There are no Food and Drug Administration approved
pharmacotherapies for
methamphetamine (METH) overdose, thus identifying novel drug targets to prevent this devastating adverse event is a public-health imperative. Previous research suggests that
serotonin and
sigma receptors may contribute to the adverse effects of METH. The present study assessed whether pretreatment with the
5-HT2A receptor antagonist
M100907 or the sigma 1 (σ1) receptor antagonist
BD 1047 attenuated METH-induced lethality,
hyperthermia, convulsions, and
seizures. Male, Swiss-Webster mice received
intraperitoneal injections of
M100907 (1 and 10 mg/kg),
BD 1047 (10 mg/kg), or a combination of
M100907 (1 mg/kg) and
BD 1047 (10 mg/kg) prior to treatment with METH (78 mg/kg). Convulsions and lethality were assessed by observation, core body temperature was assessed by surgically implanted telemetric probes, and
seizures were assessed by electroencephalography.
M100907 reduced METH-elicited lethality from 67% to 33%,
BD1047 reduced METH-elicited lethality from 67% to 50%, and combined administration of both agents eliminated lethality in all mice tested. Similarly, both agents and their combination reduced METH-elicited
seizures and convulsions. None of the treatments decreased METH-
induced hyperthermia. This research suggests that reducing METH-induced
seizures is an important factor in reducing lethality associated with METH overdose. However, future studies should examine whether
M100907 and
BD 1047 modulate METH-induced
hypertension and other adverse effects that may also contribute to METH overdose. Our data support the continued investigation of compounds that target 5-HT2A and σ1 receptors in METH-induced overdose, including their potential to yield emergency reversal agents.