Dennis McKenna - Neurochemistry and Neurotoxicity of MDMA

8/3/2019 Dennis McKenna - Neurochemistry and Neurotoxicity of MDMA

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/_! Raven _ Ltd., New York1990 International Society for Ncurochemistry

ShortReview

Neurochemistry and Neurotoxicityof 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy")

,6 DennisJ. McKennaandStephenJ.Peroutka.xxt Department of Neurology, Stanford University School of Medicine, Stanford, California, U.S,A.

[_ 3,4-Methylenedioxymethamphetamine (MDMA; acutely, but may have long-term consequences; others,' also known as "Ecstasy") is a ting-substituted phenyl- such as the rapid depletion of brain hydroxyindolesJ isopropylamine that is related to both amphetamines within hours following MDMA, appear to be unrelated

and hallucinogens, such as mescaline (Fig. 1).Although to the slower, more persistent decreases in brain hy-the drug was patented in 1914, interest in the com. droxyindoles that are among the long-term neuro-pound was minimal until the past decade. During this chemical changes that are indicative of neurotoxicity.f' period, MDMA began to be used as an adjunct to psy- Table 1 summarizes the acute and long-term effects ofchotherapy by certain therapists due to its purported MDMA. "

q/_ ability to induce a state of reduced anxiety and lowereddefensiveness (Downing, 1986; Greer and Tolbert,_4 1986). In addition, the recreational use of MDMA, ACUTE NEUROCHEMICAL EFFECTSparticularly on college campuses, appears to have in-[ creased significantly in recent years (Peroutka, 1987). Brain hydroxyindolesThe human use of this agent is of concern due to the

fact that MDMA and some of its congeners are selective One of the most characteristic acute effects oferotonergic neurotoxins in laboratory animals. MDMA is a rapid and pronounced decrease in brainlevels o f 5-hydroxytryptam ine (5-H T) and 5-hydroxy-J Partly as result of the recem interest in MDMA, nu- indoleacetic acid (5-HIAA). This effect is thought tomerous investigators have begun to explore the neu-

rochemical effects of MDMA. During the past 3 years, result from the massive release of 5-HT from presyn-iB over 80 publications on MDMA have appeared in the aptic vesicles. Reductions in brain hydroxyindole con-scientific literature. The following review attempts to centrations ofgreater than 80% by 3 h after injectionofMDMAhavebeenreportedSchmidtetal.,1986provide a brief summary of recent data on the neu-o_ rochemistry and neurotoxicity of MDMA and its de- 1987; Stone et al., 1986, 1987b; Schmidt, 1987b). Res-ivatives, toration ofbrain concentrationsof hydroxyindolesoAdministration of MDMA to animals elicits a char- control levels after a single acute dose of MDMA is_q acteristic biphasic response which, for convenience of rapid, usually occurring within 24 h post injection

_; discussion, can be categorized into acute and long-term (Schmidt, 1987b; Stone et al., 1987b; Schmidt and[ effects. Some of the acute effects of MDMA appear to Taylor, 1989).be related more directly to its behaviora l and psycho-l _ logical effects, whereas the long-term effects have been TPH activityl'yJt_ correlated with the development of serotonergic neu- The reduction in brain 5-HT and 5-HIAA is accom-rotoxicity. It should be noted, however, that the acute panied by a marked reduction in TPH activity. and long-term effects cannot be considered in isolation Whereas the hydroxyindoles are restored to controlfrom one another. Some of the effects, e.g., reduction values within 24 h after a single injection of MDMA.s_ in tryptophan hydroxylase (TPH) activity, manifest TPH activity remains significantly reduced in the stria-r-'/_ Address correspondence and reprint requests to Dr. S. J. Peroutka hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine; MDA, 3,4-at Department of Neurology, Stanford University School of Medicine, methylenedioxyamphetamine; MDE, 3,4-methylenedioxy-N-ethyl-! Stanford, CA 94305, U,S.A. amphetamine; MDMA, 3,4-methylenedioxymethamphetamine; NE.

Abbreviations used: AMT, a-methyl-p-tyrosine; DA_, dopamine; norepinephrine; PCA, p-chloroamphetamine; TH, tyrosine hydrox-DOM, 2,5-dimethoxy4-methylphenylisopropylamine; 5-H1AA, 5- ylase; TPH, tryptophan hydroxylase.

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3,4.METHYLENEDIOXYMETHAMPHETAMINE 15

O_.__NHR' results partly from the ability of the drug to modulate1_ _ 5-HT release and uptake. Differential effects of the ste-reoisomersofMDA,MDMA,and someof their ana-logues on both release and uptake of [3H]5-HT and

R R' [3H]DAhavebeen noted (Nicholsetal., 1982;Johnsonet al., 1986; Schmidt, 1987a; Schmidt et at., 1987;MDMA CH3 CH3 Steele et al., 1987). With respect to release from syn-MDA CH3 H aptosomes(Nicholsetal., 1982)orsuperfusedbrainslices (Johnson et al., 1986; Schmidt et al., 1987),MDE CH3 CH2CH3 MDMA and its analogues are more potent releasers ofBDB CH2CH3 H [3H]5-HT than of [3H]DA. Stereospecific effects onMBDB CH2CH 3 CH3 [3H]5-HT release are generally not apparent, but dif-ferential effects on DA release have been noted. For

FIG. 1. MDMA and its analogues.BDB, 1-(1,3-benzodioxol-f-yl)- example, Johnson et al. (1986) reported that racemic2-butanamine;MBDB,N-methyl-l-(1,3-benzod{oxol-S-yl)-2-butan- MDA induced a significantly greater effect than racemicamine;MOA,3,4-methylenedioxyamphetamine; MDE, 3,4-methyl- MDMA, but no differences were found between S(+)-enedioxy-N-ethylamphetamine;DMA,3,4-methylenedioxymeth- MDA and S(+)-MDMA, or between R(-)-MDA andamphetamine, R(-)-MDMA. These investigators speculated that thes, existenceofcompetitivemechanismsfortheRandStum, hippocampus, and cortex for 2 weeks or longer enantiomers of MDMA would account for these re-

