Induction of hypothermic conditions associated with increased micronuclei formation in sigma-1 receptor knockout mice after administration of the antipsychotic compound E-5842.
The antipsychotic sigma-1 (sigma(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 sigma(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 sigma(1) receptor knockout (sigma(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 sigma(1)R-KO and WT mice. Maximum decreases from preadministration temperature were 12.2 and 13.5 degrees C in sigma(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 sigma(1)R-KO and WT animals. Examination of peripheral blood samples showed a slight, although nonstatistical significant, increase in MNRET frequency in sigma(1)R-KO mice. No similar effect was observed among WT animals. The results obtained after E-5842 administration to sigma(1)R-KO mice indicate that induction of hypothermic conditions associated with increased MNPCE formation is not mediated by compound interaction with sigma(1) receptor, ruling out concern for a possible class effect of similar high affinity sigma(1) receptor ligands in the mouse MN test.
Guzmán
Antonio
A
Toxicology Department, ESTEVE, Mare de Déu de Montserrat 221, 08041, Barcelona, Spain. aguzman@esteve.es
Marín
Ana-Paz
AP
García
Concepción
C
Fernández de Henestrosa
Antonio R
AR
Ruiz
María Teresa
MT
Tortajada
Araceli
A
Marcos
Ricard
R
D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity; D001831:Body Temperature / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D007035:Hypothermia / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects*; D015162:Micronucleus Tests; D011725:Pyridines / Q000633:toxicity*; D017480:Receptors, sigma / Q000235:genetics / Q000502:physiology*; D014230:Triazoles / Q000633:toxicity*; D000097605:Sigma-1 Receptor
D014150:Antipsychotic Agents; D011725:Pyridines; D017480:Receptors, sigma; D014230:Triazoles; D000097605:Sigma-1 Receptor; C117757:E 5842