Motor behaviour deficits and their histopathological and functional correlates in the nigrostriatal system of dopamine transporter knockout mice

P.-O Fernagut, S Chalon, E Diguet, D Guilloteau, F Tison, M Jaber
Neuroscience. 2003-02-01; 116(4): 1123-1130
DOI: 10.1016/s0306-4522(02)00778-9

Fernagut PO(1), Chalon S, Diguet E, Guilloteau D, Tison F, Jaber M.

Author information:
(1)CNRS UMR 5543, Laboratoire de Neurophysiologie, 146 Rue Léo Saignat,
Université Victor Segalen Bordeaux 2, 33076 Bordeaux Cedex, France.

Chronic dysregulation of dopamine homeostasis has been shown to induce
behavioural impairment in dopamine transporter knockout mutant mice arising from
the dysfunction of the mesolimbic and hypothalamo-infundibular system. Here, we
assessed whether there are also any motor consequences of a chronic and
constitutive hyperdopaminergia in the nigrostriatal system in dopamine
transporter knockout mutant mice. For this, we analysed motor performances using
tests assessing balance, coordinated motor skills (rotarod, pole test), stride
lengths and locomotor activity. Dopamine transporter knockout mutant mice were
markedly hyperactive in the open field with central compartment avoidance, as
previously shown. However, sensorimotor integration was also found to be altered
in dopamine transporter knockout mutant mice which displayed a reduced fore- and
hind-limb mean stride length, impaired motor coordination on the pole test and
reduced rearings in the open field. Moreover, dopamine transporter knockout
mutant mice showed a slower task acquisition on the rotarod. Six-week-old
dopamine transporter knockout wild type mice having the same femur size as adult
dopamine transporter knockout mutant mice ruled out a possible size-effect bias.
Whilst there was no significant difference in the striatal volume, we found a
slight but significant reduction in neuronal density in the striatum but not in
the nucleus accumbens of dopamine transporter knockout mutant mice. There was a
reduced binding in the striatum and nucleus accumbens of dopamine(1) receptors
([(3)H]SCH 23390) and dopamine(2) receptors ([(3)H]YM-09151-2). There was no
significant difference in the number of dopaminergic neurons in the substantia
nigra between dopamine transporter knockout mutant mice and dopamine transporter
knockout wild type mice. These results suggest an impaired functioning of the
nigrostriatal system in dopamine transporter knockout mutant hyperdopaminergic
mice, as illustrated by motor and sensorimotor integration deficits, despite
their apparent hyperactivity. These dysfunctions may arise from combined
striatal cell loss and/or functional changes of dopaminergic neurotransmission.