(Schmidt and Taylor, 1987; Stone et al., 1987b). This suits. Ethylation of the side-chain nitrogen with ethyl- effect apparently is not due to direct inhibition of the to give the analogue 3,4-methylenedioxy-N-ethylam-enzyme, because MDMA exhibits no effect on TPH phetamine (MDE) results in a lowered potency for. activity in vitro (Schmidt and Taylor, 1987). The Vms, [3H]DA release compared to MDA and MDMA, butf ofTPH is reduced by 50% in treated animals, whereas all three drugs are still potent releasers of [3H]5-HT

the affinity for either of its substrates, tryptophan (Schmidt, 1987a). Pretreatment with the selective DAor the hydroxylase cofactor, 6-methyl-5,6,7,8-tetra- uptake inhibitor amfonelic acid or with the selectivehydopterine, is unchanged (Schmidt and Taylor, 1987, 5-HT uptake inhibitor, citalopram, blocks the MDMA-1989). Simultaneous administration of the 5-HT up- induced release of [3H]DA or [3H]5-HT in vitro.take inhibitor, citalopram, with MDMA completely Methamphetamine and p-chloroamphetamine (PCA)prevents the acute depletion of cortical hydroxyindoles, are significantly more potent releasers of [3H]DA thanbut only slightly attenuates the reduction in cortical MDMA, but MDMA and PCA are equipment and sig-f TPH activity. However, fluoxetine, given 3 h post nificantly more potent than methamphetamine asMDMA does facilitate the recovery of TPH activity [3H]5-HT releasers (Schmidt et al., 1987).

- levels to control values within I week (Schmidt and The effects of the enantiomers of MDMA and itsTaylor, 1987, 1989). analogues on the synaptosomal uptake of 3H-mono-- amines (5-HT, DA, and NE) have been compared withChanges in dopamine and other monoamines those of the isomers of amphetamine and the hallu-In contrast to the rapid and marked reductions in cinogenic phenylisopropylamine, 2,5-dimethoxy-4-

, 5-HT and its metabolite, 5-HIAA, similar changes in methylphenylisopropylamine (DOM) (Steele et al.,levels or turnover ofdopamine (DA) or norepinephrine 1987). Both enantiomers of MDA and MDMA po-(NE) in response to acute treatment with MDMA haves not been observed. Schmidt et al. (1986) reported aslight, but significant, rise in neostriatal concentrations TABLE 1. Summary of the neurochemicaleffects of MDMAin DA and its metabolite, homovanillic acid, at 3 hfollowing administration of MDMA. Levels of dihy- Acuteeffects(36h)elicits a dose-dependent release of DA in the nucleus Persistentslowdecreasein 5-HT and 5-HIAAfollowingnitialaccumbens and caudate of awake-behaving rats, mca- recovery

- sured by in vivo voltammetry and HPLC. DepressedTPHactivitypersistsDecrease in 5-HT terminal densityl- Effects on neurotransmitter release and uptake Marked species variations (mice < rats < primates), Changes are prevented by 5-HT uptake blockersThe acute effects observed on brain monoamines Slowrecovery(i.e. , months) of someparametersand their metabolites following treatment with MDMA

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_ 16 D. J. McKENNA AND $. J. PEROUTKA-_ tently inhibited the uptake of [3H]5-HT, but only the TABLE 2. MDMA interactionswith--_ S(+) enantiomers inhibited [3H]DA uptake. By con- neurotransmitterreceptorstrast, both enantiomers of amphetamine were more Neurotransmitter _ v_ potent inhibitors of [3H]DA uptake compared to that bindingsite Radioligand (gf [3H]5-HT. Th e stereoisomers of th e M DMA-related

compounds and amphetamine were equipotent inhib- Serotonergictors of [3H]NE uptake into hypothalamic synapto- Uptake [3H]Paroxetine 0.6somes. Neither isomer of DOM inhibited synaptosomal 5-HT2A [7?BrlDOB 1.5[ uptake of any of the monoamines examined. 5-HT_A [3H]8-OH-DPAT 10 +Both Schmidt et al. (1987) and Wang et al. (1987) 5-HTm [3H]5-HT 10 +

E found little evidence for carder-mediated uptake of 5-HT2 [_HlSpiperone 20 _[3H]MDMA into synaptosomes, suggesting that Adrene_,ic

'-_ MDMA probably enters the neuron by passive mech- tl 2 [3H]Aminoclonidine 3.6 +anisms where it causes the displacement and release of t_ [3H]Dihydroalprenolol 19 +al [_H]Prazosin 20 +c,x_ monoamines; this release, however, is carrier-mediated/" and blocked by uptake inhibitors. DopamineL D2 {3H]Spiperone 95 +_ Receptor interactions D, [3HISCH23990 150+It is presently unclear whether the psychoactive, as MuscariniccholinergicM_ [3H](-)-QNB 5.8 +opposed to the neurotoxic, effects of MDMA and its M2 [3H](-)-QNB 15_glil congeners result from the presynaptic release of 5-HT_ from serotonergic terminals, or from interactions with Opioidt9 postsynaptic target receptors, particularly 5-HT recep- _' [3H]Dihydromorphine >5tors. Nichols (1986) has argued in favor ofa presynaptic b [3HlD-Ala,D-Leu-enkephalin >5K [3HlEthylketazocine > 5[' mechanism, based on the fact that the S(+) enantiomer

ofMDMA ismore potent than the R(-) enantiomer, Othersites/_ which is the opposite of what would be expected if a HistamineH_ [3H]Mepyramine 6 -+Benzodiazepine 13H]Flunitrazepam >50postsynaptic interaction similar to that involving DOM CRF _2_I-CRF >5,q4 or other 5-HT2-selective hallucinogens were respon- Ca:+ channels [3HlNitrendipine >5,_" sible for the psychotropic effects. Conceivably, thenique psychotropic effectsofMDMA may result from Dataare derived from Pierce and Peroutka (1988) and Bat

a combination of pre- and postsynaptic actions. A et al. (1988a). CRF, corticotropin releasing factor; DOB, 2,5-dthoxy-4-bromophenylisopropylamine; 8-OH-DPAT, 8-hydroxy-2umber of investigators have examined the receptor n-propylamino)tetralin; QNB, quinuclidinyl benzilate.

