ABSTRACT
Healthy action selection relies on the coordinated activity of striatal direct and indirect pathway neurons. In Parkinson’s disease (PD), in which loss of midbrain dopamine neurons is associated with progressive motor and cognitive deficits, this coordination is disrupted. Dopamine replacement therapy can remediate motor symptoms, but can also cause impulse control disorder (ICD), which is characterized by pathological gambling, hypersexuality, and/or compulsive shopping. The cellular and circuit mechanisms of ICD remain unknown. Here we developed a mouse model of PD/ICD, in which ICD-like behavior was assayed with a delay discounting task. We found that in parkinsonian mice, the dopamine agonist pramipexole drove more pronounced delay discounting, as well as disrupted firing in both direct and indirect pathway neurons. We found that chemogenetic inhibition of indirect pathway neurons in parkinsonian mice drove similar phenotypes. Together, these findings provide a new mouse model and insights into ICD pathophysiology.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
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Supplementary Figure S3 includes DREADD slice validation data that was also used to validate DREADD use in a recent BioRxiv manuscript (Twedell et al) from our lab. We revised the Figure legend & methods section to reflect this fact.