Behavioral Disturbances Associated with Hyperdopaminergia in Dopamine-Transporter Knockout Mice

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