Sex differences in the behavioural responses to olanzapine in rats

There are significant differences in the pharmacokinetics, pharmacodynamics, brain structure, neurochemistry and sex hormones of males and females, yet females are precluded from preclinical studies, with conclusions drawn from male only results and applied to females. Thus, females are still treated with the same dose of many drugs, including antipsychotics, as males. To investigate whether any sex differences were evident in the responses exhibited by male and female rats after acute exposure to the commonly used atypical antipsychotic olanzapine, several behaviours were observed. These were anxiety, locomotor activity and spatial working memory, the effects of antipsychotics on which are controversial, and often unexplored in comparison to commonly researched extrapyramidal side effects. 80 PVG/c hooded rats were randomly assigned to one of four groups in which they were administered a low, medium or high dose of olanzapine, or vehicle for control animals at post-natal day (PND) 70 for 42 days. Immediately after 21 days of treatment at PND91, and after 42 days at PND112, subjects were tested in the zero maze, light-dark box, open field and the Y-maze. It can be concluded that there are marked differences in the behavioural responses to olanzapine in males and females, eliciting a clear anxiogenic effect for females in several measures, especially at higher doses with regard to males. There is strong evidence to suggest that olanzapine has an anxiogenic effect on anxiety-related behaviours, however anxiolytic effects are still apparent. Nevertheless, it is clear that it does have an effect on anxiety-related behaviour. Olanzapine also has an overall negative effect on locomotor activity over time, though this effect is dose dependent. With regard to spatial working memory, there are also considerably contradictory findings, with the suggestion of a negative effect of olanzapine on memory over time, however it appears that females may be more resilient to this effect than males. Overall, it can be concluded that the response of males and females to olanzapine differs in many cases. These results may have implications for the use of the drug with humans as it has been proven that females do experience significantly more adverse effects of the drug with respect to males