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The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk\/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2\/D3 receptor pharmacotherapy in PD patients.<\/jats:p>","DOI":"10.3390\/ijms25168849","type":"journal-article","created":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T09:20:51Z","timestamp":1723627251000},"page":"8849","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Pramipexole Hyperactivates the External Globus Pallidus and Impairs Decision-Making in a Mouse Model of Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"25","author":[{"given":"Hisayoshi","family":"Kubota","sequence":"first","affiliation":[{"name":"Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), Fujita Health University, Toyoake 470-1192, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinzhu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), Fujita Health University, Toyoake 470-1192, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9660-8816","authenticated-orcid":false,"given":"Xinjian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), Fujita Health University, Toyoake 470-1192, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8553-8536","authenticated-orcid":false,"given":"Hirohisa","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine, Fujita Health University, Toyoake 470-1192, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5050-7748","authenticated-orcid":false,"given":"Taku","family":"Nagai","sequence":"additional","affiliation":[{"name":"Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), Fujita Health University, Toyoake 470-1192, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1136\/jnnp.2007.131045","article-title":"Parkinson\u2019s disease: Clinical features and diagnosis","volume":"79","author":"Jankovic","year":"2008","journal-title":"J. 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