Psychotropic drug-induced locomotor hyperactivity and prepulse inhibition regulation in male and female aromatase knockout (ArKO) mice: role of dopamine D1 and D2 receptors and dopamine transporters.

RATIONALE AND

OBJECTIVES

The aim of the present study was to investigate the possible role of oestrogen in schizophrenia by comparing aromatase knockout (ArKO) mice, which are unable to produce oestrogen, with wild-type controls using two behavioural animal models with relevance to the illness, psychotropic drug-induced locomotor hyperactivity and prepulse inhibition (PPI).

RESULTS

Baseline PPI was not different between ArKO and controls. Treatment with apomorphine, MK-801 and amphetamine caused disruption of PPI in all groups. However, in female but not male ArKO mice, the effect of both apomorphine and amphetamine was reduced. In female ArKO mice, amphetamine-induced hyperlocomotion was markedly reduced, but in male mice, the genotype difference was far smaller. Female but not male ArKO mice also showed a reduction of phencyclidine-induced locomotor hyperactivity. The density of dopamine transporters, but not D1 and D2 receptors, was significantly increased in the caudate putamen of male but not female ArKO mice compared to wild-type mice. This could represent a compensatory dopaminergic upregulation in male ArKO mice.

CONCLUSION

Because of their lack of oestrogen production, it was anticipated that ArKO mice would display enhanced effects of amphetamine on locomotor activity and PPI. Instead, in these animals, aromatase knockout appeared to be 'protective'. This may represent limitations in the ability to model a complex illness such as schizophrenia in a constitutive knockout model, such as ArKO mice. Moreover, the current results may point at the involvement of other sex steroids, which are also altered in ArKO mice, in dopaminergic control of behaviour.