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.

Fig. 1

Results of (±)-MDMA (X), S(+)-MDMA (closed square), and R(-)-MDMA (open square) on movement time (top), movement distance (middle), velocity (bottom) in mice. Ordinate: Mean (with ± S.E.M.) values were obtained after the intraperitoneal administration of 10 ml/kg of 0.9% saline (i.e. S; N = 24) or doses of each compound (n = 8 mice at each point). Abscissa: Drug doses plotted on a logarithmic scale. An asterisk (*) denotes a dose that produced a statistically significant difference (p ≤ 0.05) in a measure as compared with saline vehicle (S).

Fig. 2

Results of (±)-MDMA (X), S(+)-MDMA (closed square), and R(-)-MDMA (open square) on movement episodes in mice. Ordinate: Mean (with ± S.E.M.) episodes were obtained after the intraperitoneal administration of 10 ml/kg of 0.9% saline (i.e. S; N = 24) or doses of each compound (n = 8 mice at each point). Abscissa: Drug doses plotted on a logarithmic scale. See Fig. 1 for further details.

Fig. 3

Results of (±)-MDMA (top), S(+)-MDMA (middle), and R(-)-MDMA (bottom) on margin distance (left ordinate – solid line) and margin time (right ordinate – broken line) in mice. Mean (with ± S.E.M.) values were obtained after the intraperitoneal administration of 10 ml/kg of 0.9% saline (i.e. S; N = 24) or doses of each compound (n = 8 mice at each point). Abscissa: Drug doses plotted on a logarithmic scale. See Fig. 1 for further details.

Fig. 4

Results of (±)-MDMA (X), S(+)-MDMA (closed square), and R(-)-MDMA (open square) on center entries (upper left). Results of (±)-MDMA (upper right), S(+)-MDMA (bottom left), and R(-)-MDMA (bottom right) on center distance (left ordinate – solid line) and center time (right ordinate – broken line) in mice. Mean (with ± S.E.M.) values were obtained after the intraperitoneal administration of 10 ml/kg of 0.9% saline (i.e. S; N = 24) or doses of each compound (n = 8 mice at each point). Abscissa: Drug doses plotted on a logarithmic scale. See Fig. 1 for further details.

Fig. 5

Results of (±)-MDMA (X), S(+)-MDMA (closed square), and R(-)-MDMA (open square) on clockwise rotations (top) and counterclockwise rotations (bottom) in mice. Ordinate: Mean (with ± S.E.M.) values were obtained after the intraperitoneal administration of 10 ml/kg of 0.9% saline (i.e. S; N = 24) or doses of each compound (n = 8 mice at each point). Abscissa: Drug doses plotted on a logarithmic scale. See Fig. 1 for further details.

Fig. 6

Results of (±)-MDMA (top), S(+)-MDMA (middle), and R(-)-MDMA (bottom) on clockwise rotations (solid line) and counterclockwise (broken line) in mice. Mean (with ± S.E.M.) rotations were obtained after the intraperitoneal administration of 10 ml/kg of 0.9% saline (i.e. S; N = 24) or doses of each compound (n = 8 mice at each point). Abscissa: Drug doses plotted on a logarithmic scale. An asterisk (*) denotes a dose that produced a statistically significant difference (t-test, p ≤ 0.05) between counterclockwise rotations as compared to clockwise rotations.

Fig. 7

Results of (±)-MDMA (X), S(+)-MDMA (closed square), and R(-)-MDMA (open square) on retraced episodes (upper left). Results of (±)-MDMA (upper right), S(+)-MDMA (bottom left), and R(-)-MDMA (bottom right) on retraced movements (left ordinate – solid line) and retraced time (right ordinate – broken line) in mice. Mean (with ± S.E.M.) values were obtained after the intraperitoneal administration of 10 ml/kg of 0.9% saline (i.e. S; N = 24) or doses of each compound (n = 8 mice at each point). Abscissa: Drug doses plotted on a logarithmic scale. See Fig. 1 for further details.

Fig. 8

Results of (±)-MDMA (X), S(+)-MDMA (closed square), and R(-)-MDMA (open square) on vertical entries (top), vertical time (middle), and vertical distance (bottom) in mice. Ordinate: Mean (with ± S.E.M.) values were obtained after the intraperitoneal administration of 10 ml/kg of 0.9% saline (i.e. S; N = 24) or doses of each compound (n = 8 mice at each point). Abscissa: Drug doses plotted on a logarithmic scale. See Fig. 1 for further details.

Fig. 9

Results of (±)-MDMA (X), S(+)-MDMA (closed square), and R(-)-MDMA (open square) on jumps in mice. Ordinate: Mean (with ± S.E.M.) jumps were obtained after the intraperitoneal administration of 10 ml/kg of 0.9% saline (i.e. S; N = 24) or doses of each compound (n = 8 mice at each point). Abscissa: Drug doses plotted on a logarithmic scale. See Fig. 1 for further details.