Background: A major risk-factor for developing Parkinson's disease (PD) is genetic variability in leucine-rich repeat kinase 2 (LRRK2), most notably the p.G2019S mutation. Examination of the effects of this mutation is necessary to determine the etiology of PD and to guide therapeutic development. Objective: Assess the behavioral consequences of LRRK2 p.G2019S overexpression in transgenic rats as they age and test the functional integrity of the nigro-striatal dopamine system. Conduct positron emission tomography (PET) neuroimaging to compare transgenic rats with previous data from human LRRK2 mutation carriers. Methods: Rats overexpressing human LRRK2 p.G2019S were generated by BAC transgenesis and compared to non-transgenic (NT) littermates. Motor skill tests were performed at 3, 6 and 12 months-of-age. PET, performed at 12 months, assessed the density of dopamine and vesicular monoamine transporters (DAT and VMAT2, respectively) and measured dopamine synthesis, storage and availability. Brain tissue was assayed for D2, DAT, dopamine and cAMP-regulated phosphoprotein (DARPP32) and tyrosine hydroxylase (TH) expression by Western blot, and TH by immunohistochemistry.

Heightened motor impulsivity and increased novelty-seeking commonly co-occur in psychiatric disorders, including drug addiction. However, the relationship between these two phenomena remains unclear. One-time tests of novelty sensitivity commonly used in preclinical experiments, such as the open-field or novel-object test, fail to capture the fact that novelty-seekers repeatedly experience novel, stimulating situations. The present study therefore investigated whether repeated exposure to a novel, stimulating environment (SE) altered impulsive action. Male Long-Evans rats were trained to perform the five-choice serial reaction time task (5CSRTT) which measures motor impulsivity in the form of premature responding as well as attention and motivation. Animals were then exposed to a novel SE (1 h/day for 16 days) immediately prior to the 5CSRTT. Significant increases in premature responding were observed in a subgroup of reactive animals termed high responders (HR-SE). These rats were not more impulsive at baseline, and levels of impulsivity normalised once exposure to the SE was discontinued. No other aspect of 5CSRTT performance was affected by the SE challenge. We also determined that HR-SE rats were hyperactive in a novel environment. Biochemical analyses revealed changes in gene and protein expression within the dorsal hippocampus of HR-SE rats, including decreases in mRNA encoding the dopamine D1 receptor and brain-derived neurotrophic factor. These results indicate a novel mechanism by which impulsivity and novelty-reactivity interact that may enhance addiction vulnerability synergistically. Furthermore, studying such context-induced impulsivity may provide insight into the process by which environmental load precipitates psychiatric symptoms in impulse control disorders.