selectivities and affinities of MDMA and its derivatives *These are I_ovalues in human cortex; KD values for these rusing radioligand binding assays (see summary in Ta- ligandshavenot beendeterminedin human tissue.ble 2).13 Lyon and co-workers (1986) examined the affinities, ofracemic MDA and MDMA and their optical isomers lng site labeled by R(-)-2,5-dimethoxy-4-[77Br]bromo-[ at 5-HT2, 5-HTr, and DA D2 sites. None of the deriv- phenylisopropylamine (Pierce and Peroutka, 19tives showed significant affinity for the DA D2 site. MDA displayed moderate (< 10 taM) affinity for th4 The most potent compound was R(-)-MDMA at the HT_A, 5-HTm, and a2-adrenergic sites. Affinity-HT2 site labeled with [3H]ketanserin (3.3 taM), al- MDA and the other derivatives was greater than,_ though this compound was slightly less potent (4.2 _1_/) tam at all other sites measured.

at 5-HT_ sites labeled by [3H]5-HT. Racemic MDMA Gehlert and co-workers (1985) reported the spec[ and S(+)-MDMA were less potent at both sites. The binding of [3H]MDMA to rat cortical membranes, wpotency of MDA and its stereoisomers was comparable an apparent KD of 99 nM and Bm_ of 30 fmol/mgl_ to that of MDMA at both sites, protein. These findings were questioned, however,Battaglia et al. (1988a) screened racemic MDMA at Wang et al. (1987) who reported on "specific" bind. a variety ofneurotransmitter recognition sites and up- of [3H]MDMA to glass fiber filters in the absence

take sites. MDMA showed the highest affinity overall brain membranes. The artifactual binding yielded for the [3H]paroxetine-labeled 5-HT uptake site (0.61 parent Kt>and B_ values similar to those determinet_ taM), followed by the a2-adrenergic receptor (3.6 taM), in the presence of membrane homogenates and

the 5-HT2 receptor (5.1 taM), the histamine H_ receptor played a distinct pharmacological profile, with ri[ Mz receptor (5.8 #M). substituted amphetamines and 5-HI uptake inhibit(5.7 taM), an d th e muscarinicThe potency at all other sites examined was 10 tzM or displacing apparent specific binding with the grea'_q greater, potency. Pretreatment of the glass fiber filters with 0

Pierce and Peroutka (1988) reported that racemic polyethylenimine completely eliminated "specifi,q.x MDA, MDMA, and MDE displayed highest affinity [3H]MDMA binding in both the presence and abseni (approximately I /_M) for the putative 5-HT2A bind- ofbrain tissue.

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3,4-METHYLENEDIOXYMETHAMPHETAMINE 17Neuroendocrine responses tential neurotoxicity of MDMA and its analogues.Nash et al. (1988) reported that intraperitoneal ad- Schmidt and Taylor (1987) found that cortical TPHministration of MDMA resulted in a rapid elevation activity remained significantly depressed as long as 7of serum corticosterone and prolactin levels, and sig- days after injection of MDMA. These authors specu-nificantly elevated body temperature. Both the eleva- lated that the relatively long period required for recov-tion ofcorticosterone levels and the hyperthermia were ery of TPH activity ind icated an irreversible inacti-5 blocked by the 5-HT2 antagonists, ketanserin and vation of the enzyme, requiring synthesis of new en-' mianserin, but not by 5-HTr^ antagonists or nonse- zyme for full restoration ofactivity. Stone et al. (1987b)lective 5-HT antagonists. These data suggest that reported significant and long-term reductions of TPHMDMA induces hyperthermia and corticosterone se- activity in the neostriatum, hippocampus, and hypo-cretion via a 5-HT2 receptor-mediated mechanism (ei- thalamus, as well as the cortex.th er d irect o r ind irect). Th e effect o n pro lactin secre-1 tion, however, appears to be mediated by a 5-HT re- 5-HT uptake site densityceptor different from both the 5-HTr^ and 5-HT2 In addition to long-term changes in neurochemicalreceptors. Evidence that the effect is mediated via a 5- parameters, M DMA also causes pronounced reduc-HT receptor was provided by the fact that prior depletions in the density of 5-HT uptake sites and histolog-tion of 5-HT by p-chlorophenylalanine abolished the ical changes in the distribution and density of seroto-effectof MDMA on prolactin secretion. None of the nergic nerve fibers. Both of these parameters are in-5-HT antagonists blocked the M DMA-induced ele- dicative ofa neurodegenerative process. Battaglia et al.vation of prolactin, indicating that neither the 5-HTr^ (1987) reported a 50-75% reduction in the density ofnor the 5-HT2 receptor mediated the response. In a [3H]paroxetine-labeled 5-HT uptake sites in the cortex,separate study , M erchant et al. (1 98 7) reported that h ippocampus, striatum, hypothalamus, and midbrainmultiple doses of MDA, MDMA, and methamphet- at 2weeks following repeated systemic administrationamine significantly elevated neurotensin-like immu- of MDMA and MDA. Scatchard analyses ofthese datanoreactivity 18h after treatment in the substantia nigra, indicated a significant reduction in the Bmax values instria tum, and nucleus accumbens of rat brain , the treated an imals with no significant altera tion in theKDvalues. In a subsequent study, in vitro autoradi-LONG-TERM EFFECTS ography with [3H]paroxetine was used to determinefurther the neuroanatomical localization of MDA-in-Brain 5-HT and 5-HIAA levels duced lesions (De Souza and Kuyatt, 1987). They re-Long-term reductions in brain levels of 5-HT and ported greater than 70% reductions in [3H]paroxetinelia 5-HIAA induced by M DM A can be read ily quantifiede- binding in the frontal cortex, pyriform cortex, and ol-di- with HPLC and areamong the indices ofneurotoxicity factory tubercles. Similar observations have been madethat have received the most attention . Long-term de- when the reduction in synaptosomal uptake of [3H]5-- pletions of 5-HT and its metabolite by MDMA were HT in MDMA-treated animals is used as a means offirst reported by Schmidt eta l. (1986), and Ricaurte et quantifying the reduction of 5-HT uptake sites (Ri-al. (1985)had noted a similar action of MDA. In sub- caurte et al., 1 98 5; Commins et al., 1 98 7; Schmidt,sequent studies (Schmidt, 1987b; Schmidt et al., 1987), 1987b).S(+)-MDMA was significantly more potent than R(-)-. MDMA in producing long-term 5-HT depletion, but Histopathology- the reverse relationship was found for the acute deple-f tion. Since these initial reports, other investigators have A variety of histological techniques have been usedconfirmed that MDMA can induce significant, long- to visualize the neurodegenerative changes induced byM DMA. Commins et al. (1 98 7) and Ricaurte et al.term, and regionally specific reductions in 5-HT and (1985) utilized the Fink-Heimer staining method toc 5-HIAA, which in some instances can persist for Up to12 months following repeated administration (Mokler localize degenerating nerve terminals in the striatumand somatosensory cortex of rats following acute or 'f et al., 1987; Stone et al., 1987b; Battaglia etal., 1988b). chronic treatments with MDA or MDMA. O'Hearny Both Mokler et al. (1987) and Stone et al. (1987b) re- and co-workers (1988) utilized 5-HT specific immu-g ported that serotonergic neurons in the frontal cortex, nocytochemistry to document the extensive loss of 5-

