Increased Impulsivity following progressive nigral degenereation and chronic pramipexole treatment in an animal model of Parkinson's disease

Dopamine agonists (DA) that are widely used to treat motor deficits in patients with Parkinson’s disease (PD) are frequently associated with the development of abnormal-impulsive behaviors (AIB). The pathophysiology of AIB is poorly understood and there is a need for reliable animal models. We have analyzed the behavior of parkinsonian (injection of adeno-associated viral vectors (AAV) encoding for A53T mutated hα-syn in the substantia nigra compacta) and control (AAV- GFP expression) rats under chronic treatment with the D2/D3 receptor DA pramipexole (PPX) during 4 weeks, in OFF and ON medication states, using the 5-Choice Serial Reaction Time-Task (5-CSRTT). Before PPX treatment, the dopaminergic lesion increased the premature responses rate (waiting impulsivity) that was further increased with PPX during the 4 weeks of treatment in ON medication state and that was significantly higher than in control rats. A similar pattern of changes was observed in the variables related to attention (reduced accuracy in the responses and increased omissions). Premature response rate before and after treatment (both in ON and OFF medication) were correlated. In turn, premature responses before treatment and in OFF correlated with the striatal dopaminergic depletion (Dopamine transporter (DAT) immunochemistry). No significant changes were observed in OFF medication state in premature responses rate respect to the pretreatment state. The striatal expression of FosB/ΔFosB inversely correlated with the DAT expression and was higher in the lateral region of both striata and in the shell and core of the nucleus accumbens in parkinsonian than in control rats. In conclusion, these results indicate that the dopaminergic lesion is a risk factor to develop abnormal impulsive behaviors in PD under DA treatment and that this model could be a valid tool to investigate the pathophysiology of AIB in PD (DFG11/019, PI11/02109).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Different susceptibility to pramipexole-induced impulsivity in a rat model of parkinson’s disease

Impulse Control Disorders (ICD) in patients with Parkinson’s disease are abnormal behaviors caused by long-term use of dopamine agonists, which pathophysiology is poorly understood. Using parkinsonian rats (adeno-associated viral vectors-mediated overexpression of A53T human α-synuclein in the substantia nigra compacta), we evaluated the impulsive behaviour under acute (0.25 and 3 mg/kg) and chronic (0.25 mg/kg for 4 weeks) administration of pramipexole (PPX) with the Variable Delay-to-Signal (VDS) task (motor and choice impulsivities). Changes in striatal D1 and D2 receptors expression were also analysed. Before treatment, the striatal dopaminergic depletion caused a significant increase of both impulsivity domains with respect to basal condition. In lesioned rats, acutely given PPX 0.25 mg/kg dose increased choice impulsivity only with regard to basal values. Meanwhile, 3 mg/kg PPX increased choice impulsivity compared to their own values at different conditions: basal, before treatment and after acute 0.25 mg/kg PPX administration. After chronic administration, two populations of lesioned animals were distinguished, one showing the same behaviour as control animals and other displaying an increased motor/response (first week of treatment) and cognitive/choice impulsivities (third week of treatment) compared to control animals. This impulsive behaviour disappeared when animals were tested in OFF state. Lower D2 expression in both Caudate-Putamen and Nucleus Accubens and lower D1 levels in Nucleus Accumbens in lesioned rats than in control animals were observed. Therefore, our results indicate that the pro-impulsive effect of PPX in this animal model of PD depends on the dose and administration paradigm employed and the individual predisposition, and it is associated to striatal dopamine receptors expression changes, especially in Nucleus Accumbens. Thus, this model could constitute a valid tool to investigate the pathophysiology of ICD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. DFG11/019, PI11/0210