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. 2007 Nov;88(1):18-27.
doi: 10.1016/j.pbb.2007.06.007. Epub 2007 Jul 6.

MDMA-like behavioral effects of N-substituted piperazines in the mouse

H L Yarosh  1 , E B Katz, A Coop, W E Fantegrossi
Affiliations

MDMA-like behavioral effects of N-substituted piperazines in the mouse

H L Yarosh et al. Pharmacol Biochem Behav. 2007 Nov.

Abstract

Few studies have characterized the subjective effects of N-substituted piperazines, but these drugs show potential for abuse in humans, and have often been associated with MDMA ("ecstasy") in this regard. The aim of the present study was to test the capacity of N-substituted piperazines to induce a head twitch response, alter locomotor activity, and induce MDMA-like discriminative stimulus effects in mice. Various doses of l-benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl) piperazine (TFMPP), 1-(3-methoxybenzyl) piperazine (m-MeO-BZP) or meta-chlorophenyl piperazine (m-CPP) were administered to mice to determine the effects on these behavioral endpoints. BZP, but not its meta-methoxyl analogue, increased locomotor activity in a dose-dependent manner; the phenylpiperazines and m-MeO-BZP only decreased locomotor activity. TFMPP was the only compound active in the head twitch assay, eliciting a moderate head twitch response which was comparable to that previously observed with the MDMA enantiomers. BZP, TFMPP and m-CPP fully substituted in S(+)-MDMA-trained animals, but did not elicit significant drug lever responding in mice trained to discriminate R(-)-MDMA. m-MeO-BZP partially substituted for both training drugs. The present results suggest that BZP has stimulant-like effects, and that TFMPP has hallucinogen-like effects. Their structural analogues, however, do not share these behavioral profiles. Further studies into the relationships between the N-substituted piperazines and MDMA are warranted.

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Figures

Figure 1
Figure 1
Chemical structures of the drugs used in this study. A. l-benzylpiperazine (BZP), B. 1-(3-Methoxybenzyl)piperazine (m-MeO-BZP), C. trifluoromethylphenyl-piperazine (TFMPP), D. m-chlorophenylpiperazine (m-CPP).
Figure 2
Figure 2
Effects of substituted piperazines in mice trained with 1.5 mg/kg S (+)-MDMA (closed circles) or 1.5 mg/kg R (−)-MDMA (open circles) as a discriminative stimulus (N=6 per group), then tested with BZP (A.), m-MeO-BZP (B.), TFMPP (C.), or m-CPP (D.). All points represent the mean ± SEM, and any points without error bars indicate instances in which the SEM is encompassed by the data point. Abscissae: Dose of drug expressed as mg/kg and plotted on a log scale. The points at SAL and TD represent saline and MDMA training sessions, respectively. Ordinates: Percent MDMA-appropriate responding. A numeral adjacent to a symbol indicates the number of animals completing the test, if less than 6.
Figure 3
Figure 3
Effects of substituted piperazines on head twitch behavior. All points represent the mean ± SEM (N = 6 mice per group), and any points without error bars indicate instances in which the SEM is encompassed by the data point. Abscissa: Dose of drug expressed as mg/kg on a log scale. Ordinate: Mean head twitches recorded over a 10 minute observation period. Asterisks indicate significant differences from saline controls (open squares) (P<0.05) by ANOVA and Tukey’s post hoc test.
Figure 4
Figure 4
Left panel: Effects of 10.0 mg/kg TFMPP on head twitch behavior in mice trained to discriminate S(+)-MDMA or R(−)-MDMA from saline. Graph properties as described in Figure 3. Asterisks indicate significant differences from drug-naive controls receiving this dose (open triangles in Figure 3) (P<0.05) by ANOVA and Tukey’s post hoc test. Right panel: Effects of 30.0 mg/kg BZP on locomotor activity summed over 2 hours in mice trained to discriminate S(+)-MDMA or R(−)-MDMA from saline. Graph properties as described in Figure 5.
Figure 5
Figure 5
Effects of substituted piperazines on locomotor behavior summed over 2 hours (left panels) or expressed as mean ambulatory counts across successive 5 minute bins (right panels, any points without error bars indicate instances in which the SEM is encompassed by the data point). Abscissae: Dose of drug expressed as mg/kg (left panels) or time after injection in minutes (right panels). Ordinates: Mean total ambulatory activity recorded over the entire 2 hour experiment (left panels) or mean ambulatory activity per 5 minute interval (right panels). Asterisks in left panels indicate significant differences from saline controls (open bars) (P<0.05) by ANOVA and Tukey’s post hoc test; double asterisks indicate significant differences from both saline controls and the lower drug dose using the same statistical tests. To preserve figure readability, indicators of statistical significance have been omitted from graphs in the right panels, but have been outlined in the Results section.
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