f hippocampus, and striatum weremore sensitiveto the HT axons 2weeksafter systemictreatment withMDA- effect ofMDMA than those in the hypothalamus. Theyd suggested that the h igher density o f fibers of passage or MDMA. They reported a selective vulnerability of- and cell bodies in the hypothalamus might account for 5-HT axon terminals originating primarily in the dorsalraph e nucleus, wh ereas beaded ax ons h aving large var-- its reduced sensitivity.rs icositiesndoriginatingrimarilynthemedianapheest TPH activity nucleiwerelargelyspared.Preterminalaxons,fibersofLong-term depression of TPH activity typically ac- passage, and raphe cell bodies were not damaged (Mol-c" companies the reduction in brain hydroxyindoles fol- liver, 1987;O'Hearn et al., 1988). Wilson et al. (1989)e lowing MDMA. Most investigators regard this as an reported a similar differential vulnerability to MDMA

additional biochemical marker indicative of the po- of dorsal raphe 5-HT axons in the macaque monkey.J. Neurochem., Vol. 54, No. 1, 1990


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18 D. J. McKENNA AND S. J. PEROUTKA

q'_ FACTORS GOVERNING THE rats and mice to single and multiple injections of_ DEVELOPMENT OF NEUROTOXICITY MDMA. They reported that although a single 10 mg/kg dose in rats produced both an acute and long-termDosage and treatment regimen depression of TPH activity, 5-HT, and 5-HIAA, similarlong-term effects were not observed in mice after a sin-oth the acute and long-term neurochemical effects

of MDMA are influenced by the dosage used and by gte 15 mg/kg dose. Brain hydroxyindoles and TPH ac-he treatment regimen (i.e., whether single or multiple tivity were significantly reduced, however, in micedoses are administered). The acute neurochemical el- given multiple injections of MDMA (6 X 15 mg/kg).fects of MDMA (cf. Table 1) can result from a single These authors attributed the greater sensitivity of ratsdose of approximately 5-10 mg/kg (Schmidt and Tay- to metabolic differences between the two species. In

[ lor, 1987; Battaglia et al., 1988b). By contrast, long- rats, the primary metabolic route is via ring para-hy-erm serotonergic deficits develop in response to either droxylafion, which could be impaired due to the pres-a single administration of a comparatively large dose(20 rog/kg) or repeated, frequent administration of ence of the methylenedioxy substituent. In mice, how-ever, side-chain deam ination and ring hydroxy lation

4 smaller doses (8 5 mg/kg) (Battaglia et al., 1988b, metabolic and thus thear e equally important routes,r 1989). Therefore, the degree of MDMA-induced neu- drug could be eliminated more quickly from brain. In_. rotoxicity is a cumulative, dose-related phenomenon, a similar study, Peroutka (1988) measured the acuteand long-term effects of single (1, 3, 10, or 30 mg/kg)_ Route of administration and multiple (8 1, 3, 10, or 30 mg/kg) injections of

Oral ingestion is the most common route of admin- MDMA in mice using [3H]paroxetine to label 5-HTi istration used by human consumers of MDMA. Ani- uptake sites. No significant changes in either the KD or,_ mai studies, by contrast, routinely employ subcuta- Bmr, values of [3H]paroxetine binding compared toneous or in trape ritoneal in jections. D ifferen tial effects contro ls were found w ith any of the dose regimens used.o' of the route of administration on MDMA-mediated By contrast, rats administered a single injection ofneurotoxicity have been examined by several investi- MDMA (30 mg/kg) showed a 44% reduction in B_,ators (Finnegan et al., 1988; Ricaurte et al., 1988a; with respect to controls, with no change in KD. These

q% Slikker et al., 1988). Finnegan et al. (1988) found no r esul ts d emonst ra te d that mice ar e relatively insensitivesignificant difference in the dose-dependent reduction to the neurotoxic effects of MDMA.4 in 5-HT concentrations in rats administered MDMA Primates are even more sensitive to MDMA than

orally compared to rats treated subcutaneously. Ri- rats, by both the oral and subcutaneous routes of ad-caurte et al. (1988a), however, reported that in the ministration (Ricaurte et al., 1988a; Slikker et al.,squirrel monkey, oral administration of multiple doses 1988). In one important study, Ricaurte and co-work-of MDMA (8 5 mg/kg)was approximately one-third ers (1988b) measured 60% lower levels of the 5'HTto one-half as effective as subcutaneous administration, metabolite 5-HIAA in CSF of squirrel monkeys treatedIn additional experiments, multiple oral doses pro- with toxic doses of MDMA (8 5 mg/kg). Brain levelsuced significant reductions in 5-HT levels in all brain of 5-HT and 5-HIAA in the same animals were 94 toregions, but single oral doses resulted in significant re- 73% lower than the saline controls. These results in-3 ductions only in the hypothalamus and thalamus, dicate that the quantitative assay of CSF5 -HIAA levels

[ Slikker et al. (I 988)assessed long-term neurochemical in human users of MDMA might be used as a diag-nd histological changes in the rat given large oral doses nostic tool to assess serotonergic damage.of MDMA. Histological studies show a 90% increase4 in silver-stained terminals (indicative of terminal de- Stereochemical and structure/activity parameters, generation) at 18 h after a single 40 mg/kg dose of Stereochemical and structural parameters appear to,xl, MDMA, and a 105% increase after a single 80 mg/kg be important determinants of neurotoxicity forose. In the same study, these workers reported sig- MDMA and its analogues. Schmidt (1987a) observed[ nificant (70-80%) reductions in 5-HT and 5-HIAA that both isomers of MDA produced long-term deple-

levels in the frontal cortex and hippocampus after tions of cortical 5-HT. However, the same study re-l_ multiple oral doses of MDMA (8 40 or 8 80 mg/ ported that although racemic MDA, MDMA, andi _ kg over 4 days). Nonsignificant reductions were also MDE all caused acute depletion of cortical 5-HT, onlydetected in the caudate nucleus, racemic MDA and MDMA caused a long-term deple-t' tion of 5-HT and loss of 5-HT uptake sites. Schmidtta Species differences (1987b) demonstrated that both enantiomers of

