Involvement of sigma (σ) receptors in the acute actions of methamphetamine: Receptor binding and behavioral studies

Methamphetamine interacts with sigma (σ) receptors, suggesting that the drug produces some of its physiological and behavioral effects through these sites. Therefore, in the present report, receptor binding and pharmacological studies were performed to characterize the interaction between methamphetamine and σ receptors. Of the two major σ receptor subtypes, σ1 and σ2, competition binding studies showed that methamphetamine has a 22-fold preferential affinity for the σ1 subtype. Saturation binding studies using the σ1 selective radioligand [3H](+)-pentazocine showed that in the presence of methamphetamine, there was a significant change in Kd, but not Bmax, suggesting competitive interactions. In behavioral studies, pretreatment of Swiss Webster mice with the σ1 receptor antagonists, BD1063 or BD1047, significantly attenuated the locomotor stimulatory effects of methamphetamine. Mice that were administered an antisense oligodeoxynucleotide to down-regulate brain σ1 receptors also exhibited a reduced locomotor stimulatory response to methamphetamine, as compared to control mice receiving mismatch oligonucleotides. Together, the data suggest that σ1 receptors are involved in the acute actions of methamphetamine and that antagonism of this subtype is sufficient to prevent the locomotor stimulatory effects of methamphetamine.