Attenuation of methamphetamine-induced effects through the antagonism of sigma (σ) receptors: Evidence from in vivo and in vitro studies

Abstract

Methamphetamine (METH) and many other abused substances interact with σ receptors. σ Receptors are found on dopaminergic neurons and can modulate dopaminergic neurotransmission. Antisense knock down of σ receptors also mitigates METH-induced stimulant effects, suggesting that these proteins are viable medication development targets for treating pscyhostimulant abuse. In the present study, AC927, a σ receptor antagonist, was evaluated for its ability to attenuate METH-induced effects in vivo and in vitro. Radioligand binding studies showed that AC927 had preferential affinity for σ receptors compared to 29 other receptors, transporters and ion channels. Pretreatment of male, Swiss Webster mice with AC927 significantly attenuated METH-induced locomotor stimulation, striatal dopamine depletions, striatal dopamine transporter reductions, and hyperthermia. When the neurotoxicity of METH was further examined in vitro under temperature-controlled conditions, coincubation with AC927 mitigated METH-induced cytotoxicity. Together, the results demonstrate that AC927 protects against METH-induced effects, and suggests a new strategy for treating psychostimulant abuse.

Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone

“…Horizontal hyperlocomotion is primarily mediated by the increase in DA signaling elicited by METH treatment, as mice lacking in DAT expression or treated with pharmacological agents interfering with the ability of METH to release DA have been shown to attenuate the acute motor stimulant effect of the drug (Fukushima et al, 2007;Matsumoto et al, 2008;Yoo et al, 2008;Kaushal et al, 2011). Interestingly, it has been demonstrated by Glickstein and Schmauss (2004) that an intermediate dose of METH (5 mg/kg) in mice initially elicited an increase in horizontal locomotor activity, but after multiple injections in a binge regimen, mice exhibited predominantly stereotyped behavior, a change not observed in mice that lacked D 2 DA receptors.…”

Synthesis and Pharmacological Evaluation of 6-Acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a Cocaine Antagonist, in Rodents

“…The affinity of SN79 for σ and non-σ binding sites was determined by competition binding assays in homogenates of rat brain tissues. The receptor binding assays were performed as described earlier (25,26). The total reaction volume in each tube was 500 μl.…”

Regulation of σ-1 Receptors and Endoplasmic Reticulum Chaperones in the Brain of Methamphetamine Self-Administering Rats

“…Repeated methamphetamine treatment causes an increase of -1 receptors in the mouse brain (Ujike et al, 1992;Itzhak, 1993), and the behavioral sensitization associated with repeated methamphetamine treatment can be blocked by a -1 receptor antagonist (Takahashi et al, 2000). High doses of methamphetamine cause cytotoxicity that is mediated via -1 receptors (Matsumoto et al, 2008). Methamphetamine, in a dose sufficient to produce apoptosis and neuronal degeneration, can increase the expression of the ER chaperone BiP, presumably by causing ER stress in the brain (Jayanthi et al, 2004).…”

“…However, nondopaminergic receptors have also been implicated in methamphetamine's abuse-related effects. The -1 receptor is one of those receptors (Ujike et al, 1992;Itzhak, 1993;Takahashi et al, 2000;Matsumoto et al, 2008).…”