Perspectives in Pharmacology 3,4-Methylenedioxymethamphetamine (MDMA) as a Unique Model of Serotonin Receptor Function and Serotonin- Dopamine Interactions

(1)-3,4-Methylenedioxymethamphetamine (MDMA; “ecstasy”; “X”; “E”) is a popular recreational amphetamine analog that produces a unique set of effects in humans and animals. MDMA use is often associated with dance parties called “raves”, but its use has increased in all segments of society and around the world. Like amphetamine, MDMA elicits hyperactivity when administered to rodents. Unlike amphetamine, which has effects mediated by the release of dopamine (DA) from nerve terminals, MDMA-induced hyperactivity is thought to be dependent upon the release of 5-hydroxtryptamine (5HT). However, MDMA elicits large increases in synaptic concentrations of both DA and 5-HT, and the interaction between these neurotransmitters may account for the unique characteristics of the drug. Comparisons between MDMA, the selective DA releaser amphetamine, and the selective 5-HT releaser fenfluramine are used in the present discussion to highlight the ability of MDMA to model the locomotor activation induced by the interaction of DA and 5-HT. Furthermore, this review summarizes evidence to suggest that the influence of 5-HT receptors on behavioral function is dependent upon the specific neurochemical environment evoked by a given drug, specifically discussed here with regard to the interaction between 5-HT and DA systems. 3,4-Methylenedioxymethamphetamine (MDMA; “ecstasy”; “X”; “E”) is an increasingly popular recreational drug in the U.S.A. and abroad. Use of MDMA in teens and young adults occurs commonly in the context of “rave” parties, and the frequency of acute MDMA poisonings (malignant hyperthermia, organ failure, coma, and death) (Fineschi et al., 1999) has been linked to drug use under conditions of dehydration, high temperature, and the extensive strenuous dancing typically experienced at raves (Fineschi et al., 1999). In addition to this systemic toxicity, exposure to MDMA damages the terminals of serotonin (5-hydroxytryptamine; 5-HT) neurons resulting in neurotoxicity in animals (Schmidt and Kehne, 1987) and possibly humans with repeated recreational abuse (McCann et al., 2000). The positive subjective effects of MDMA that presumably account for its popularity include feelings of mental stimulation, emotional warmth, closeness and empathy for others, a general sense of well being, and decreased anxiety (Vollenweider et al., 1998). Enhanced sensory perception is an additional hallmark of the “high” associated with MDMA use (Vollenweider et al., 1998); this profile is dissimilar to that evoked by the chemically similar psychostimulant amphetamine and the hallucinogen mescaline. The mode of action for MDMA is based upon its ability to bind to the transporters for 5-HT, dopamine (DA), and norepinephrine (Slikker et The work was supported in part by the National Institute on Drug Abuse Grants DA 006511, DA 00260, and DA 07287. This review was presented by M.G.B. in partial fulfillment of the requirements for the Ph.D. degree to the Graduate School of Biomedical Sciences at the University of Texas Medical Branch. We apologize to those scientists whose research in the areas of 5-HT and MDMA neuropharmacology was not referenced due to the citation limits. ABBREVIATIONS: (1)-MDMA, (1)-3,4-methylenedioxymethamphetamine; 5-HT, 5-hydroxytryptamine; DA, dopamine; DOI, (6)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; GR 127935, [29-methyl-49-(5-methyl-(1,2,4)oxadiazol-3-yl)-biphenyl-4-carboxylic acid (4-methoxy-3-(4methyl-piperazin-1-yl)-phenyl-amide); M100907, [R-(1)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol]; NAc, nucleus accumbens; RU 24969, [5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole]; SB 206553, [N-3-pyridinyl-3,5-dihydro-5-methylbenzo(1,2-b: 4,5-b9)dipyrrole-1(2H) carboxamide]; VTA, ventral tegmental area; SERT, 5-HT transporter; DAT, DA transporter; R, receptor(s); SN, substantia nigra; GABA, g-aminobutyric acid; MCPP, m-chlorophenylpiperazine 0022-3565/01/2973-846–852$3.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 297, No. 3 Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics 900022/904895 JPET 297:846–852, 2001 Printed in U.S.A. 846 at A PE T Jornals on O cber 7, 2017 jpet.asjournals.org D ow nladed from al., 1989), resulting in the release of monoamine neurotransmitters via reversal of the transporter (Rudnick and Wall, 1992). However, while enhanced DA neurotransmission is thought to predominantly mediate the behavioral effects of amphetamine, a unique contribution of 5-HT has been proposed to underlie the neuropsychopharmacology of MDMA (Callaway et al., 1991; McCreary et al., 1999). Thus, the goal of this review is to summarize data supporting the role of specific 5-HT receptors in mediating the in vivo effects of MDMA and to critically analyze the role for 5-HT-DA interactions in the behavioral effects of MDMA. Furthermore, this review will highlight evidence to suggest that the neurochemical environment produced by MDMA provides a unique model of the link between neurotransmitter function and behavior, specifically targeting the interaction between 5-HT and DA. Finally, this review will represent the authors’ perspective that the 5-HT system is dynamic and may function in starkly different ways, depending upon the neurochemical environment in the brain. The literature discussed in this review covers doses of MDMA ranging from “low” [3 mg/kg (1)-MDMA, the more potent isomer] to “high” [20 mg/kg (6)-MDMA]. The contrast between low and high doses provides evidence that differing doses of MDMA elicit