Plants - Drugs Mind - Spirit Freedom - Law Arts - Culture Library  
Donations MATCHED in September
Contribute $20 or more during our annual support-a-thon
and your donation will be DOUBLED.
Help spread accurate info about psychoactive substances!
E for Ecstasy
by Nicholas Saunders

[ Appendix 4 sec. 3 ] [ Index ] [ Appendix 4 sec. 5 ]

Appendix 4: Bibliography in vitro studies

Azmitia, E.C., Murphy, R.B. and Whitaker-Azmitia, P.M. MDMA (Ecstasy) Effects on Cultured Serotonergic Neurons: Evidence for Ca 2+ -Dependent Toxicity Linked to Release. Brain Research 510 97-103 (1990).

The relationship of MDMA with serotonin neurons, and with calcium cation release has been determined in the fetal cells of newborn rats. Long-term serotonin changes are blocked by 5-HT re-uptake blockers, and the interactions between MDMA and caffeine have been reported. It has been suggested that Ca cation release may play a role in MDMA toxicity.

Battaglia, G., Brooks,B.P., Kulsakdinum, C. and De Souza, E.B. Pharmacologic Profile of MDMA 3,4-Methylenedioxymeth-amphetamine at Various Brain Recognition Sites. Eur.J.Pharmacol. 149 159-163 (1988).

The affinity of MDMA for various neurotransmitter receptor and uptake sites was studied in vivo, using competition with various radioligands. Comparisons with MDA, MDE, amphetamine and methamphetamine are reported.

Berger, U.V., Gu, X.F. and Azmitia, E.C. The Substituted Amphetamines 3,4-Methylenedioxymethamphetamine, Methamphetamine, p-Chloroamphetamine and Fenfluramine Induce 5-Hydroxytryptamine Release via a Common Mechanism Blocked by Fluoxetine and Cocaine. Eur. J. Pharmacol. 215 153-60 (1992).

An in vitro assay has been used to compare several drugs for their ability to induce synaptosomal serotonin release. Para-chloroamphetamine and fenfluramine were equally effective, MDMA less so, and methamphetamine very much less so still. Evidence is presented that the serotonin release produced by these drugs employs a common mechanism.

Bradberry, C.W., Sprouse, J.S., Aghajanian, G.K. and Roth, R.H. 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Release of Endogenous Serotonin from the Rat Dorsal Raphe Nucleus in vitro: Effects of Fluoxetine and Tryptophan. Neurochem. Int. 17 509-513 (1990).

Brain slices of the dorsal raphe nucleus were exposed to a medium containing MDMA and the released serotonin was measured. A serotonin transport inhibitor (Fluoxetine) reduced the amount released, whereas the addition of tryptophan increased the amount released.

Bradberry, C.W., Sprouse, J.S., Sheldon, P.W., Aghajanian, G.K. and Roth, R.H. In Vitro Microdialysis: A Novel Technique for Stimulated Neurotransmitter Release Measurements. J. Neuroscience Methods. 36 85-90 (1991).

A novel technique allowing measurement of neurotransmitter release and single unit recordings from brain slices is described. The effects of MDMA on slices of dorsal raphe nucleus and frontal cortex were used to demonstrate it.

Brady, J.F., Di Stephano, E.W. and Cho, A.K. Spectral and Inhibitory Interactions of (+/-)-3,4-Methylenedioxyamphetamine (MDA) and (+/-)-3,4-Methylenedioxymethamphetamine (MDMA) with Rat Hepatic Microsomes. Life Sciences 39 1457-1464 (1986).

Both MDA and MDMA were shown to form complexes with cytochrome P-450 that were inhibitory to its function as to demethylation of benzphetamine and carbon monoxide binding. Liver microsome studies showed the metabolic demethylation of MDMA and the N-hydroxylation of MDA.

Frye, G. and Matthews, R. Effect of 3,4-Methylenedioxymethamphetamine (MDMA) on Contractive Responses in the G. Pig Ileum. The Pharmacologist 28 149 (1986).

