Long-lasting blocking of interoceptive effects of cocaine by a highly efficient cocaine hydrolase in rats
Year: 2024
Type: article
Abstract: 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.
Source: Scientific Reports
Authors: Huimei Wei, Johnathan E. LeSaint, Zhenyu Jin, Chang-Guo Zhan, Fang Zheng
Institution: University of Kentucky
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,590
Awards: Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse, Long-acting aldicarb hydrolase as a medical countermeasure for aldicarb poisoning, Ghrelin Deacylase as a Treatment for Opioid Polysubstance Abuse, G5330388222, Development of a Cocaine-Metabolizing Enzyme for Drug Overdose Treatment, Development of a Long-acting Enzyme Therapy for Treatment of Cocaine Abuse, Validation of ghrelin hydrolysis as an effective approach to treatment of substance use disorders, Long-lasting cocaine-metabolizing enzyme for cocaine addiction treatment, Redesign of Butyrylcholinesterase for Cocaine Metabolism, G9000059500, G9000223770, Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse
OpenAlex ID: W4390725997