N-phenylpropyl-N'-substituted piperazines occupy sigma receptors and alter methamphetamine-induced hyperactivity in mice

Abstract

This study examined the effect of the N-phenylpropyl-N'-substituted piperazine ligands SA4503 (3.4-dimethoxyphenethyl), YZ-067 (4-methoxyphenethyl), YZ-185 (3-methoxyphenethyl) and Nahas-3h (4-methoxybenzyl) on methamphetamine-induced hyperactivity in mice. In a previous study in rats, SA4503 increased methamphetamine-induced hyperactivity at a lower ligand dose and enhanced it at a higher dose. The other ligands have not been investigated in this assay. Presently, mice were administered sigma ligands, and specific [¹²⁵I]E-IA-DM-PE-PIPZE and [¹²⁵I]RTI-121 binding was measured to determine σ1 sigma receptor and dopamine transporter occupancy, respectively. Mice were also administered sigma ligands followed by methamphetamine, and locomotor activity was measured. Each of the ligands occupied σ1 sigma receptors (ED₅₀=0.2-0.6μmol/kg) with similar potency, but none occupied the transporter (ED₅₀>10μmol/kg). At the highest dose tested (31.6μmol/kg) all four sigma ligands significantly attenuated methamphetamine-induced hyperactivity. Interestingly, SA4503, YZ-067 and Nahas-3h, but not YZ-185, enhanced methamphetamine-induced hyperactivity at lower ligand doses (1-3.16μmol/kg). These results suggest that these ligands function as stimulant agonists at lower doses and as antagonists at higher does, with subtle changes in the substitution pattern at the 3- and 4-positions of the phenethyl group contributing to the nature of the interactions. Overall, these data indicate a complex role for σ1 sigma receptor ligands in methamphetamine's behavioral effects.

Keywords: Behavior; Dopamine transporter; Locomotor activity; Methamphetamine; Mouse; Receptor occupancy; Sigma receptor.

Fig. 1

Structures of the N-phenylpropyl-N´-substituted piperazine sigma receptor ligands examined.

Fig. 2

N-phenylpropyl-N´-substituted piperazine sigma receptor ligands dose-dependently inhibit [¹²⁵I]E-IA-DM-PE-PIPZE specific binding to σ1 receptors in vivo at 30 min in mouse brain. ED₅₀ values were calculated from sigmoidal logistic fits with bottom plateaus constrained to zero.

Fig. 3

N-phenylpropyl-N´-substituted piperazine sigma receptor ligands do not inhibit [¹²⁵I]RTI-121 specific binding to DAT in vivo at 30 min in mouse brain. The DAT inhibitor GBR-12909 was also examined (10 µmol/kg) and asterisks designate a significant (p < 0.05) difference from the control group.

Fig. 4

SA4503 attenuates and enhances methamphetamine-induced hyperactivity. Mice were placed in an activity monitor for 45 min, injected (i.p.) with SA4503 (1 – 31.6 µmol/kg) or saline, returned to the monitor for 15 min, injected (i.p.) with methamphetamine (0.5 mg/kg) or saline, and placed in the monitor for 60 min. Panel A depicts distance traveled (in cm) summed across the 60-min period after methamphetamine or saline injection. The asterisk designates a significant (p < 0.05, Tukey post-hoc analysis) difference from the group administered saline and methamphetamine. Panels B, C and D depict distance traveled (in cm) in 5-min intervals. The left arrow designates SA4503 or saline injection and the right arrow designates methamphetamine or saline injection. Asterisks designate a significant (p < 0.05, Tukey post-hoc analysis) difference from the group administered saline and methamphetamine at the respective time point.

Fig. 5

YZ-185 attenuates methamphetamine-induced hyperactivity. Mice were placed in an activity monitor for 45 min, injected (i.p.) with YZ-185 (0.1 – 31.6 µmol/kg) or saline, returned to the monitor for 15 min, injected (i.p.) with methamphetamine (0.5 mg/kg) or saline, and placed in the monitor for 60 min. Panel A depicts distance traveled (in cm) summed across the 60-min period after methamphetamine or saline injection. The asterisk designates a significant (p < 0.05, Tukey post-hoc analysis) difference from the group administered saline and methamphetamine. Panels B, C and D depict distance traveled (in cm) in 5-min intervals. The left arrow designates YZ-185 or saline injection and the right arrow designates methamphetamine or saline injection.

Fig. 6

YZ-067 attenuates and enhances methamphetamine-induced hyperactivity. Mice were placed in an activity monitor for 45 min, injected (i.p.) with YZ-067 (3.16 or 31.6 µmol/kg) or saline, returned to the monitor for 15 min, injected (i.p.) with methamphetamine (0.5 mg/kg) or saline, and placed in the monitor for 60 min. Panel A depicts distance traveled (in cm) summed across the 60-min period after methamphetamine or saline injection. Panels B and C depict distance traveled (in cm) in 5-min intervals. The left arrow designates YZ-067 or saline injection and the right arrow designates methamphetamine or saline injection. Asterisks designate a significant (p < 0.05, Tukey post-hoc analysis) difference from the group administered saline and methamphetamine at the respective time point. The plus signs designate a significant (p < 0.05, Tukey post-hoc analysis) difference from the group administered two saline injections at the respective time point.

Fig. 7

Nahas-3h attenuates and enhances methamphetamine-induced hyperactivity. Mice were placed in an activity monitor for 45 min, injected (i.p.) with Nahas-3h (3.16 – 31.6 µmol/kg) or saline, returned to the monitor for 15 min, injected (i.p.) with methamphetamine (0.5 mg/kg) or saline, and placed in the monitor for 60 min. Panel A depicts distance traveled (in cm) summed across the 60-min period after methamphetamine or saline injection. The asterisk designates a significant (p < 0.05, Tukey post-hoc analysis) difference from the group administered saline and methamphetamine. Panels B and C depict distance traveled (in cm) in 5-min intervals. The left arrow designates Nahas-3h or saline injection and the right arrow designates methamphetamine or saline injection. Asterisks designate a significant (p < 0.05, Tukey post-hoc analysis) difference from the group administered saline and methamphetamine at the respective time point.