MDMA (N-methyl-3,4-methylenedioxyamphetamine) and its stereoisomers: Similarities and differences in behavioral effects in an automated activity apparatus in mice

Abstract

Racemic MDMA (0.3-30 mg/kg), S(+)-MDMA (0.3-30 mg/kg), R(-)-MDMA (0.3-50 mg/kg) and saline vehicle (10 ml/kg) were comprehensively evaluated in fully automated and computer-integrated activity chambers, which were designed for mice, and provided a detailed analysis of the frequency, location, and/or duration of 18 different activities. The results indicated that MDMA and its isomers produced stimulation of motor actions, with S(+)-MDMA and (+/-)-MDMA usually being more potent than R(-)-MDMA in measures such as movement (time, distance, velocity), margin distance, rotation (clockwise and counterclockwise), and retraced activities. Interestingly, racemic MDMA appeared to exert a greater than expected potency and/or an enhanced effect on measures such as movement episodes, center actions (entries and distance), clockwise rotations, and jumps; actions that might be explained by additive or synergistic (i.e. potentiation) effects of the stereoisomers. In other measures, the enantiomers displayed different effects: S(+)-MDMA produced a preference to induce counterclockwise (versus clockwise) rotations, and each isomer exerted a different profile of effect on vertical activities and jumps. Furthermore, each isomer of MDMA appeared to attenuate the effect of its opposite enantiomer on some behaviors; antagonism effects that were surmised from a lack of expected activities by racemic MDMA. S(+)-MDMA (but not R(-)-MDMA), for example, produced an increase in vertical entries (rearing) and a preference to increase counterclockwise (versus clockwise) rotations; (+/-)-MDMA also should have induced such effects but did not. Apparently, R(-)-MDMA, when combined with S(+)-MDMA to form (+/-)-MDMA, prevented the appearance of those increases (from control) in activities. Similarly, R(-)-MDMA (but not S(+)-MDMA) produced increases in episodes (i.e. jumps) and vertical distance that racemic MDMA also should have, but were not, exhibited. Evidently, the presence of S(+)-MDMA in the racemic mixture inhibited the appearance of those increases (from control) in behavior. Taken together, the various and complex effects of MDMA and its stereoisomers are noted and a strategy is suggested for future studies that stresses the importance of steric effects and interplay, probable interaction(s) with various neurotransmitters, and interaction(s) with the particular behavioral or biological event (or action) being measured.

Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms

“…However, evidence exists that the effects of MDMA are stereospecific, as indicated by the finding that S(+)-MDMA induces motor activation more efficiently than R(−)-MDMA (Young and Glennon, 2008). Moreover, it has been reported that S(+)-MDMA elevates body temperature, while R(−)-MDMA does not (Fantegrossi et al, 2003).…”

Current problems of in vivo developmental neurotoxicity tests and a new in vivo approach focusing on each step of the developing central nervous system

“…Some chemicals such as azocytidine (Battino et al. ), ethylenethiourea (Young and Glennon ), 5‐fluorouracil (Kuwagata et al. ; Chaturvedi et al.…”

“…The usefulness of fetal brain observation needs to be verified using these chemicals. Some chemicals such as azocytidine (Battino et al 1992), ethylenethiourea (Young and Glennon 2008), 5-fluorouracil Chaturvedi et al 2006), hydroxyurea (Woo et al 2006), thalidomide (Narita et al 2002), toluene (Gospe and Zhou 1998), propylthiouracil (Dowling et al 2001), and methanol (Rogers and Mole 1997) are already known to induce DNT, as detected by fetal brain observation. There are some agendas for cerebellar study and for detection of delayed neurotoxicity by fetal brain observation.…”

Ethylenedioxy homologs of N -methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its corresponding cathinone analog methylenedioxymethcathinone: Interactions with transporters for serotonin, dopamine, and norepinephrine

“…For example, MDMA ( 1 ) is considered an “ empathogen ” to distinguish its subjective effects in humans from those of classical phenylalkylamine hallucinogens and phenylalkylamine central stimulants [5] – even though MDMA, and its individual optical isomers, display some degree of stimulant character [e.g. 6]. MDMA’s actions are associated with its non-selective neurotransmitter releasing effects at the membrane transporters for 5-HT, dopamine, and norepinephrine (i.e., SERT, DAT, and NET, respectively) [7,8].…”