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Serotonin 2A and Sigma 1 Receptor Antagonists Synergize to Block the Acute Toxicity of Methamphetamine
Author(s) -
Ray Azizi
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.665.12
Subject(s) - methamphetamine , meth , pharmacology , antagonism , serotonin , medicine , antagonist , receptor antagonist , hyperthermia , receptor , chemistry , monomer , organic chemistry , acrylate , polymer
Currently 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. Determine whether antagonism of serotonin 2A (5‐HT 2A ) and sigma 1 (σ 1 ) alone or in combination attenuates METH‐induced lethality, hyperthermia, convulsions, and seizures. Male, Swiss Webster mice received intraperitoneal injections of the selective 5‐HT 2A receptor antagonist M100907 (1–10 mg/kg), the selective σ 1 receptor antagonist BD 1047 (10–30 mg/kg), and a combination of M100907/BD 1047 (1:10 mg/kg) prior to treatment with METH (78 mg/kg ‐ LD 67 ). Convulsions and lethality were assessed by observation, core body temperature was assessed by surgically implanted telemetric probes, and seizures were assessed by electroencephalography. M100907 and BD 1047 administered alone had no significant effect on METH‐induced lethality. However, combined antagonism of 5‐HT 2A and σ 1 receptors eliminated lethality in all mice tested (a reduction from LD 67 to LD 0 ). Similarly, only the combination of 5‐HT 2A and σ 1 receptor antagonism eliminated seizure activity. All three treatments decreased tonic‐clonic convulsions as measured on a modified Racine scale. None of the treatments decreased METH‐induced hyperthermia. This research suggests that reducing METH‐induced seizures may be critical for reducing METH‐induced lethality. These data support the continued investigation of the role of 5‐HT 2A and σ 1 receptors in METH overdose, including their potential to yield emergency reversal agents. Support or Funding Information These studies were supported by the National Institutes on Drug Abuse [NS100512] and by funding from the Mercer University College of Pharmacy (Murnane KS‐ Principal Investigator; Canal CE– Principal Investigator) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .