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.
OBJECTIVE
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.


CONCLUSIONS
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.
Chavez
Carolina
C
Behavioural Neuroscience Laboratory, Mental Health Research Institute, 155 Oak Street, Parkville, Melbourne, Victoria, 3052, Australia.
Gogos
Andrea
A
Jones
Margaret E
ME
van den Buuse
Maarten
M
D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001141:Aromatase / Q000172:deficiency*; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal / Q000187:drug effects; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010622:Phencyclidine / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011571:Psychoacoustics; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011897:Random Allocation; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects; D012737:Sex Factors; D013997:Time Factors
D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018691:Excitatory Amino Acid Antagonists; D011619:Psychotropic Drugs; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016291:Dizocilpine Maleate; D001141:Aromatase; D010622:Phencyclidine; D001058:Apomorphine