Behavioral alterations in models of Parkinson's disease

This work characterizes the behavioral effects of altered dopamine transmission and tests the hypothesis that manipulating behavior impacts recovery following injury in models of Parkinson’s disease (PD). The MPTP mouse model of PD has been limited by the lack of measurable and persistent motor deficits. We developed several sensitive measures of motor impairment in MPTP mice. These tests could detect motor deficits that were persistent over time, reversed through L-DOPA treatment, and highly correlated to striatal dopamine and dopaminergic terminal markers. We also identified a specific olfactory deficit in mice with altered dopamine neurotransmission (dopamine transporter or D2 receptor knockout mice) implicating the D2 receptor in the olfactory dysfunction seen in patients with disorders involving dopamine systems. Understanding of these early behavioral and sensory symptoms of altered dopamine transmission will allow for earlier detection of the disorder and improved prognosis for PD patients. Significant declines in physical activity begin years before the diagnosis of PD. We believe that this striking inactivity is not only a symptom of the dopamine neuron degeneration, but could also be contributing to the progression of the disease. Therefore, we manipulated the level of activity following nigrostriatal injury in both 6-hydroxydopamine (6-OHDA) and MPTP retirebreeder mouse models of PD. In both models, moderate running following injury resulted in long-term behavioral improvements and increased striatal dopamine system integrity. In addition, we tested the hypothesis that decreased physical activity during nigrostriatal degeneration could augment dopamine cell loss. Rats given doses of 6-OHDA that would normally result in only mild loss of DA and no measurable behavioral deficit were forced to disuse the lesioned motor system. In these animals, the neurochemical and behavioral deficit was similar to that of a severe lesion. MPTP mice with lateralized use of the forelimbs (one forelimb casted to prevent movement) showed sustained asymmetry of behavior and striatal dopaminergic markers. These studies support the role of physical therapy in the treatment of PD, and strongly suggest that decreased activity is not only a symptom of dopamine loss, but plays an active role in the progressive degeneration in PD.