Behavioural disturbances associated with hyperdopaminergia in dopamine-transporter knockout mice

Abstract

Mice lacking the dopamine transporter (DAT-/-) are characterized by high extracellular dopamine levels and spontaneous hyperlocomotion. We performed a detailed analysis of the behavioural phenotype of DAT-/- mice in order to identify other behavioural impairments associated with the hyperdopaminergic tone of these mutant mice. In particular, we investigated locomotor activity, exploration, and social and maternal behaviours, which are known to be regulated by dopamine. DAT-/- mice were easily aroused by novelty and always responded with hyperlocomotion, which interfered with habituation to the testing environment, exploratory behaviour in an open field and the coping response to forced swimming stress. Social behaviours such as interaction with an unknown congener or aggressiveness were not modified in DAT-/- mice compared with DAT+/- and DAT+/+ mice, although the maternal behaviour of mutant females was severely disturbed. Haloperidol and clozapine reversed the hyperactivity in DAT-/- mice, with a rightward shift of the dose-response curve compared with control animals, suggesting a dopamine-mediated effect. These results emphasize the role of dopamine regulation in locomotion, exploration and maternal behaviours and suggest that mice with a genetic deletion of DAT may represent a useful model to elucidate the altered behavioural processes accompanying pathological conditions associated with hyperdopaminergic function.