Behavioral and pharmacological characterization of 3,4-methylenedioxymethamphetamine, its enantiomers, and related compounds.

Abstract

3,4-methylenedioxymethamphetamine (MDMA) is a widespread drug of abuse worldwide, and has been argued to represent a new pharmacological class, known as the <italic>entactogens</italic>, that is distinct from both the psychomotor stimulants and the traditional hallucinogens. Racemic MDMA and its stereoisomers maintained contingent responding in rhesus monkeys, but did so less effectively than both cocaine and methamphetamme. MDMA-maintained behavior, was suppressed by 5-HT₂ antagonists at doses that did not alter responding for cocaine. Racemic 3,4-methylenedioxyamphetamine (MDA) and its S(+) enantiomer were also effective reinforcers in rhesus monkeys, but R(-)-MDA and racemic N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB) had only transient reinforcing effects in some animals, similar to those observed with the indolealkylamine hallucinogens N,N-dimethyltryptamine (DMT) and psilocybin as well as the phenylisopropylamine hallucinogen mescaline. Responding for MDMA and its enantiomers gradually decreased over a period of approximately 18 months of intermittent access, although response rates for contingent cocaine were unaltered. Quantification of vesicular monoamine transporters (VMAT) via positron emission tomography (PET) using [<super> 11</super>C]dihydrotetrabenazine (DTBZ) did not uncover any differences between monkeys with a history of MDMA self-administration and their controls. However, determination of levels of brain monoamines and their major metabolites using reverse phase high pressure liquid chromatography (HPLC) revealed depletions of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) throughout the brain, and more profound depletions of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) in several discrete brain regions. MDMA and its enantiomers produced aggregate toxicity in mice. This effect was attenuated by ketanserin, MDL100907, the serotonin selective reuptake inhibitor fluoxetine, and by lowering of the ambient temperature, although there was significant stereoselectivity in all cases. Racemic and S(+)-MDMA dose-dependently induced hyperthermia at sublethal doses, but R(-)-MDMA did not increase core temperature at any dose. All forms of MDMA produced locomotor stimulation: racemic MDMA was more effective than S(+)-MDMA, and R(-)-MDMA was least effective. Pretreatments of ketanserin, MDL10097, or fluoxetine attenuated both the hyperthermic and locomotor stimulant effects of racemic MDMA, had no effect of S(+)-MDMA-induced hyperthermia, and potentiated the locomotor stimulant effects of S(+)-MDMA.