ESTRADIOL INHIBITS DOPAMINE-MEDIATED BEHAVIOR IN RATS - AN ANIMAL-MODEL TO EXAMINE SEX-SPECIFIC DIFFERENCES IN SCHIZOPHRENIA

We found in a representative sample of 392 first hospital admissions for schizophrenia a higher mean age at onset in females by 3.2 to 3.9 years, whereas the lifetime risk was equal for both sexes. In males the rates of onset show a steep increase reaching the maximum value in the age group 15-24 years, followed then by a steady decrease. Females reach the first peak with a clear delay between 20 and 29 years. After the decrease a second smaller peak is observed consistently in females within the age group 45-49 years and over. After having excluded alternative explanations for this gender differences (for example, diagnosis artefacts, sociocultural factors), we hypothesized that the effect of oestradiol on the dopaminergic system enhances the vulnerability threshold for schizophrenia, which is lowered again during the menopause. Alternatively we assumed that testosterone reduces the vulnerability threshold and thus furthers the earlier onset of schizophrenia in males. We tested these hypotheses in animal models by investigating the effects of the gonadal hormones on haloperidol-induced catalepsy and on apomorphine-induced stereotypies in both neonatal and adult rats. Testosterone showed no clear influence on the tested dopamine-mediated behaviour. Oestradiol caused a significant reduction on both dopamine-agonist and dopamine-antagonist induced behaviour. These effects were stronger in neonatal animals. Since oestradiol caused a 2.8-fold reduction of dopamine receptor affinity for sulpiride, we assumed that the behavioural changes caused by oestradiol were accounted for by a down-regulation of the dopaminergic system. The results from our animal experiments suggest that in schizophrenia the higher age at onset and the second peak of onset after menopause in females may be due to functional and possibly also to structural effects of oestrogens on the dopaminergic system.