Interactions between 3,4-methylenedioxymethamphetamine and sigma1 receptors

Abstract

Methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) are structurally similar and represent a serious and growing health threat. Earlier studies in our laboratory have shown that methamphetamine interacts with sigma receptors and that antagonism of these receptors can attenuate methamphetamine-induced locomotor stimulation and neurotoxicity. However, no research exists which characterizes the interaction between sigma receptors and MDMA. Therefore, the goal of the present study was to determine whether sigma receptors are involved in the actions of MDMA. In the first part of the study, competition and saturation binding assays were performed to measure the interaction of MDMA with sigma receptors. The receptor binding assays revealed that MDMA interacts preferentially with the sigma(1) subtype, as compared to the sigma(2) subtype, and that this interaction occurs in a competitive manner. The second part of the study focused on behavioral measurements in male, Swiss Webster mice to determine whether a selective sigma(1) receptor antagonist, BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine, 0-30 mg/kg, i.p.) could attenuate the locomotor stimulant actions of MDMA (0-50 mg/kg, i.p.). BD1063 alone had no effect on locomotor activity, but dose-dependently attenuated the locomotor stimulant effects of MDMA and produced a significant shift to the right in the MDMA dose response curve. Together, the data support the functional relevance of the interaction of MDMA with sigma(1) receptors, and suggest that these receptors are involved in the stimulant actions of MDMA.

Fig. 1

Scatchard plots of representative saturation assays, in dpm units. [³H]-(+)-Pentazocine was used to label σ₁ receptors in brain homogenates in the absence (control) and presence of MDMA (3 μM) or BD1063 (6 nM). The concentration of MDMA and BD1063 used in the assays corresponded to their K_i values in competition binding studies. There was a significant change in K_d, but not B_max when MDMA or BD1063 was present.

Fig. 2

Swiss Webster mice were treated (i.p.) with saline, MDMA (5-20 mg/kg) or BD1063 (10-30 mg/kg). Horizontal locomotor activity was quantified as disruptions in a 4 x 4 photobeam grid for 90 min. MDMA dose-dependently increased locomotor activity, while BD1063 produced effects that were not statistically different from the saline controls. ^**P<0.01, post-hoc Dunnett’s tests.

Fig. 3

Swiss Webster mice were pretreated (i.p.) with saline or BD1063 (10-30 mg/kg) followed 15 min later with MDMA (20 mg/kg). Horizontal locomotor activity was quantified as disruptions in a 4 x 4 photobeam grid for 90 min. BD1063 pretreatment significantly attenuated MDMA-induced locomotor activity in a dose dependent manner. ^**P<0.01, ^***P<0.001, post-hoc Student-Newman-Keuls tests.

Fig. 4

Swiss Webster mice were pretreated (i.p.) with saline or BD1063 (20 mg/kg) followed 15 min later by MDMA (0-50 mg/kg). Horizontal locomotor activity was quantified as disruptions in a 4 × 4 photobeam grid for 90 min. BD1063 pretreatment significantly shifted the MDMA dose response curve to the right. MDMA ED₅₀ = 8 mg/kg, i.p. in the absence of BD1063, and 24 mg/kg in its presence. Sal=saline.