AC927, A SELECTIVE SIGMA RECEPTOR ANTAGONIST, ATTENUATES THE LOCOMOTOR STIMULANT AND NEUROTOXIC EFFECTS OF METHAMPHETAMINE IN MICE

Methamphetamine (METH) interacts with σ receptors and accumulating evidence suggests that antagonism of these proteins can mitigate the behavioral effects of psychomotor stimulants. Therefore, the goals of the present study were to evaluate the selectivity of AC927, a σ receptor antagonist, and evaluate its effects on METH‐induced locomotor activity, hyperthermia, and dopamine damage in the mouse brain. Radioligand binding studies showed that AC927 exhibits preferential affinity for σ receptors compared to 29 other receptors, transporters and ion channels. Pretreatment of male, Swiss Webster mice with AC927 significantly attenuated the locomotor stimulant effects of METH. Pretreatment of mice with AC927 also attenuated METH‐induced hyperthermia and dopamine depletions in the mouse striatum and cerebellum. There were dose‐related differences between the ability of AC927 to attenuate METH‐induced hyperthermia and dopamine depletions, suggesting that the two events were not causatively linked. When AC927 was administered with saline instead of METH, it had no significant effects on basal locomotor activity, core body temperature, or dopamine levels in the striatum and cerebellum. These results demonstrate that AC927 protects against METH‐induced effects in the mouse brain, and suggests σ receptors as a potential medication development target for the treatment of METH abuse.