unique effects. Because neuropharmacological studies of the reinforcing and discriminative stimulus effects of MDMA are limited, we focus here on the better-described effects of MDMA on locomotor activity. To appreciate the distinctive aspects of MDMA, we compare MDMA with its congeners, the DA releaser amphetamine and the 5-HT releaser fenfluramine. These studies indicate that 5-HT plays an intricate role in the behavioral effects of MDMA dependent on the tone of DA neurotransmission. Furthermore, 5-HT receptors appear to function in a manner that is unique to the neurophysiological environment elicited by MDMA, setting the stage for its distinctive set of emotional, psychological, and perceptual sequelae and unique pattern of abuse. MDMA as a Psychostimulant The drug-induced behavioral syndrome associated with MDMA differs from that evoked by either amphetamine or fenfluramine. Both MDMA and amphetamine robustly increase locomotor activity in rodents (Gold et al., 1989; Gold and Koob, 1989), but the pattern of activity evoked by the two drugs is qualitatively different. Amphetamine increases locomotion throughout the activity monitor, while the activity evoked by MDMA is confined predominantly to the periphery of the chamber (Rempel et al., 1993). On the other hand, hypomotility is evoked by fenfluramine in animals naı̈ve to the test environment (Aulakh et al., 1988), and no change in activity levels is seen following fenfluramine administration in animals habituated to the test environment (M. G. Bankson and K. A. Cunningham, submitted). At higher doses, MDMA (7.5 mg/kg (6)-MDMA) (Spanos and Yamamoto, 1989) and amphetamine (Ellinwood and Balster, 1974) can evoke repetitive, stereotypical movements, such as head weaving and sniffing, although the stereotypies evoked by high doses of MDMA more closely resemble components of the “5-HT syndrome”, including flat body posture, lateral head weaving, forepaw treading, and piloerection (Spanos and Yamamoto, 1989). Fenfluramine, as a more selective 5-HT releaser, can evoke most components of the full 5-HT syndrome (e.g., hyperactivity, hyperreactivity, hindlimb abduction, lateral head weaving, reciprocal forepaw treading, rigidity, Straub tail, and tremor) (Trulson and Jacobs, 1976). These distinct effects of MDMA, amphetamine, and fenfluramine are apparently based upon the differential interactions of these drugs with the monoamine substrates underlying these behaviors (see Fig. 1). Upon binding to the monoamine transporters, MDMA binds with highest affinity to the 5-HT transporter (SERT) and inhibits 5-HT reuptake into hippocampal synaptosomes (EC50 5 0.35 6 0.03 mM) more potently than DA uptake into striatal synaptosomes (EC50 5 1.14 6 0.03 mM) (Crespi et al., 1997). On the other hand, amphetamine binds with highest affinity to the DA transporter (DAT) and inhibits DA reuptake into striatal synaptosomes (EC50 5 0.13 6 0.04 mM) more potently than 5-HT reuptake into hippocampal synaptosomes (EC50 5 4.51 6 0.64 mM). Lastly, fenfluramine binds with highest affinity to SERT and is a much more potent inhibitor of 5-HT reuptake (EC50 5 0.90 6 0.40 mM) over DA reuptake (EC50 5 11.2 6 0.1.3) (Crespi et al., 1997). It is important to note, however, that although MDMA has a higher affinity for the 5-HT transporter, there is a greater total efflux of extracellular DA over that seen for 5-HT at behaviorally active doses (White et al., 1996). This may be related to higher basal DA levels in a given brain region or to the potentially higher maximal response of the DA system to MDMA over the 5-HT system (for review, see White et al., 1996). A vast body of literature suggests a significant role for DA in the mediation of the psychomotor stimulation evoked by amphetamine, and neuropharmacological analyses indicate that DA also plays a role in the behavioral effects of MDMA (Gold et al., 1989). However, some unique characteristics of the behavioral effects of MDMA appear to be related to preferential release of 5-HT from nerve terminals (Callaway et al., 1990). Thus, the focus of this review will be to use a comparison of MDMA, fenfluramine, and amphetamine to illustrate that the combination of 5-HT and DA release elicited by MDMA produces a unique behavioral response. More specifically, we will focus on the changing nature of the role of 5-HT1 receptors (5-HT1R) and 5-HT2 receptors (5-HR2R) in mediating the behaviors associated with these drugs. Serotonin released from terminals by MDMA will expose seven classes of 5-HT receptors and 14 distinct 5-HT receptor subtypes (Barnes and Sharp, 1999) to the endogenous ligand. The 5-HT1 receptor (5-HT1AR, 5-HT1BR, 5-HT1DR, 5-HT1ER, and 5-HT1FR) exhibits high affinity for 5-HT, is generally negatively linked to adenylyl cyclase activity, and causes induction of membrane hyperpolarization (Barnes and Sharp, 1999). The 5-HT2R (5-HT2AR, 5-HT2BR, and 5-HT2CR) exhibits slightly lower affinity for 5-HT. Stimulation of 5-HT2R evokes a depolarization of the cell membrane via a phospholipase C-mediated activation of the inositol 1,4,5-trisphosphate/diacylglycerol pathway; a 5-HT2R-mediated stimulation of the arachidonic acid cascade via phospholipase A2 has also been identified (Barnes and Sharp, 1999). Although the other 5-HT receptors (i.e., 5-HT3R, 5-HT4R, 5-HT5AR, 5-HT6R, and 5-HT7R) may be important in the effects of MDMA and other psychostimulants, the present review focuses on the role of 5-HT1BR, 5-HT2AR, and 5-HT2CR in mediating the behavioral effects of MDMA. Serotonin neurons innervate DA nigrostriatal and mesoMDMA as a Model of 5-HT Function 847 at A PE T Jornals on O cber 7, 2017 jpet.asjournals.org D ow nladed from