{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:49:19Z","timestamp":1788544159410,"version":"build-2803163510"},"reference-count":72,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T00:00:00Z","timestamp":1671580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-75-20069"],"award-info":[{"award-number":["21-75-20069"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["93018770"],"award-info":[{"award-number":["93018770"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004285","name":"St. Petersburg State University","doi-asserted-by":"publisher","award":["21-75-20069"],"award-info":[{"award-number":["21-75-20069"]}],"id":[{"id":"10.13039\/501100004285","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004285","name":"St. Petersburg State University","doi-asserted-by":"publisher","award":["93018770"],"award-info":[{"award-number":["93018770"]}],"id":[{"id":"10.13039\/501100004285","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Parkinson\u2019s disease is the second most common neurodegenerative pathology. Due to the limitations of existing therapeutic approaches, novel anti-parkinsonian medicines with non-dopamine mechanisms of action are clearly needed. One of the promising pharmacological targets for anti-Parkinson drug development is phosphodiesterase (PDE) 10A. The stimulating motor effects of PDE10A inhibition were detected only under the conditions of partial dopamine depletion. The results raise the question of whether PDE10A inhibitors are able to restore locomotor activity when dopamine levels are very low. To address this issue, we (1) developed and validated the rat model of acute severe dopamine deficiency and (2) tested the action of PDE10A inhibitor MP-10 in this model. All experiments were performed in dopamine transporter knockout (DAT-KO) rats. A tyrosine hydroxylase inhibitor, \u03b1-Methyl-DL-tyrosine (\u03b1MPT), was used as an agent to cause extreme dopamine deficiency. In vivo tests included estimation of locomotor activity and catalepsy levels in the bar test. Additionally, we evaluated the tissue content of dopamine in brain samples by HPLC analysis. The acute administration of \u03b1MPT to DAT-KO rats caused severe depletion of dopamine, immobility, and catalepsy (Dopamine-Deficient DAT-KO (DDD) rats). As expected, treatment with the L-DOPA and carbidopa combination restored the motor functions of DDD rats. Strikingly, administration of MP-10 also fully reversed immobility and catalepsy in DDD rats. According to neurochemical studies, the action of MP-10, in contrast to L-DOPA + carbidopa, seems to be dopamine-independent. These observations indicate that targeting PDE10A may represent a new promising approach in the development of non-dopamine therapies for Parkinson\u2019s disease.<\/jats:p>","DOI":"10.3390\/biom13010009","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T03:59:26Z","timestamp":1671595166000},"page":"9","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Inhibition of PDE10A in a New Rat Model of Severe Dopamine Depletion Suggests New Approach to Non-Dopamine Parkinson\u2019s Disease Therapy"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9251-9923","authenticated-orcid":false,"given":"Ilya","family":"Sukhanov","sequence":"first","affiliation":[{"name":"Valdman Institute of Pharmacology, Pavlov First St. Petersburg State Medical University, 197022 St. Petersburg, Russia"},{"name":"Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1142-6325","authenticated-orcid":false,"given":"Artem","family":"Dorotenko","sequence":"additional","affiliation":[{"name":"Valdman Institute of Pharmacology, Pavlov First St. Petersburg State Medical University, 197022 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoia","family":"Fesenko","sequence":"additional","affiliation":[{"name":"Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5851-9102","authenticated-orcid":false,"given":"Artem","family":"Savchenko","sequence":"additional","affiliation":[{"name":"Valdman Institute of Pharmacology, Pavlov First St. Petersburg State Medical University, 197022 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9641-515X","authenticated-orcid":false,"given":"Evgeniya V.","family":"Efimova","sequence":"additional","affiliation":[{"name":"Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikael S.","family":"Mor","sequence":"additional","affiliation":[{"name":"Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina V.","family":"Belozertseva","sequence":"additional","affiliation":[{"name":"Valdman Institute of Pharmacology, Pavlov First St. Petersburg State Medical University, 197022 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana D.","family":"Sotnikova","sequence":"additional","affiliation":[{"name":"Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raul R.","family":"Gainetdinov","sequence":"additional","affiliation":[{"name":"Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia"},{"name":"St. Petersburg University Hospital, St. Petersburg State University, 199034 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/978-94-007-5416-4_16","article-title":"Parkinson\u2019s Disease","volume":"65","author":"Mhyre","year":"2012","journal-title":"Subcell. 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