This Conference was held at the Natcher Auditorium on the NIH Campus, July 19-20, 2001.
Significance of Serotonin Receptors in the Behavioral Effects of
(+)-3,4-Methylenedioxymethamphetamine [(+)-MDMA, Ecstasy]
M.J. Bubar, D.V. Herin, M.G. Bankson, E.J. Shank, S. Liu, K.A. Cunningham
Department of Pharmacology and Toxicology
University of Texas Medical Branch
The rapid rise in abuse of MDMA underscores the importance of understanding its mechanisms of action as a prelude to establishing therapeutic means to control overdose, toxicity, and overt psychological and physiological responsivity to MDMA. MDMA binds to the serotonin (5-HT) transporter (SERT) with high affinity and reverses SERT to result in 5-HT release from nerve terminals; in addition, MDMA is reported to bind to 5-HT2 receptors (5-HT2R). In the current series of experiments, pharmacological ligands specific for 5-HT1BR, 5-HT2AR, and 5-HT2CR were employed to analyze the role of these receptors in the hyperactivity induced by acute or chronic administration of (+)-MDMA. Systemic administration of the 5-HT1BR antagonist GR 127935 and the 5-HT2AR antagonist M100907 effectively suppressed (+)-MDMA-induced activity. Thus, release of 5-HT consequent to (+)-MDMA binding to SERT results in a stimulation of 5-HT1BR and 5-HT2AR to result in hyperactivity. In contrast, the indirect stimulation of 5-HT2CR serves to mask expression of (+)-MDMA-induced hyperactivity as evidenced by the observation that blockade of the 5-HT2CR with SB 206553 or SB 242084 results in a dramatic increase in (+)-MDMA-evoked hypermotive effects. Following repeated, intermittent administration of (+)-MDMA, an enhancement of the acute hyperactive effects of (+)-MDMA was observed (termed "behavioral sensitization"). During withdrawal from this MDMA pretreatment regimen, enhanced hyperactivity and reduced hypomotility were observed upon administration of a 5-HT1BR (RU 24969) or a 5-HT2CR agonist (MK 212), respectively; these data support the hypothesis that chronic (+)-MDMA administration is associated with adaptational modifications in the function of 5-HT1BR and 5-HT2CR. In keeping with these results, withdrawal from a chronic treatment regimen of MK 212 resulted in sensitization to (+)-MDMA-induced hyperactivity, suggesting that adaptation of 5-HT2CR function contributes to the modifications that underlie expression of sensitization. Thus, 5-HT1BR, 5-HT2AR, and 5-HT2CR are important mediators of the acute and chronic effects of MDMA, and the role of these 5-HT receptors indicates a number of directions to pursue in our understanding of the clinical pharmacology of MDMA.
Research was supported by DA 06511, DA 00260, DA 13595, and DA 07287.
Acute Transcriptional Effects of MDMA on the Rat Cortex: Evidence From cDNA Analysis
Jean Lud Cadet, Nathalie Thiriet
Molecular Neuropsychiatry Section
Intramural Research Program
National Institute on Drug Abuse
3,4-Methylenedioxymethamphetamine (MDMA) is an analogue of methamphetamine (METH). It is related to both amphetamines and hallucinogens. METH and MDMA are known toxins with a plethora of acute effects. Both the acute and long-term effects of MDMA appear to involve the production of oxygen-based reactive species since MDMA perturbs the activity of various antioxidant enzymes (Cu/Zn superoxide dismutase, catalase, glutathione peroxidase). Using cDNA array technique, we have further investigated the acute effects of MDMA on the rat cortex. Some of these data will be discussed in view of their support for the possible involvement of multiple systems in the effects of MDMA.
Visual Cortex Activation Using the fMRI Blood Oxygen Level-Dependent (BOLD) Method in Human MDMA (Ecstasy) Users
R.L. Cowan, B. deB. Frederick, E. Haga, M. Rohan, J. Levin, P.F. Renshaw, S.E. Lukas
Brain Imaging Center and Behavioral Psychopharmacology Research Laboratory
Department of Psychiatry
Harvard Medical School
The recreational club drug ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is selectively toxic to the axons arising from the serotonergic dorsal raphe nucleus (DRN) in animals. Human studies using a variety of techniques also indicate that MDMA produces long-lasting alterations in serotonergic function. Because serotonin plays an important role in sensory function, with serotonin axons densely innervating visual cortex, we chose to use the functional magnetic resonance imaging (fMRI) BOLD method to study the effects of prior MDMA use on visual cortical activation during photic stimulation. Studies were performed on a small group of male and female MDMA users and controls using photic stimulation with red and blue light at 8 Hz with echoplanar imaging at 1.5 tesla.
