Developmental 3,4-methylenedioxymethamphetamine (MDMA) impairs sequential and spatial but not cued learning independent of growth, litter effects or injection stress

Williams, Michael T.; Morford, LaRonda L.; Wood, Sandra L.; Rock, Stephanie; McCrea, Anne E; Fukumura, Masao; Wallace, Tanya L.; Broening, Harry W.; Moran, Mary S.

doi:10.1016/s0006-8993(02)04278-6

Cited by 62 publications

(112 citation statements)

References 39 publications

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“…Similarly, adolescent rats lost over ten grams, 8% of pre-drug weight, only hours after MDMA treatments [121]. The molecular mechanisms of MDMA induced weight loss are incompletely understood but are quite likely to involve systemic norepinephrine release by this sympathomimetic and binding to alpha1 or beta3 adrenergic receptors followed by activation Body weight exhibits dose dependent reductions at all exposure ages tested [1,11,50,71,75,76,99,118,119,121,166,167]. Intermittent MDMA (20 mg/kg/day) delivery every fifth day from PD 35 to 60 to rats reduced the rate of weight gain [118,119].…”

Section: Physiologicalmentioning

confidence: 99%

“…The behavioral effects of MDMA (Table 2) are not limited to the period immediately after drug exposure as changes have also been documented weeks to months after MDMA [16,17,[24][25][26][27]92,93,118,119,155,159,166,168].…”

Section: Long-term Behavioral Consequencesmentioning

confidence: 99%

“…Both male and female MDMA exposed pups took less time to identify familiar smells [147]. Importantly, Vorhees and colleagues have determined that cognitive deficits are not due to the MDMA induced reduction in weight gain by running an additional large litter vehicle treated group [166].…”

Section: Learning and Memorymentioning

confidence: 99%

“…Early developmental MDMA produces equivalent changes in body weight [76,99], tyrosine hydroxylase [75], brain derived neurotrophic factor [76], olfactory discrimination [147] and 5-HT [11,76] in males and females. There are also few consistently obtained sex differences following neonatal MDMA for spatial learning and memory [11,166].…”

Section: Sex-differencesmentioning

confidence: 99%

“…Treatments (10-40 mg/kg/day) during a longer period (PD 1-10 or 11-20) attenuated the body mass such that there were still small (5-10%) deficits in adulthood (PD 82) [11]. Importantly, as will also be discussed later, [166] determined that the amount of weight loss caused by MDMA was inadequate to affect learning and memory. …”

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confidence: 94%

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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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Section: Physiologicalmentioning

confidence: 99%

Section: Long-term Behavioral Consequencesmentioning

confidence: 99%

Section: Learning and Memorymentioning

confidence: 99%

Section: Sex-differencesmentioning

confidence: 99%

mentioning

confidence: 94%

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

Piper

2007

Neurotoxicology and Teratology

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Delayed effects of chronic variable stress during peripubertal‐juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats

et al. 2004

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Animal studies on the effects of chronic variable stress during the peripubertal-juvenile period on hippocampal structure and function are lacking. Twenty-eight-day-old Sprague-Dawley rats were subjected to random, variable physical or social stress regimens for 4 weeks. Hippocampal volume was found to continue to grow in all lamina examined during the transition into young adulthood. Our variable physical stress paradigm led to inhibition of this growth in the CA1 pyramidal cell layer (PCL) and in the dentate gyrus-granular cell layer (DG-GCL), which reached full arrest in the CA3-PCL. Volume deficits were first observed after chronic stress exposure when 3 weeks, but not 24 h, of recovery had elapsed. Moreover, these volume deficits were associated with impairments in the Morris water-maze navigation, sustained down-regulation in the basal hippocampal glucocorticoid receptor gene expression, and deficits in the shutdown of acute stress-induced corticosterone secretion. Volume changes both due to normal maturation and after chronic stress exposure were independent of neuron number. Thus, a peripubertal-juvenile chronic stress paradigm that leads to significant alterations in the limbic-hypothalamic-pituitary-adrenal axis can produce robust effects in hippocampal structure and cognitive ability, lasting into adulthood.

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Metyrapone attenuates the sequential learning deficits but not monoamine depletions following d,l‐fenfluramine administration to adult rats

Skelton

Blankenmeyer

Gudelsky

et al. 2004

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Fenfluramine (FEN) is a substituted amphetamine known for its anorectic effects, without the stimulatory or abuse potential associated with other amphetamine derivatives. FEN is a potent serotonin (5-HT) releaser and reuptake inhibitor and has been shown to cause depletions of 5-HT that can last days and even weeks after administration. Administration of FEN four times on a single day also causes a prolonged increase of corticosterone (CORT) that lasts approximately 72 h following the first FEN dose. This dosing regimen also produces deficits in sequential learning as measured in the Cincinnati water maze (CWM). Adrenalectomy blocks this effect but removes more than CORT. Accordingly, the purpose of this study was to determine whether inhibiting glucocorticoid production, by administration of the 11 beta-hydroxylase inhibitor metyrapone (MET), will similarly attenuate or eliminate the sequential learning deficits seen with FEN exposure. MET (50 mg/kg) injections were administered 90 min prior to and for 3 days after FEN (four doses given at 2-h intervals). Animals pretreated with MET and treated with FEN showed no sequential learning deficits when tested 1 week following FEN administration compared to FEN alone. The depletions of monoamines were similar following FEN administration, regardless of MET treatment. Taken together, this suggests that a potential mechanism for the sequential learning deficits in FEN-treated animals is a result of prolonged increases in CORT output.

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Developmental 3,4-methylenedioxymethamphetamine (MDMA) impairs sequential and spatial but not cued learning independent of growth, litter effects or injection stress

Cited by 62 publications

References 39 publications

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

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

Delayed effects of chronic variable stress during peripubertal‐juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats

Metyrapone attenuates the sequential learning deficits but not monoamine depletions following d,l‐fenfluramine administration to adult rats

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