Release parameters during progressive degeneration of dopamine neurons in a mouse model reveal earlier impairment of spontaneous than forced behaviors

To determine the role of reduced dopaminergic transmission for declines of forced versus spontaneous behavior, we used a model of Parkinson's disease with progressive degeneration of dopamine (DA) neurons, the MitoPark mouse. Mice were subjected to rotarod tests of motor coordination, and open field and cylinder tests for spontaneous locomotor activity and postural axial support. To measure DA release in dorsal striatum and the shell of Nucleus Accumbens (NAc), we used ex vivo fast-scan cyclic voltammetry in 6- to 24-week-old mice. To determine decline of DA transporter function, we used 18FE-PE2I positron emission tomography. We show here that fast-scan cyclic voltammetry is a sensitive tool to detect evoked DA release dysfunction in MitoPark mice and that electrically evoked DA release is affected earlier in nigrostriatal than mesolimbic DA systems. DA reuptake was also affected more slowly in NAc shell. Positron emission tomography data showed DA uptake to be barely above detection levels in 16- and 20-week-old MitoPark mice. Rotarod performance was not impaired until mice were 16 weeks old, when evoked DA release in striatum had decreased to approximate to 40% of wild-type levels. In contrast, impairment of open field locomotion and rearing began at 10 weeks, in parallel with the initial modest decline of evoked DA release. We conclude that forced behaviors, such as motivation not to fall, can be partially maintained even when DA release is severely compromised, whereas spontaneous behaviors are much more sensitive to impaired DA release, and that presumed secondary non-dopaminergic system alterations do not markedly counteract or aggravate effects of severe impairment of DA release.