Hallucinogenic Amphetamine Selectively Destroys Brain Serotonin Nerve Terminals

Ricaurte, George A.; Bryan, Guy K.; Strauss, Léo; Seiden, Lewis S.; Schuster, Charles R.

doi:10.1126/science.4023719

Cited by 334 publications

(163 citation statements)

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“…Within 2-3 d after PCA administration, extremely enlarged, fragmented 5-HT-and tryptophan hydroxylase-immunoreactive axon terminals are found in cortex, indicative of axonal degeneration (Axt et al, , 1994. Silver impregnation studies reveal degenerating, argyrophilic axon terminals in striatum l-2 d after MDMA, MDA or PCA administration (Ricaurte et al, 1985;Commins et al, 1987). Further evidence that these drugs cause axon degeneration is the presence of activated microglia (Wilson and Molliver, 1994) and astrocytes (Axt et al, 1994) in cortex between l-6 weeks after treatment with PCA.…”

Section: Discussionmentioning

confidence: 99%

“…Further evidence that these drugs cause axon degeneration is the presence of activated microglia (Wilson and Molliver, 1994) and astrocytes (Axt et al, 1994) in cortex between l-6 weeks after treatment with PCA. The acute cytopathic changes are accompanied by a marked and long-lasting loss of 5-HT and 5-HIAA levels, 5-HT-immunoreactive axon terminals, tryptophan hydroxylase activity, high-affinity 5-HT uptake and binding sites for the 5-HT transporter in the forebrain (Sanders-Bush et al, 1972, 1975Fuller and Snoddy, 1974;Ricaurte et al, 1985;Stone et al, 1987;Battaglia et al, 1988;Mamounas et al, 1991Mamounas et al, , 1992Scanzello et al, 1993). These serotonergic deficits were shown to persist for at least 3-4 months and, in some studies, up to one year after drug treatment, thus strongly indicating 5-HT axon degeneration.…”

Section: Discussionmentioning

confidence: 99%

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Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain

et al. 1995

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A pathology of brain serotonergic (5-HT) systems has been found in psychiatric disturbances, normal aging and in neurodegenerative disorders including Alzheimer's and Parkinson's disease. Despite the clinical importance of 5-HT, little is known about the endogenous factors that have neurotrophic influences upon 5-HT neurons. The present study examined whether chronic pain parenchymal administration of the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or NGF could prevent the severe degenerative loss of serotonergic axons normally caused by the selective 5-HT neurotoxin p-chloroamphetamine (PCA). The neurotrophins (5–12 micrograms/d) or the control substances (cytochrome c or PBS vehicle) were continuously infused into the rat frontoparietal cortex using an osmotic minipump. One week later, rats were subcutaneously administered PCA (10 mg/kg) or vehicle, and the 5-HT innervation was evaluated after two more weeks of neurotrophin infusion. As revealed with 5-HT immunocytochemistry, BDNF infusions into the neocortex of intact (non-PCA-lesioned) rats caused a substantial increase in 5-HT axon density in a 3 mm diameter region surrounding the cannula tip. In PCA-lesioned rats, intracortical infusions of BDNF completely prevented the severe neurotoxin-induced loss of 5-HT axons near the infusion cannula. In contrast, cortical infusions of vehicle or the control protein cytochrome c did not alter the density of serotonergic axons in intact animals, nor did control infusions prevent the loss of 5-HT axons in PCA-treated rats. NT-3 caused only a modest sparing of the 5-HT innervation in PCA-treated rats, and NGF failed to prevent the loss of 5-HT axon density. The immunocytochemical data were supported by neurochemical evaluations which showed that BDNF attenuated the PCA-induced loss of 5-HT and 5- HIAA contents and 3H-5-HT uptake near the infusion cannula. Thus, BDNF can promote the sprouting of mature, uninjured serotonergic axons and dramatically enhance the survival or sprouting of 5-HT axons normally damaged by the serotonergic neurotoxin PCA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain

et al. 1995

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“…Eight years later, the U.S. government classified MDMA as a Schedule I drug following a report that administration of a chemically similar compound to rats caused a profile of chemical changes that was interpreted as indicative of 5-HT neurotoxicity [131]. MDMA has acute and longterm effects on 5-HT in several species including several non-human primates (baboons, marmosets, squirrel, rhesus, and cynomologous monkeys), pigeons, rabbits, guinea-pigs, rats, and some mouse strains [58,100,113,130,145].…”

Section: Historymentioning

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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“…MDMA also produces a stimulatory effect on the release of acetylcholine in the rat prefrontal cortex, striatum, and dorsal hippocampus (Acquas et al, 2001;Nair and Gudelsky, 2006). After the initial increase in synaptic levels of 5-HT, long-term depletions of this neurotransmitter and decreased 5-HT transporter binding have been frequently reported in rats (Boot et al, 2002;McGregor et al, 2003;Ricaurte et al, 1985). Repeated MDMA administration also induces a sustained loss in DA, but not in 5-HT, in the mouse striatum (Colado et al, 2004;Escobedo et al, 2005;Stone et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Rewarding Effects and Reinstatement of MDMA-Induced CPP in Adolescent Mice

Daza-Losada

Couto

Manzanedo

et al. 2007

Neuropsychopharmacol

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Although the rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in self-administration and conditioned place preference (CPP) procedures, its addictive potential (ie, the vulnerability to relapse, measured by its ability to induce reinstatement of an extinguished response), remains poorly understood. In this study, the effects of MDMA (5, 10, and 20 mg/kg) on the acquisition, extinction and reinstatement of CPP were evaluated in mice, using two different protocols during acquisition of CPP. In the first experiment, animals were trained using a two-session/day schedule (MDMA and saline for 4 consecutive days), whereas in the second experiment, they were trained using an alternating day schedule (MDMA and saline each 48 h). After extinction, the ability of drug priming to reinstate CPP was evaluated. In Experiment 1, MDMA did not significantly increase the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, although the preference was evident a week afterwards, lasting between 2 and 21 weeks. No reinstatement was observed after MDMA priming. In Experiment 2, all doses produced CPP in Post-C, which lasted between 1 and 4 weeks. MDMA induces reinstatement at doses up to 4 times lower than those used in conditioning. The analyses of brain monoamines revealed that the daily schedule of treatment induces a non-dose-dependent decrease in dopamine and serotonin (5-HT) in the striatum, whereas the alternating schedule produces a dose-dependent decrease of 5-HT in the cortex. These results demonstrate that MDMA produces long-lasting rewarding effects and reinstatement after extinction, suggesting the susceptibility of this drug to induce addiction.

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Hallucinogenic Amphetamine Selectively Destroys Brain Serotonin Nerve Terminals

Cited by 334 publications

References 27 publications

Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain

Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain

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

Rewarding Effects and Reinstatement of MDMA-Induced CPP in Adolescent Mice

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