A 3x8 pixel region of right and left visual cortex was analyzed for BOLD signal change in response to red or blue light at a frequency of 8 Hz. Linear regression methods were used to assess the statistical significance of the findings. A small cohort of males (6 MDMA users, 6 controls) and females (10 MDMA users, 5 controls) was studied. MDMA users and controls showed overlap in BOLD signal change in response to photic stimulation. Left-sided activation showed no clear trend in mean BOLD signal change to blue or red light in either males or females. However, right hemisphere mean BOLD signal change showed a nonsignificant trend for decreased activation to blue light in the male and female MDMA users, and right hemisphere activation to red light showed a similar trend for reduced activation in MDMA users, with significant reductions in mean activation in activated pixels for the male group (p<.05). These findings support the possibility that MDMA use can produce impairment in visual cortical activation in response to photic stimuli.
Control subjects and MDMA users reported similar history of at least one use of alcohol and marijuana, but MDMA users were generally heavier users of both substances. Compared with controls, MDMA users also reported more use of other drugs, including cocaine, opiates, amphetamine, sedative-hypnotic, or hallucinogen use. These preliminary data in a small sample that is unequally matched for other polydrug use suggest that MDMA use may lead to altered sensory processing as assayed by fMRI using a photic stimulation paradigm. A much larger sample, controlling for other drug use, duration of abstinence from MDMA, and degree of prior MDMA exposure, is necessary to confirm the specificity of these findings.
MDMA Produces Glycogenolysis and Increases the Extracellular
Concentration of Glucose in the Rat Brain
Altaf S. Darvesh, M.S., Mahalakshmi Shankaran, Ph.D., Gary A. Gudelsky, Ph.D.
College of Pharmacy
University of Cincinnati
Oxidative and/or bioenergetic stress is thought to contribute to the mechanism of neurotoxicity of amphetamine derivatives, e.g., MDMA. In the present study, the effect of MDMA on brain energy regulation was investigated by examining the effect of MDMA on brain glycogen and glucose. A single injection of MDMA (10-40 mg/kg, sc) produced a dose-dependent decrease (40 percent) in brain glycogen, which persisted for at least 1 hour. MDMA (10 and 40 mg/kg, sc) also produced a significant and sustained increase in the extracellular concentration of glucose in the striatum. Subjecting rats to a cool ambient temperature of 17 0C significantly attenuated MDMA-induced hyperthermia and glycogenolysis. Amphetamine analogues, e.g., methamphetamine and parachloroamphetamine, which produce hyperthermia, also produced glycogenolysis, whereas fenfluramine, which does not produce hyperthermia, did not alter brain glycogen content. MDMA-induced glycogenolysis also was prevented by treatment of rats with the 5-HT2 antagonists LY-53,857 (3 mg/kg), desipramine (10 mg/kg), and iprindole (10 mg/kg). LY-53,857 also attenuated the MDMA-induced increase in the extracellular concentration of glucose. These results support the view that MDMA promotes energy dysregulation and that hyperthermia may play an important role in MDMA-induced alterations in cellular energetics.
Research was supported by DA07427.
Discriminative Stimulus Properties of 4-MTA and the Optical Isomers of PMA
Malgorzata Dukat, Ph.D., Richard Young, Ph.D., Richard A. Glennon, Ph.D.
