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 = 0.2–0.6 µmol/kg) with similar potency, but none occupied the transporter (ED50 > 10 µmol/kg). At the highest dose tested (31.6 µmol/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 (1–3.16 µmol/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.

Chronic opipramol treatment extinguishes cocaine craving through Rac1 in responders: A rat model study

“…Hence, opipramol, in the long term, behaves as a partial agonist and protects from a relapse. Moreover, Miller et al showed that σ‐1R ligands might act as agonists or antagonists depending on their dose 37 . Furthermore, σ‐1R can be expressed as either a monomer or an oligomer, each of which determines it being an antagonist or agonist by the substances bound to it 38 .…”

The sigma-1 receptor as a regulator of dopamine neurotransmission: A potential therapeutic target for methamphetamine addiction

“…All ligands tested had high affinity for the σ 1 R and no appreciable affinity for DAT. They found that higher doses of the compounds attenuated METH-induced (0.5 mg/kg) locomotor activity, whereas lower doses potentiated it (Miller et al, 2016). Utilizing a different selective σ 1 R agonist, our laboratory recently revealed that 8 mg/kg PRE-084 attenuates acute METH-stimulated (2 mg/kg) locomotor activity.…”

“…Administration of the selective σ 1 R agonist SA4503 dose dependently affected METH-induced (0.5 mg/kg) locomotor activity with lower doses enhancing hyperactivity and higher doses inhibiting it (Rodvelt et al, 2011b). More recently, Miller et al, 2016 investigated the effect of different N-phenylpropyl-N′-substituted piperazine ligands, including SA4503, on METH-induced hyperactivity (Miller et al, 2016). All ligands tested had high affinity for the σ 1 R and no appreciable affinity for DAT.…”