

Peterson²,

Ricaurte³

2007

Neuropsychopharmacol

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(7) 3, 4-Methylenedioxymethamphetamine (MDMA) is a popular recreational drug of abuse and a brain serotonin (5-HT) neurotoxin in animals. Growing evidence suggests that humans who use MDMA recreationally can also develop 5-HT neurotoxic injury, although functional consequences have been difficult to identify. Twenty-five abstinent MDMA users and 23 non-MDMA using controls were studied to determine whether pharmacologic depletion of brain catecholamines by alpha-methyl-para-tyrosine (AMPT) would differentially effect MDMA users on measures of cognition and sleep, two processes dually modulated by brain serotonergic and catecholaminergic neurons. During a 5-day in-patient study, all subjects underwent formal neuropsychiatric testing, repeated computerized cognitive testing, and all-night sleep studies. At baseline, MDMA users had performance deficits on tasks of verbal and visuospatial working memory and displayed increased behavioral impulsivity on several computerized tasks, reflecting a tendency to perform quickly at the expense of accuracy. Baseline sleep architecture was also altered in abstinent MDMA users compared to controls. AMPT produced differential effects in MDMA users compared to controls on several cognitive and sleep measures. Differences in cognitive performance, impulsivity, and sleep were significantly correlated with MDMA use. These data extend findings from earlier studies demonstrating cognitive deficits, behavioral impulsivity, and sleep alterations in abstinent MDMA users, and suggest that lasting effects of MDMA lead to alterations in the ability to modulate behaviors reciprocally influenced by 5-HT and catecholamines. More research is needed to determine potential relationships between sleep abnormalities, cognitive deficits and impulsive behavior in abstinent MDMA users.

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A neurotoxic regimen of MDMA suppresses behavioral, thermal and neurochemical responses to subsequent MDMA administration

Abstract: It is concluded that the long-term depletion of brain 5-HT produced by MDMA is accompanied by impairments in 5-HT function, as evidenced by the deficits in the neurochemical, thermal and behavioral responses to subsequent MDMA administration.

Cited by 107 publications

References 30 publications

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

A developmental comparison of the neurobehavioral effects of ecstasy (MDMA)

The Effect of Catecholamine Depletion by Alpha-Methyl-Para-Tyrosine on Measures of Cognitive Performance and Sleep in Abstinent MDMA Users

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