Mammalian species 'vary in their sensitivity to the MDMA caused an acute depletion of cortical 5-HT,[' neurotoxic effects of MDMA. Differential species sen- but only S(+)-MDMA resulted in significant depletions

sitivity has been noted in rats, guinea pigs, mice, rhesus of 5-HT and 5-HT uptake sites 7 days after injection,monkeys, and squirrel monkeys (Stone et al., 1987c, Johnson et al. (1988b) reported that the S(+) isomers_,,_ Battaglia et al., 1988b; Finnegan et al., 1988; Peroutka, of both MDA and MDMA were more potent than theq-_ 1988; Ricaurte et al., 1988a; Slikker et al., 1988). Stone R(-) isomers in depleting 5-HT and 5-HIAA and in_, and co-workers (1987c) compared the sensitivities of depressing TPH activity in cortex, hippocampus, and

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J

3,4-METHYLENEDIOXYMETHAMPHETAMINE 19f neostriatum, in rats killed 18 h following multiple raphe system represents one possible mode of recovery.treatments (5 X 3.5, 5, or 10 mg/kg, s.c.). On the other hand, MDMA is toxic to the terminals

Several independent studies (Johnson et al., 1987; of 5-HT neurons while sparing the cell bodies, so re-r Ricaurte et al., 1987; Stone et al., 1987a)haveprovided generation of the terminal from the affected neuronsevidence that MDE, the N-ethyl congener of MDMA, is also possible.- is significantly less toxic in terms of its effects on long-term markers for neurotoxicity. The acute effects of Prevention of neurotoxieity

. MDE are similar to those of MDMA and include tran- Both the acute and long-term neurochemical deficitssient reductions of 5-HT, 5-HIAA, and TPH (Johnson produced by MDMA or MDA can be blocked corn-et al., 1987; Stone et al., 1987a). However, recovery pletely by co-administration of a selective 5-HT uptake- from MDE appears to be more rapid than with blocker, such as fluoxetine or citalopram (Schmidt,- MDMA, because neurochemical parameters in MDE- 1987b; Schmidt and Taylor, 1987; Schmidt et al.,- treated animals are not significantly different from 1987). For example, rats given a single dose of fluox-those in control animals at 1-2 weeks following treat- etine (5 mg/kg) at 3 or 6 h after MDMA displayed ament (Stone et al., 1987a). Ricaurte et al. (1987) found reduction in the depletion of cortical 5-HT levelsmea-that approximately fourfold higher doses of MDE than sured 7 days later (Schmidt, 1987b). Fluoxetine corn-MDMA are required to produce comparable long-term pletely antagonized 5-HT depletion in animals treated) depletions of 5-HT. 3 h after MDMA. At 6 h after MDMA, 5-HT levels inf Neurotoxicity to monoaminergic systems is also a fluoxetine-treated animals were 72% of controls, andproperty of several other amphetamine derivatives at 12 h, 5-HT values were not different from those ofr (Fuller et al., 1975; Sanders-Bush et al., 1975; Sanders- animals given MDMA alone (39% of controls). This

Bushand Sterenka, 1978;Fuller and Hemrick-Luecke, antagonistic effect of a 5-HT uptake inhibitor on the. 19824Peat et al., 1985; Schmidt et al., 1985). MDMA, long-term 5-HT depletion, even up to 6 h post MDMA,f fenfluramine, and PCA are similar in that their neu- suggests that the neurotoxic action of MDMA mightmtoxic action primari y affects the serotonergic system, involve its extracellular conversion to a toxic metab-whereas methamphetamine and amphetamine neu- olite, which (unlike MDMA itself) has significant af-mtoxicityischaracterized by long-term deficitsin both finity for the 5-HT uptake carrier. Schmidt and Taylor5-HT and DA neuronal systems (Clineschmidt et al., (1987) also found that fluoxetine given 3 h after1978;Peat et al., 1985;Schmidt et al., 1985, 1987; MDMA treatment facilitatedthe recoveryofTPH ac-- Schuster et al., 1986; Kleven et al., 1988; Wagner and tivity; 7 days after treatment, fiuoxetine-treated animals, Peroutka, 1988).As pointed out previously in the sec- given MDMA had recovered 100% of TPH activity,- tion on acute neurochemieal effects , the changes in whereas animals treated on ly with MDMA remainedcatecholaminergic systems caused by MDMA and its at 54% of controls.congeners are transient and relatively slight. No long- Other pharmacological interventions have beens term deficits in DA, NE, and their metabolites or in shown to have attenuating effects on both the acutethe activity of TH following MDMA administration and long-term neurochemical effects of MDMA- have been reported. (Schmidt and Taylor, 1987; Johnson et al., 1988a;

ls Stoneetal.,1988).Forexample,SchmidtndTaylor- Recoveryof the serotonerglc system (I 987)found that co-administration of5-HT2selectiveRelatively few investigations have focused on the antagonists, or the nonspecific 5-HT antagonist me-recovery of the serotonergic system after exposure to tbiothepin, partially blocked MDMA-induced reduc-neurotoxic doses of MDMA. Stone et al. (1987b) re- tions in cortical TPH activity. By contrast, treatmentported that, in rats, striatal TPH, 5-HT, and 5-HIAA with yohimbine, a-methyl-p-tyrosine (AMT), or reser-r remainedsignificantly depressed 110days after expo- pine had no effecton the acute MDMA-induced lossed sureto multipledosesof MDMA.Battagliaet al. ofTPH activity.- (1988b)found a slow regeneration of 5-HT uptake site Stone et al. (1988) investigated the role ofDA in the ,- densitiesover a 12-month period, with aconcomitant acute and long-term serotonergic deficits induced by

recoveryincortical 5-HTlevels.At 6months, theden- MDMA. They foundthat pretreatment withAMT,re-airyof 5-HT uptake sites was only 75% of controls, serpine, or reserpine plus AMT significantly reduced- whereas by 12 months the densities had returned to the acute loss of neostriatal TPH activity with respectt contro l levels . This study d id not determine whether to MDMA alone. Reserpine plus AMT did not affo rdf therecoveryresulted fromregeneration of neurons that any additional protection over reserpine alone. Con-, hadundergone terminal degeneration or from an in- current treatment withAMT and MDMA significantlys creasedcollateral sprouting of neurons unaffected by attenuated the loss of TPH activity in animals killed. thetreatment. MDMA is selectivelyneurotoxic to fine 18hafter treatment. Prior lesioning of the neostriatum5-HT nerve terminals originating in the dorsal raphe with local injections of 6-hydroxydopamine providedaxons, while sparing the varicose terminals originating significant pro tection against loss of neostriatal TPHin the median raphe nuclei (Molliver, 1987; O'Hearn activity at 3 h after MDMA versus sham-lesioned an-et al., 1988), so collateral sprouting from this median imals receiving equivalent doses. TPH activity in the

