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Induction of hypothermic conditions associated with increased micronuclei formation in sigma‐1 receptor knockout mice after administration of the antipsychotic compound E‐5842
Author(s) -
Guzmán Antonio,
Marín AnaPaz,
García Concepción,
de Henestrosa Antonio R. Fernández,
Ruiz María Teresa,
Tortajada Araceli,
Marcos Ricard
Publication year - 2008
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.20428
Subject(s) - micronucleus test , hypothermia , bone marrow , pharmacology , knockout mouse , receptor , micronucleus , ratón , sigma receptor , chemistry , biology , endocrinology , toxicity , medicine , immunology , biochemistry
The antipsychotic sigma‐1 (σ 1 ) receptor ligand E‐5842 has been shown to increase micronucleated polychromatic erythrocyte (MNPCE) frequency in mouse bone marrow secondary to compound‐induced hypothermia. Interaction with σ 1 receptor has been considered a plausible contributing factor for E‐5842‐induced hypothermia, raising concern for a possible class effect of sigma receptor ligands in the mouse micronucleus (MN) test. We assessed the potential of E‐5842 (200 mg/kg, oral) to produce hypothermic conditions associated with increased micronuclei formation in σ 1 receptor knockout (σ 1 R‐KO) and wild type (WT) mice. After administration, animal's rectal temperature was recorded and peripheral blood and bone marrow samples were obtained (48 hr) and assessed for induction of micronucleated reticulocytes (MNRET) and MNPCE, respectively. E‐5842 administration produced marked hypothermia both in σ 1 R‐KO and WT mice. Maximum decreases from preadministration temperature were 12.2 and 13.5°C in σ 1 R‐KO and WT mice, respectively. Temperature returned to normal approximately 32 hr after administration. Bone marrow examination revealed a statistical significant increase ( P < 0.05) in MNPCE frequency both in σ 1 R‐KO and WT animals. Examination of peripheral blood samples showed a slight, although nonstatistical significant, increase in MNRET frequency in σ 1 R‐KO mice. No similar effect was observed among WT animals. The results obtained after E‐5842 administration to σ 1 R‐KO mice indicate that induction of hypothermic conditions associated with increased MNPCE formation is not mediated by compound interaction with σ 1 receptor, ruling out concern for a possible class effect of similar high affinity σ 1 receptor ligands in the mouse MN test. Environ. Mol. Mutagen., 2008. © 2008 Wiley‐Liss, Inc.