Aberrant striatal firing mediates impulsive decision-making in a mouse model of Parkinson's disease

Parkinson's disease (PD) is characterized by progressive neurodegeneration, which is associated with motor and non-motor symptoms. Dopamine replacement therapy can remediate motor symptoms, but can also cause impulse control disorder (ICD), characterized by pathological gambling, hypersexuality and/or compulsive shopping. Approximately 14%-40% of all medicated PD patients suffer from ICD. Despite the high prevalence of ICD in medicated PD patients, we know little of its mechanisms, and the main therapeutic strategy is reducing or eliminating dopamine agonist medication. Human imaging studies suggest that the input nucleus of the basal ganglia, the striatum, may be a critical site of circuit dysfunction in ICD. To explore the cellular and circuit mechanisms of ICD, we developed a mouse model in which we administered the dopamine D2/3 agonist pramipexole to parkinsonian and healthy control mice. ICD-like behaviour was assessed using a delay discounting task. Delay discounting is a normal cognitive phenomenon, in which the value of a reward decreases according to the time needed to wait for it. Impulsivity is measured as the preference for immediate (small) over delayed (large) rewards. We combined this mouse model with chemogenetics and in vivo optically identified single-unit recordings to examine how dopamine agonists act on vulnerable striatal circuitry to mediate impulsive decision-making. We found that in parkinsonian mice, therapeutic doses of dopamine D2/3 receptor (D2/3R) or D1 receptor (D1R) agonists drove more pronounced delay discounting, reminiscent of what has been reported in PD/ICD patients on medication. In contrast, healthy mice did not become more impulsive when given the same dose of dopamine agonist. The clinically relevant dopamine D2/3R agonist pramipexole induced marked bidirectional changes in the firing of striatal direct and indirect pathway neurons in parkinsonian mice. Chronic pramipexole treatment potentiated these changes in striatal physiology and decision-making behaviour. Furthermore, chemogenetic excitation of direct pathway striatal neurons or inhibition of indirect pathway neurons induced impulsive decision-making in the absence of dopamine agonists. These findings indicate that abnormal striatal activity plays a causal role in mediating ICD-like behaviours. Together, they provide a robust mouse model and insights into ICD pathophysiology.