Using the longitudinal muscle of the guinea pig ilium, MDMA evoked dose-related, transient contractions, but failed to reduce contractions produced by serotonin, acetylcholine, or GABA. The MDMA contractions were blocked by atropine, and do not appear to involve serotonin receptors.

Gehlert, D.R., Schmidt, C.J., Wu, L. and Lovenberg, W. Evidence for Specific Methylenedioxymethamphet-amine (Ecstasy) Binding Sites in the Rat Brain. Europ. J. Pharmacol. 119 135-136 (1985).

Evidence is presented from binding to rat brain homogenate studies. The use of the serotoninergic re-uptake inhibitor, active in vivo ,does not antagonize this binding, nor in studies with uptake into striatal microsomes.

Levin, J.A., Schmidt, C.J. and Lovenberg, W. Release of [3H]-Monoamines from Superfused Rat Striatal Slices by Methylenedioxymethamphetamine (MDMA). Fed. Proc. 45 1059 (#5265) April 13-18, 1986.

The release of tritiated serotonin and dopamine from superfused rat striatal slices was observed for three amphetamine derivatives. MDMA and p-chloroamphetamine were equivalent, and about 10x the potency of methamphet amine. This last compound was, however, some 10x more effective than MDMA in the release of dopamine.

Lyon, R.A., Glennon, R.A. and Titeler, M. 3,4-Methylenedioxymethamphetamine (MDMA): Stereoselective Interactions at Brain 5- HT1 and 5-HT2 Receptors. Psychopharmacology 88 525-526 (1986).

Both MDMA and MDA, and their respective optical isomers, were assayed as to their affinity at radio-labelled serotonin (5-HT1 and 5-HT2) and dopamine (D2) binding sites. The "R" isomers of both drugs showed a moderate affinity at the 5-HT2 receptor (labelled with 3H ketanserin), and the "S" isomers were lower. Affinities for the 5-HT1 site were similar, but that for D2 sites were very low. Since the "S" isomer of MDMA is the more potent in man, it may not work primarily through a direct interaction at 5-HT receptors.

Nichols, D.E., Lloyd, D.H., Hoffman, A.J., Nichols, M.B. and Yim, G.K.W. Effects of Certain Hallucinogenic Amphetamine Analogues on the Release of [3H] Serotonin from Rat Brain Synaptosomes. J. Med. Chem. 25 530-535 (1982).

The optically active isomers of MDMA (as well as those for MDA, PMA and the corresponding phentermine analogs) have been evaluated as to their effect on the release of serotonin from rat brain synaptosomes. The (+) isomer of MDMA was the more effective (this is the active isomer in humans) suggesting that serotonin release may play some role in the psychopharmacological activity. The alpha-alpha dimethyl homologues were inactive even at the highest concentrations studied.

Rempel, N.L., Callaway, C.W. and Geyer, M.A. Serotonin-1B Receptor Activation Mimics Behavioral Effects of Presynaptic Serotonin Release. Neuropsychopharm. 8 201-11 (1993).

The locomotor hyperactivity induced by MDMA in rats appears to be due to the drug-induced release of presynaptic serotonin. It appers to act as indirect serotonin agonist, acting probably at the 5-HT1B receptor.

Ricaurte, G.A., Markowska, A.L., Wenk, G.L., Hatzidimitriou, G., Wlos, J. and Olton, D.S. 3,4-Methylenedioxymethamphetamine, Serotonin, and Memory. J. Pharmacol. Exptl. Therap. 266 1097-1105 (1993).

A series of behavioral studies in the rat were conducted to assay the effect of serotonin neuron lesions on memory. MDMA was used for selective reduction of serotonin, and 5,7-dihydroxytryptamine for more extensive nerve damage than can be achieved with MDMA. The MDMA treated rats had no impairment of memory, but the more extensively damaged animals (involving both serotonin and norepinephrine systems) showed a disruption of recently aquired memory.

