Long-lasting blocking of interoceptive effects of cocaine by a highly efficient cocaine hydrolase in rats.


Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
09 Jan 2024
Historique:
received: 12 09 2023
accepted: 22 12 2023
medline: 10 1 2024
pubmed: 10 1 2024
entrez: 9 1 2024
Statut: epublish

Résumé

Cocaine dependence is a serious world-wide public health problem without an FDA-approved pharmacotherapy. We recently designed and discovered a highly efficient long-acting cocaine hydrolase CocH5-Fc(M6). The present study examined the effectiveness and duration of CocH5-Fc(M6) in blocking interoceptive effects of cocaine by performing cocaine discrimination tests in rats, demonstrating that the duration of CocH5-Fc(M6) in blocking cocaine discrimination was dependent on cocaine dose and CocH5-Fc(M6) plasma concentration. Particularly, a dose of 3 mg/kg CocH5-Fc(M6) effectively attenuated discriminative stimulus effects of 10 mg/kg cocaine, cumulative doses of 10 and 32 mg/kg cocaine, and cumulative doses of 10, 32 and 56 mg/kg cocaine by ≥ 20% for 41, 19, and 10 days, and completely blocked the discriminative stimulus effects for 30, 13, and 5 days with corresponding threshold plasma CocH5-Fc(M6) concentrations of 15.9, 72.2, and 221 nM, respectively, under which blood cocaine concentration was negligible. Additionally, based on the data obtained, cocaine discrimination model is more sensitive than the locomotor activity to reveal cocaine effects and that CocH5-Fc(M6) itself has no long-term toxicity regarding behavioral activities such as lever pressing and food consumption in rats, further demonstrating that CocH5-Fc(M6) has the desired properties as a promising therapeutic candidate for prevenance of cocaine dependence.

Identifiants

pubmed: 38195724
doi: 10.1038/s41598-023-50678-0
pii: 10.1038/s41598-023-50678-0
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

927

Subventions

Organisme : NIH HHS
ID : U01 DA051079
Pays : United States
Organisme : NIH HHS
ID : UH2/UH3 DA041115
Pays : United States
Organisme : NIH HHS
ID : R01 DA056646
Pays : United States
Organisme : NIH HHS
ID : UG3 NS134920
Pays : United States
Organisme : NIH HHS
ID : U18 DA052319
Pays : United States
Organisme : NIH HHS
ID : R01 DA035552
Pays : United States
Organisme : NIH HHS
ID : R01 DA032910
Pays : United States
Organisme : NIH HHS
ID : R01 DA013930
Pays : United States

Informations de copyright

© 2023. The Author(s).

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Auteurs

Huimei Wei (H)

Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA.

Johnathan E LeSaint (JE)

Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA.

Zhenyu Jin (Z)

Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA.

Chang-Guo Zhan (CG)

Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA. zhan@uky.edu.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA. zhan@uky.edu.

Fang Zheng (F)

Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA. fzhen2@uky.edu.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, USA. fzhen2@uky.edu.

Classifications MeSH