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20 D. J. McKENNA AND 5'. J. PEROUTKA,q._ frontal cortex and hippocampus, which did not receive (1987) found no evidence of neurotoxicity following' local 6-hydroxydopamine, was still significantly de- systemic administration of the major metabolites oL pressed 3 h after MDMA in both sham-operated and MDA or MDMA (a-methyldopamine, 4-hydroxy-3-

lesioned animals. Prior depletion of DA and other methoxyamphetamine, ot-methylnorepinephrine, andonoamines with reserpine significantly attenuated the a-methylepinephfine).,_ long-term loss of TPH activity. A similar protectiveeffect was found for pretreatment with AMT, which Possible formation of a toxic DA metabolite

protected against loss of TPH activity and also pre- DA has been implicated as a possible mediator o3] vented long-term reductions in 5-HT, but not 5-HIAA. the neurotoxicity produced by both methamphetamine(Schmidt et al., 1985) and MDMA (Stone et al., 1988)GBR 12909, a DA-specific uptake inhibitor, provided Interestingly, selective 5-HT uptake blockers blocka significant protective effect with respect to all threeparameters. The authors speculated that their results methamphetamine-induced changes in the serotonergic

_ implied a role for endogenous DA in mediating system, but do not alter its effects on dopaminergicystems (Hotchkiss and Gibb, 1 98 0 ; Bakhit et al., 1 98 1_ MDMA neurotoxicity. Hekmatpanah et al. (1989), Schmidt and Gibb, 1985). By contrast, MDMA is se

x'xxar' however, reported that prior depletion of central 5-HTand DA with reserpine (5 mg/kg) did not prevent the lectively neurotoxic to the serotonergic system withL decrease in density of 5-HT uptake sites measured by relatively little effect on markers for dopaminergic[3H]paroxetine binding 2 weeks after a single exposure neurotoxicity, such as brain catecholamine levels oTH activity. Nevertheless, MDMA elicits DA release_i to MDMA (30 mg/kg, i.p.), in vitro (Schmidt et al., 1987)and in vivo (Yamamotoi MECHANISMS OF NEUROTOXICITY and Spanos, 1988), and inhibition of DA synthesis bypretreatment with AMT results in a significant atten-'_ Although the serotonergic neurotoxicity of MDMA uation of the neurotoxic effects of MDMA (Stone ec, is now well established, the underlying mechanisms of al., 1988)._[ action remain unknown. Although various theories Gibb and colleagues (1989) have speculated that in-ave been proposed, two major hypotheses have been terruption of the normal route of DA catabolism req/,_ advanced to explain MDMA-induced neurotoxicity, suiting from MDMA-induced blockade ofmonoamine, oxidasecouldresultinhighconcentrationsfextr4 Possible formation of a toxicMDMA metabolite cellular DA adjacent to 5-HT neurons, enhancing the_'i The finding, previously mentioned above, that carrier-mediated uptake of DA, an effect specificallyMDMA-induced neurotoxicity can be specifically blocked by 5-HT uptake inhibitors, such as fluoxetine,[ blocked by 5-HT uptake inhibitors (Schmidt, 1987b) Oxidative processes inside the 5-HT terminal could

illustrates the importance of the 5-HT uptake carrier result in the generation ofcytotoxic metabolites capablein mediating the neurotoxic effects of MDMA. How- of reacting covalently with nucleophilic cell compo-

ever, MDMA itself does not appear to be transported nents, such as enzymes and cell membranes. A similars) directly into 5-HT nerve terminals (Schmidt et al., role for autooxidation products of endogenous DA in1987; Wang et al., 1987). The fact that fluoxetine can the neurotoxicity of amphetamine and methamphet-13 provide significant protective effects up to 6 h post amine has also been proposed (Fuller and Hemrick-

MDMA (Schmidt, 1987b) is evidence that the neuro- Luecke, 1982; Schmidt et al., 1985). The differential%[ toxic agent may be a metabolite of either MDMA or neurotoxicity of MDMA on serotonergic terminalsn endogenous substance. Additional support for the versus dopaminergic terminals could result from factorsexistence ofa neurotoxic metabolite is the finding that such as drug affinity for DA and 5-HT uptake carriers,_" direct intracerebral injection of MDMA yielded no ev- drug metabolism and half-life in brain, and the inherent._xS idence of a neurotoxic response, whereas systemic ad-inistration produces the long-term serotonergic del- metabolic differences which exist between catechol-x',' amineand5-HTneurons(Hillarpetal.,1966).Agaiq

icits associated with neurotOxicity (Molliver et al.,1986). the DA theory of MDMA-induced neurotoxicity is thefact that 5-HT terminal damage can be observed_ Schmidt (1987b) speculated that demethylation of throughout the central nervous system, whereas DAthe side-chain nitrogen followed by intramolecular cy- systems are essentially localized to the basal ganglia.._lt clization could result in formation of an indolic 5-HT and mesolimbic system.neurotoxinstructurallyelatedto5,6-dihydroxytryp-

tamine. However, the possibility that N-demethylation CONCLUSIONSt_ of MDMA to its more neurotoxic congener MDAmight constitute an intermediate step in the formation MDMA causes an acute, but reversible, depletion

_ { of a neurotoxic metabolite was rendered unlikely by of 5-HT, an effect which may account for its psycho-Schmidt and Taylor (1987), who established that pre- logical effects. In addition, MDMA and some of it_'_ treatment with the selective N-demethylase inhibitor, derivatives have long-term effects on the nervous sys,! piperonyl butoxide, had no effect on the acute depletion tem which are indicative ofserotonergic neurotoxicity:,,_ of cortical 5-HT or on suppression of TPH activity long-term depletions of 5-HT, 5-HIAA, and TPH ac-''_ [ induced by MDMA. In a separate study, Yeh and Hsu tivity; histopathologic changes in 5-HT-containing

