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.

Object recognition impairment and rescue by a dopamine D2 antagonist in hyperdopaminergic mice

“…In order to differentiate whether a possible memory deficit could be due to memory acquisition, or specifically related to the memory consolidation phase, we performed injections of haloperidol at low dose both before and after object exploration. The injection of 0.3 mg/Kg haloperidol before the exploration phase results in partial deficit of movement that impairs object exploration [17,21]. Therefore, we could not determine whether the decrease in object recognition was due to impaired consolidation, or to a deficit in locomotor activity during the exploration phase.…”

“…On the other hand, animals with high levels of synaptic DA, namely knockout mice for the DA transporter (DAT-KO), show impairment in the Morris water maze task [9], and also impairment of spatial memory in the Y-maze [16]. These animals presented, however, less immobility time in the forced swimming task [17], and exhibited an increase in locomotion, reversed by D2 receptor blocking [17].…”

“…We also performed the difference between the group (vehicle or haloperidol) and the ratio = 1 (described above), t test against 1, to find out if the preference ratio presented by WT groups was significant different of the hypothesis of non-recognition of objects. To verify possible effects of haloperidol in the motor and motivation system [8,17] we measured the total distance traveled and the total time spent in object exploration.…”

“…DAT-KO mice exhibit hyper locomotion [18] and this phenotype can be reversed by haloperidol injection [17,20]. DAT-KO animals also exhibit a preference for the borders of an open field [20], and a decrease of immobility time in the forced swimming task [17].…”

“…In contrast, only a few studies have been published on DAT +/− mice, a mild model of hyperdopaminergia. In this model, a mild disbalance of dopamine results in several cognitive changes [17,19,20]. DAT +/− mice exhibit less immobility time during the forced swimming test [17], higher time spent in the center of an open field [20], and more time spent in the open arms in comparison to WT mice in a plus maze [19] or zero maze [20].…”