A THERAPEUTIC DOSE OF ALPRAZOLAM AND ITS EFFECT ON PERINATAL OUTCOMESOF INBRED MICE

Objective: The purposes of the investigation were 2-fold: to establish the most efficacious anxiolytic dose of alprazolam in four inbred mou se strains and to determine whether this dose given prenatally has any effect on perinatal outcome. Methods: Gravid and nongravid inbred mic e (C3H/He, C57BL/6, A/J, and DBA/2), selected to give variable efficac y, were given alprazolam via gavage. The doses, from 0.0032 to 3.2 mg/ kg, were used to establish threshold, therapeutic, and adverse levels. The anxiolytic effects were assessed at 15, 30, and 60 min using the mirror chamber aversion and elevated plus maze tasks. Maternal serum a nd fetal brains were collected for tissue levels of alprazolam. Outcom es were assessed in gravid mice for litter size, malformations, surviv al, or growth during the perinatal period. Analysis was accomplished w ith ANOVA and Spearman testing. Results: Threshold and maximum anxioly tic efficacy of alprazolam occurred at 0.032 and 0.32 mg/kg in the C3H /He and C57BL/6 but not the DBA/2 strain. Adverse effects were found i n all strains using a 0.56 mg/kg dose. Efficacy was observed with seru m concentrations between 6 and 60 ng/ml. Efficacy and serum concentrat ions were similar in gravid and nongravid mice. Maternal serum and fet al brain concentrations were greater than 20 ng/mg. Gravid mice given alprazolam or placebo on gestation day 18 showed no significant differ ences in offspring litter size, malformations, survival rates, and bra in and body weights. Conclusions: An anxiolytic dose of alprazolam for inbred mice was determined, giving serum concentrations in the human therapeutic range but without impairing perinatal outcome.