Oral administration of E-5842, a new σ1 receptor ligand being developed as an antipsychotic drug, to male mice at single doses of 50, 100, 200 and 400mg/kg produced marked and sustained decreases in rectal temperature. Both the intensity and the duration of the hypothermic effect increased with dose. Maximum decreases from the mean pre-administration temperature (36.2°C) ranged from 7.5 to 12.9°C for animals receiving 50 and 400mg/kg doses, respectively. Examination of bone-marrow smears obtained 24, 48 and 72h after administration revealed a slight but statistically significant (p <0.05) increase in the frequency of micronucleated polychromatic erythrocytes (MNPCE) at the 48h sampling for animals receiving the 200mg/kg dose. These animals showed decreases from pre-administration temperature of approximately 12°C, with recovery being observed 24h after administration. When the hypothermic effect of E-5842 administration was avoided by housing treated animals under conditions of increased environmental temperature (30°C) for 24h, MNPCE frequency reverted to vehicle control values. Further, in E-5842-treated animals with an increased MNPCE frequency there was a shift in the distribution of the relative areas of micronuclei in MNPCE towards higher values. In addition, there was a statistically significant increase (p <0.001) in the number of relatively large micronuclei (micronucleus diameter≥1/4 cytoplasm diameter) similar to that produced by administration of the mitotic spindle inhibitor colchicine (1mg/kg), suggesting disturbance of mitotic apparatus as the possible underlying mechanism. The results suggest that the slight increase in MNPCE frequency observed 48h after administration of a 200mg/kg dose of E-5842 is due to a hypothermic effect and not to a direct effect of E-5842 on DNA.