Abstract

Recently, 3, 4-methylenedioxymethamphetamine (MDMA) became popular as a recreational substance of abuse and was subsequently placed into Schedule I of the Controlled Substances Act. Although MDMA is structurally related to the hallucinogenic amphetamines, it may possess novel psychoactive properties. In view of MDMA's recreational popularity, and its potentially novel pharmacological properties, it is important to understand how MDMA works. This proposal describes a comprehensive program to: 1. study the behavioral properties of MDMA and related compounds, in the drug discrimination paradigm in rats, and to compare MDMA with other, known psychoactive phenethylamine derivatives in this model, 2. to study the biochemical pharmacology of MDMA and related compounds for an effect on monoamines neurotransmitter function in rat brain synaptosomes, with particular emphasis on comparison of neurotransmitter uptake and release mechanisms, 3. to measure the binding affinity of 3H-labeled enantiomers of MDMA and its alpha-ethyl congener MBDB, and to generate displacement curves with a variety of neurochemicals to fully characterize MDMA binding sites, and 4. to synthesize a series of structurally-related compounds, and to assay their pharmacology. These studies will provide further elucidation of the mechanism of action of MDMA and related compounds, and will define the structure-activity relationships wherein compounds with an MDMA-like effect are likely to be found.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004758-03
Application #
3210455
Study Section
Special Emphasis Panel (SRCD (25))
Project Start
1988-08-01
Project End
1991-09-29
Budget Start
1990-08-01
Budget End
1991-09-29
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
Purdue University
Department
Type
Schools of Pharmacy
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907

  Publications

Selken, Jennifer; Nichols, David E (2007) Alpha1-adrenergic receptors mediate the locomotor response to systemic administration of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) in rats. Pharmacol Biochem Behav 86:622-30
Kanthasamy, A; Sprague, J E; Shotwell, J R et al. (2002) Unilateral infusion of a dopamine transporter antisense into the substantia nigra protects against MDMA-induced serotonergic deficits in the ipsilateral striatum. Neuroscience 114:917-24
Sprague, J E; Worst, T J; Haynes, K et al. (2001) The pharmacodynamic characterization of an antisense oligonucleotide against monoamine oxidase-B (MAO-B) in rat brain striatal tissue. Cell Mol Neurobiol 21:53-64
Sprague, J E; Everman, S L; Nichols, D E (1998) An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine. Neurotoxicology 19:427-41
Parker, M A; Marona-Lewicka, D; Kurrasch, D et al. (1998) Synthesis and pharmacological evaluation of ring-methylated derivatives of 3,4-(methylenedioxy)amphetamine (MDA). J Med Chem 41:1001-5
Marona-Lewicka, D; Nichols, D E (1998) Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents. Psychopharmacology (Berl) 138:67-75
Cozzi, N V; Frescas, S; Marona-Lewicka, D et al. (1998) Indan analogs of fenfluramine and norfenfluramine have reduced neurotoxic potential. Pharmacol Biochem Behav 59:709-15
Marona-Lewicka, D; Nichols, D E (1997) 5-HT2A/2C receptor agonists potentiate the discriminative cue of (+)-amphetamine in the rat. Neuropharmacology 36:1471-5
Marona-Lewicka, D; Rhee, G S; Sprague, J E et al. (1996) Reinforcing effects of certain serotonin-releasing amphetamine derivatives. Pharmacol Biochem Behav 53:99-105
Sprague, J E; Nichols, D E (1995) The monoamine oxidase-B inhibitor L-deprenyl protects against 3,4-methylenedioxymethamphetamine-induced lipid peroxidation and long-term serotonergic deficits. J Pharmacol Exp Ther 273:667-73

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