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i 3,4-METHYLENEDIOXYMETHAMPHETAMINE 21

nerve terminals; and ablation of 5-HT uptake sites, causes a long-term depletion of serotonin in mt brain. Brainof The neurochemical and neurotoxic properties of Res. 447, 141-144.uller R. W. and Hemrick-Luecke S. K. (1982) Further studies onMDMA and its derivatives are similar in many respects the long-term depletion of striatal dopamine in iprindole-treatedto those of other neurotoxic amphetamine derivatives, rats by amphetamine. Neuropharmacology 21, 433--438.such as methamphetamine, PeA, and fenfluramine, Fuller R. W., Perry K. W., and Molloy B.B . (1975) Reversible andand it is likely that common mechanisms mediate both irreversible phases of serotonin depletion by 4-chloroamphet-the acute and long-term actions of some or all of these amine. Eur. J. Pharmacol. 33, i 1 9-124.G eh lert D . R ., Sch mid t C . J., W u L., an d L ove nbe rg W . (1 98 5) Ev-

of agents. Although enantiomers and structural analogues idencefor specificmethylenedioxymethamphetamine (ecstasy)e of MDMA exhibit clear differences in neurotoxic po- binding sites inthe rat brain. Eur. J. Pharmacol. 119, 135-136.tential, a complete understanding of the structural de- Gibb J. W., Stone D. M., Johnson M., and Hanson J. R. (1989)k terminants of neurotoxicity within the methylene- Neurochemical effects of MDMA, in MDMA: "Ecstasy" and/orHumanNeurotoxin(Peroutka S.J., ed),pp. 133-150. Kluweric dioxyamphetamines is still lacking. AcademicPublishers,Norwell,Massachusetts.The possible clinical significance of the neurotoxic Greer G. and Toibert R. (1986) Subjective reports of the effects of1; potential of MDMA in human users of the drug re- MDMA in a clinical setting. J. PsychoactiveDrugs 18, 319-328.e- mains unknown. The difficulty in extrapolating the Hekmatpanah C. R., McKenna D. J., and Peroutka S.J. (1989) Re-h data derived in laboratory animals to humans is corn- serpine does not prevent 3,4-methylenedioxymethamphetamine-induced neurotoxicity. Neurosci. Lett. (in press).

pounded by the lack of a reliable clinical index ofhu- Hillarp N.-A., Fuxe K., and Dahlstrom A. B. (1966) Demonstrationor man serotonergic function and the lack of a readily and mapping of central neurons containing dopamine, nor-e recognizable pathological syndrome resulting from se- adrenaline, and 5-hydroxytryptamine and their reactions to

rotonergic deficits. It is hoped that significant progress psychopharmaca. Pharmacol. Rev. 18, 727-741.Hotchkiss A. and Gibb J. W. (1980) Long-term effects of multipleby on both of these fronts: will be achieved in the near d os es o f m etbam ph etam in e o n try pto ph an h yd ro xy la se an d ty -future. In the meantime, MDMA and its congeners rosine hydroxylase activity in rat brain. J.Pharmacol.Exp. Ther.et co_titute useful tools for the neurochemist and po- 214, 257-262.tenfial health hazards of uncertain proportions for their Johnson M. P., Hoffman A. L, and Nichols D. E.0986) Effectsofin- human users, the enantiomers of MDA, MDMA, and related analogues on

re- [aH]serotonin and [3H]dopamine release from superfused ratbrain slices.Eur. J. Pharmacol. 132,269-276.a- REFERENCES Johnson M., Hanson G. R., and Gibb J. W. (1987) Effects of N-ethyl-3,4-methylenedioxyamphetamine (MDE) on central se-e BakhitC ., Morgan M. E., and Gibb J. W. (1981) Long-term effects rotonergic and dopaminergic systems of the rat. Biochem. Phar-

of methamphetamine on the synthesis and metabolism of 5- macol. 36, 4085--4093.hydroxytryptamine in various regions of the rat brain. Neuro- Johnson M., Hanson G. R., and Oibb I. W. (1988a) Effects ofd 'pharmacology 20, 1135- I 140. paminergic and serotonevgicreceptor blockade on neurochemicald BattagliaG., Yeh S. Y., O'Hearn E., Molliver M. E., Kuhar M.J.," changes induced by acute administration ofmethamphetaminee and De Souza E. B. (1987) 3,4-Methylenedioxymethamphet- and 3,4-methylenedioxymethamphetamine. Neuropharrnacology- amine and 3,4-methylenedioxyamphetamine destroy serotonin 27, 1089-1096.terminals in rat brain: quantification of neurodegeneration by Johnson M., Letter A. A., Merchant K., Hanson G. R., and Gibbmeasurement of [3H]paroxetine-labeled serotonin uptake sites. J.W. (1988b) Effects of 3,4-methylenedioxyamphetamine andin J. Pharrnacol.Exp. Ther. 242, 911-916. 3,4-methylenedioxymethampbetamine isomers on central sero-t- Battaglia G., Brooks B. P., Kulsakdinun C., and De Souza E.B. tonergic, dopaminergic and nigral neurotensin systems of the- (1988a) Pharmacologic profile ofMDMA (3,4-methylenedioxy- rat. J. Pharmacol. Exp. Ther.244, 977-982.l methamphetamine) at various brain recognition sites. Eur. J. Kleven M. S., Schuster C. R., and Seiden L. S. (1988) Effect of de-PharmacoL 149, 159-163. pletion of brain serotonin by repeated fenfluramine on neuro-BattagliaG., Yeh S. Y., and DeSouza E. B.(1988b) MDMA-induced chemical and anorectic effects of acute fenfiuramine. J. Phar-

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ylenedioxymethamphetamine (MDMA) cause selectiveablation methamphetamine: a potentially neurotoxic amphetamineof serotonergic axon terminals in forebrain: immunocytochem- alogue. Eur. J. Pharmacol. 124, i75-178.q4[ ical evidence for neurotoxicity. J. Neurosci. 8, 2788-2803. Schmidt C. J., Levin J. A., and Lovenberg W. (1987) In vitroandPeat M. A., Warren P. F., Bakhit C., and Gibb J. W. (1985) The vivoneurochemical effects ofmethylenedioxymethamphetamin

%X' acute effects ofmethamphetamine, amphetamine and p-chloro- on striatal monoaminergic systems in the rat brain. Biocheamphetamine on the cortical serotonergic system ofthe rat brain: Pharmacol. 36, 747-755.evidence fordifferences in the effects of methamphetamine and Schuster C. R., Lewis M., and Seiden L. S. (1986) Fenfluramiamphetamine. Eur. J. Pharmacol. 116, 11-16. neurotoxicity. Psychopharmacol.Bull. 22, 148- !51.

