Partial dopamine depletion in MPTP-treated mice differentially altered motor skill learning and action control

Recent findings suggest that the neurotransmitter dopamine (DA) system plays a role in motor control and the acquisition of habits and skills. However, isolating DA-mediated motor learning from motor performance remains challenging as most studies include often severely DA-depleted mice. Using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we investigated the effect of various degrees of DA-depletion in mice on three tests of motor behaviors: the accelerating rotarod, wire suspension and pole tests. Three protocols were performed to decrease DA synthesis to various extents: 4 injections (i.p.) of 9 mg/kg in 1 day; 4 injections (i.p.) of 15 mg/kg in 1 day; or 5 injections (s.c.) of 30 mg/kg in 5 days. Severity of DA-depletion was assessed by the evaluation of tyrosine hydroxylase (TH) and dopamine transporter levels in the striatum using the Western blot technique. Mice were gathered into four different groups according their TH levels: mild, moderate, marked and severe. In these mice, the general motor abilities such as coordination, motion speed and muscular strength were relatively intact whereas impaired acquisition of skilled behavior occurred in mice with marked and severe reduction in TH levels. Marked and severely DA-depleted mice exhibited lower scores within the first trials of the first training day as well as a much slower progression in the following days on the accelerating rotarod. Based on these results, we conclude that the learning of a skilled behavior is more vulnerable to DA depletion than the DA-mediated control of motor activity.