Robinson, T.E., Castaneda, E. and Whishaw, I.Q. Effects of Cortical Serotonin Depletion Induced by 3,4-Methylenedioxymethamphetamine (MDMA) on Behavior, Before and After Additional Cholinergic Blockade. Neuropsychopharmacology 8 77-85 (1993).

Studies in rats describe the effects of MDMA on a number of behavioral tests. The serotonergic denervation that resulted is not sufficient to produce marked and lasting behavioral deficits.

Romano, A.G. and Harvey, J.A. MDMA Enhances Associative and Nonassociative Learning in the Rabbit. Pharmacol. Biochem. Behav. 47 289-93 (1994).

Conditioned response studies in rabbits have shown that MDMA, like MDA, enhances the learning process. The effects seen are not known for other psychedelic drugs, and may be unique to this chemical class.

Rudnick, G., Wall, S.C. The Molecular Mechanism of "Ecstasy" [3,4-Methylenedioxymethamphetamine(MDMA)]: Serotonin Transporters are Targets for MDMA-Induced Serotonin Release. Proc. Natl. Acad. Sci USA, 89 1817-1821 (1992)

The mechanisms of MDMA action at serotonin transporters from plasma membranes and secretory vesicles isolated from human platelets have been studied and are reported.

Rudnick, G., and Wall, S. Non-Neurotoxic Amphetamine Derivatives Release Serotonin through Serotonin Transporters. Molecular Pharmacology, in press (1992).

MDMA was compared to MMA (3-methoxy-4-methylamphetamine) and MMAI ( both non-neurotoxic analogues) as to their effects on several serotonin and dopamine properties in in vitro studies.

Schuldiner, S., Steiner-Mordoch, S., Yelin, R., Wall, S.C. and Rudnick, G. Amphetamine Derivatives Interact with Both Plasma Membrane and Secretory Vesicle Biogenic Amine Transporters. Mol. Pharmacol. 44 1227-31 (1993).

The interaction of fenfluramine, MDMA and p-chloroamphetamine (PCA) with brain transporter systems have been studied. The mechanisms of inhibition are discussed.

Steele, T.P., Nichols, D.E. and Yim, G.K.W. Stereoselective Effects of MDMA on Inhibition of Monoamine Uptake. Fed. Proc. 45 1059 (# 5262) April 13-18 1986.

In the investigation of the optical isomeric difference of activities seen for amphetamine, MDMA, and DOM (the more potent isomers being the "S", "S" and "R" resp.) their abilities to inhibit the uptake of radio-labelled monoamines into synaptosomes were studied. The findings are discussed, and it is concluded that MDMA exhibits stereoselective effects similar to those of amphetamine on monoamine uptake inhibition, a parameter that is unrelated to the mechanism of action of the hallucinogen DOM.

Steele, T.D., Nichols, D.E. and Yim, G.K.W. Stereochemical Effects of 3,4-Methylenedioxymethamphetamine (MDMA) and Related Amphetamine Derivatives on Inhibition of Uptake of [3H]Monoamines into Synaptosomes from Different Regions of Rat Brain. Biochem. Pharmacol. 36 2297-2303 (1987).

MDA, MDMA, and the alpha-ethyl homologue MBDB were found to inhibit serotonin uptake in brain synaptosomes. The conclusions to a broad series of studies were that MDMA and its homologues are more closely related to amphetamine than to DOM in their biochemical actions.

Wang, S.S., Ricaurte, G.A. and Peroutka, S.J. [3H]3,4 Methylenedioxymethamphetamine (MDMA) Interactions with Brain Membranes and Glass Fiber Filter Paper. Europ. J. Pharmacol. 138 439-443 (1987).

Tritiated MDMA appears to give a pharmacological "binding profile" in rat brain homogionate studies, even in the absence of brain tissue. This appears to result from an unexpected binding of the radioligand to glass filter paper. Pretreatment with polyethylenimine eliminated this artifact.