: Peroutka S.J. (1987) Incidence ofrecreational useof 3,4-methylene- Slikker W., Ali S. F., ScalletA.C., FrithC. H., Newport G. D., a'_ dioxymethamphetamine (MDMA, "Ecstasy") on an under- Bailey J. R. (1988) Neurochemical and neurohistological algraduate campus. N. Eng. J.Med. 317, 1542-1543. ations in the rat and monkey produced by orally administer

PeroutkaS. J. (1988)Relative insensitivity ofmice to 3,4-mcthylene- methylenedioxymethamphetamine (MDMA). Toxicol. Apdioxymethamphetamine neurotoxicity. Res. Commun. Subs. Pharmacol. 94, 448--457.Abuse 9, 193-206. Steele T. D., Nichols D. E., and Yim G. K. W. (1987)StereochemiPierce P. A. and Peroutka S.J. (1988) Ring-substituted amphetamine effects of 3,4-methylenedioxymethamphetamine (MDMA) ainteractions with neurotransmitter receptor binding sites in hu- related amphetamine derivatives on inhibition of uptake of [3man cortex. Neurosci. Lett. 95, 208-212. monoamines into synaptosomes from different regions ofr Pierce P. A. and Peroutka S. J. (1989)Evidence for distinct 5- brain. Biochem. Pharmacol. 36,2297-2303.

hydroxytryptamine: binding site subtypes incortical membrane Stone D. M., Stahl D. C., Hanson G. R., and Gibb J. W. (1986) Tpreparations. J. Neurochem 52, 656-658. effects of 3,4-methylenedioxymethamphetamine (MDMA) a_ Ricaurte G., Bryan G., Strauss L, Soiden L, and Schuster C. (1985) 3,4-methylenedioxyamphetamine (MDA) on monoaminevgnerveHallucingeniCterminals.amphetaminescience29,selectivelY986_988,estroys brain serotonin StoneSyStemsD..,injohnsontheat brain.M.,ansonEUr'.G.Pharmacl'R.,nd Gibb128,.4IW.--48.

: Ricaurte G. A., Finnigan K. F., Nichols D. E., DeLanney L. E., Irwin A comparison of the neurotoxic potential of methylenediox-[ I., and Langston J. W. (1987) 3,4-Methylenedioxyethylamphet- amphetamine (MDA) and itsN-methylated and N-ethylatedamine (MDE), a novel analogue of MDMA, produces long-last- rivatives. Eur. J. Pharmacol. 134,245-248.ing depletion of serotonin in the rat brain. Eur. J. Pharmacol. StoneD .M., Merchant K. M., Hanson G. R., and Gibb J. W. (198

265-268. Immediate and long-term effects of 3,4.methylenedioxymet37 ,Ricaurte G. A., DeLanney L.E., Irwin I., and Langston J. W. (19881) amphetamine on serotonin pathways in brain of rat. Neu_ Toxic effect ofMDMA on central serotonergic neurons in the pharmacology 26, 1677-1683.primate: importance of route and frequency of drug adminis- Stone D. M., Hanson G. R., and Gibb J. W. (1987c) Differencestration. BrainRes. 4146,165-168. the central serotonergic effects of methylenedioxymethamphe

B Ricaurte G. A., DeLanney L. E., Weiner S. G., Irwin 1., and Langston amine (MDMA) in mice and rats.Neuropharmacology26, 16t J.W. (1988b) 5-Hydroxyindoleacetic acid in cerebrospinal fluid 1661.f reflects serotonergic damage induced by 3,4-methylenedioxy- Stone D. M., Johnson M., Hanson G. R., and Gibb J. W. (19methamphetamine inCNS of non-human primates. BrainRes. Role of endogenous dopamine in the central serotonergicdefiIn 474, 359-363. induced by 3,4-methylenedioxymethamphetamine. J. Ph

Sanders-Bush E. and Sterenka L. R. (1978) Immediate and long- macol. Exp. Ther.247, 79-87.term effects ofp-chloroamphetamine on brain amines. Ann.NY Wagner J. A. and Peroutka S. J. (1988) Comparative neurotoxic' Acad. Sci. 305, 208-221. of fenfiuramine and 3,4-methylenedioxymethamphetaminSanders-Bush E., Bushing J. A., and Sulser F. (1975)Long-term effects (MDMA). Soc. Neurosci. Abst. 14, 327.a ng S . S ., R ica urte G . A ., a nd P ero utka S . J . (1 98 7 ) [3H ]-3,4 -M et[. of p-chloroamphetamine and related drugs on central seroto- ylenedioxymethamphetamine (MDMA)interactions with brnergic mechanism. J. Pharmacol. Exp. Ther. 192, 33-41. membranes and glass fiber filter paper. Eur. J. PharmacoJ. 1Schmidt C.J. (19871) Acute administration of methylenedioxyam- 439-443.phetamine: comparison with the neurochemical effects ofits N- W ilson M . A ., Ricaurte G . A ., and M olliver M . E. (1 98 9) D istidesmethyi and N-ethyl analogues. Eur. J. Pharmacol. 136, 81- morphologic classes of serotonergic axons in primates exh

_, 88. differential vulnerability to the psychotropic drug 3,4-methSchmidt C.J. (1987b)Neurotoxicity of the psychedelic amphetamine, enedioxymethamphetamine. Neuroscience 28, 121-137.r' methylenedioxYmethamphetamine. J. Pharmacol. Exp. Ther. Yamamoto B.K. and SpanosL. J. (1988) The acute effects o f me240,1-7. ylenedioxymethamphetaminendopamineeleasentheawSchmidt C. J. and Gibb 1.W. (1985) Role of the dopamine uptake behaving rat. Eur. J. Pharmacol. 148, 195-203.

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