Attenuation of methamphetamine-induced effects through the antagonism of sigma (sigma) receptors: Evidence from in vivo and in vitro studies.
Methamphetamine (METH) and many other abused substances interact with sigma receptors. sigma receptors are found on dopaminergic neurons and can modulate dopaminergic neurotransmission. Antisense knock down of sigma receptors also mitigates METH-induced stimulant effects, suggesting that these proteins are viable medication development targets for treating psychostimulant abuse. In the present study, AC927, a sigma 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 sigma 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, co-incubation 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.
Matsumoto
Rae R
RR
Department of Pharmacology, University of Mississippi, University, MS 38677, USA. rmatsumoto@hsc.wvu.edu
Shaikh
Jamaluddin
J
Wilson
Lisa L
LL
Vedam
Shreedeepalakshmi
S
Coop
Andrew
A