Department of Medicinal Chemistry
Virginia Commonwealth University
1-(4-Methoxyphenyl)-2-aminopropane (PMA) and its sulfur analogue 1-(4-methylthiophenyl)-2-aminopropane (4-MTA) have been misrepresented as the controlled substance analogue MDMA (ecstasy). PMA is a Schedule I substance, and 4-MTA is currently under consideration for scheduling. Little is known about the stimulus properties of these phenylalkylamines. In general, phenylalkylamines with abuse potential can produce one or more of at least three distinct stimulus effects in animals: a stimulant or amphetamine-like effect, a hallucinogenic or DOM-like effect, and a third effect that is typified by N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA). PMMA is the N-methyl analogue of PMA. We previously demonstrated that PMA, but not PMMA, substitutes for (+)amphetamine. In the present investigation, we examined the optical isomers of PMA in PMMA-trained Sprague-Dawley rats. We also prepared 4-MTA and its N-methyl analogue 4-MTMA (i.e., the sulfur counterpart of PMMA) and examined them in rats trained to discriminate S(+)amphetamine (1 mg/kg) and PMMA (1.25 mg/kg) from vehicle. R(-)PMA (ED50 = 0.4 mg/kg) substituted for PMMA (ED50 = 0.4 mg/kg), whereas S(+)PMA produced a maximum of 72 percent PMMA-appropriate responding. 4-MTA (ED50 = 0.3 mg/kg) also substituted for PMMA. The PMMA stimulus failed to substitute for 4-MTMA (maximum 36 percent PMMA-appropriate responding). Administration of 4-MTA and 4-MTMA to (+)amphetamine-trained animals resulted only in partial generalization. Hence, R(-)PMA and 4-MTA are capable of producing PMMA stimulus effects in animals.
Research was supported in part by DA 01642.
Attachment Relationships and MDMA (Ecstasy) Use Among College Students
Carrie A. Elk, Ph.D., LMHC
Up Front Drug Information Center
Advances over the past 15 years indicate that MDMA is popular among college students. The psycho-emotional effects and context of use are described consistently as connectedness, oneness with others, increased empathy and communication, feelings of acceptance, and ease of emotive expression—a place that provides a sense of security, bonding, and attachment.
Advances in the family sciences indicate that Bowlby's Attachment Theory represents one potential familial factor for explaining the initiation of cigarette smoking, polydrug addiction, alcoholism, and opiate addiction. Theoretically, securely attached individuals have the ability to feel close to and supported by others, form satisfying relationships, and therefore are not likely to utilize maladaptive substitutes to satisfy attachment needs. The lack of positive internal working models inhibits the establishment of genuine, meaningful, interdependent relationships resulting in maladaptive strategies to induce a sense of attachment. The less securely attached may be particularly attracted to MDMA's effects of connectedness, bonding, or attachment and use it to satisfy attachment needs, although temporary and artificial.
Two major methodological challenges emerge in the investigation of attachment and MDMA use in college students. This high-functioning sample yields little variability of attachment score (93 percent moderately-highly attached). This contributes to the paucity of information provided by the attachment variable. Further, no standardized interpretive guidelines are available for this instrument, resulting in the inability to compare scores with norms.
If methodological challenges are overcome, attachment could emerge as a key risk/protective factor in the initiation of MDMA use. If so, "attachment work" may be a vital element in the prevention and treatment of MDMA abuse.
MDMA and Its Stereoisomers as Reinforcers in Rhesus Monkeys: Serotonergic Involvement
William Fantegrossi,1 Gail Winger,1 James Woods,1 Thomas Ullrich,2 Kenner Rice2
1University of Michigan
Ann Arbor, MI
2National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a ring-substituted phenethylamine structurally related to both amphetamine and mescaline. While there have been two prior assessments of racemic MDMA in IV self-administration paradigms in primates, the reinforcing effects of the stereoisomers of MDMA have not been previously assessed. In this regard, four adult male rhesus monkeys were tested twice daily in 60-minute FR10TO1min sessions alternately maintained by IV infusions of (+/-)-MDMA, (+)-MDMA, (-)-MDMA, cocaine, methamphetamine, or equivolume saline. Racemic MDMA and both enantiomers generated inverted U-shaped functions across the dose ranges tested, although response rates were generally lower than those engendered by cocaine or methamphetamine. Subsequently, five MDMA-naive adult rhesus monkeys (three male, two female) were tested twice daily in 150-minute FR30TO45sec sessions alternately maintained by four discrete IV doses of cocaine, (+)-MDMA, (-)-MDMA, or equivolume saline, thus allowing rapid dose-effect curve determination. The effects of pretreatments with the 5-HT2 antagonists ketanserin and MDL100907 on MDMA self-administration were then assessed. Neither ketanserin nor MDL100907 pretreatment affected cocaine-maintained responding; however, both antagonists shifted the (+)-MDMA dose-effect curve and completely abolished responding for
(-)-MDMA. Potential serotonergic contributions to MDMA reinforcement will be discussed.
Research was supported by USPHS grants DA-034948 and DA-05923.
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