Pharmacological characterization of 3,4-methylenedioxymethamphetamine analogues: Corollaries to mechanisms of behavioral and neurotoxic activity

Michael Parvin Johnson, Purdue University

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) has been a popular drug both for scientific research and as a drug of abuse. Many anecdotal reports have suggested that MDMA and MDMA-like drugs may be useful as adjuncts to psychotherapy. However, reports from animal studies suggest MDMA is a selective serotonin neurotoxin after single or multiple high doses. This project describes studies with a number of analogues of substituted amphetamines. The project had three parts. First, to identify MDMA-like compounds that retained the behavioral activity of MDMA but had decreased ability to induce a neurotoxic response. This was accomplished by screening analogues for behavioral activity in a two lever drug discrimination assay, and by examining serotonergic markers after high doses of the analogues. In this way, several MDMA-like drugs were identified with decreased neurotoxic liability, including 3,4-methylenedioxy-2-aminoindan (MDAI) and 5-methoxy-6-methyl-2-aminoindan (MMAI). The second phase of this project involved characterizing the pharmacological activity of this series of amphetamine analogues and comparing this to their behavioral and neurotoxic activity. In this phase, a correlation was found between the ability of the test drugs to release serotonin and their behavioral activity. Also, a correlation was noted between the ability of the test drugs to alter the dopaminergic system and induce neurotoxicity. The final phase attempted to test the involvement of dopamine in the serotonin neurotoxicity by inducing a neurotoxic response with dopaminergic agents in combination with otherwise non-neurotoxic MDMA-analogues, such as MDAI and MMAI. Of the agents and drug regimens examined, it was found that the catecholamine releaser, S-amphetamine in combination with either MDAI or MMAI using a subacute dosing regimen resulted in a neurotoxic response, while none of the treatments alone resulted in this toxic response. Therefore, these results suggest that dopamine and more specifically dopamine release is involved in the serotonin neurotoxicity of MDMA-like drugs. Furthermore, these data support the hypothesis that serotonin release is important in the behavioral effects of MDMA-like drugs. But most significantly, this project proves that it is possible to completely separate the behavioral and the neurotoxic activity of some substituted amphetamines.

Degree

Ph.D.

Advisors

Nichols, Purdue University.

Subject Area

Pharmacology|Neurology|Toxicology

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