In vivo characterization of toxicity of norcocaethylene and norcocaine identified as the most toxic cocaine metabolites in male mice

Zheng, Xirong; Shang, Linyue; Chen, Zhan; Zheng, Fang

doi:10.1016/j.drugalcdep.2019.04.033

Cited by 18 publications

(26 citation statements)

References 21 publications

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“…Concerning a potential treatment for cocaine use disorder, our previous studies demonstrated that exogenous CocHs can powerfully rescue rats from a lethal dose of cocaine by rapidly detoxifying cocaine and its toxic metabolites. 30,42 Furthermore, Fc-fused CocHs can block cocaine-induced hyperactivity, cocaine discrimination and cocaine self-administration (associated with i.v. infusion of cocaine).…”

Section: Discussionmentioning

confidence: 99%

“…[25][26][27] It has been demonstrated that these proteins are capable of accelerating cocaine metabolism, rapidly detoxifying cocaine and its toxic metabolites. 22,[27][28][29][30] A single dose of the CocH-Fc can effectively block the physiological and reinforcing effects of cocaine for a long period of time (weeks). 25,27,31 Specially, we have also demonstrated that CocH-Fc can also block cocaine-induced DAT trafficking in cocaine-naïve rats.…”

Section: Introductionmentioning

confidence: 99%

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Recovery of dopaminergic system after cocaine exposure and impact of a long‐acting cocaine hydrolase

et al. 2022

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Dysregulation of dopamine transporters (DAT) within the dopaminergic system is an important biomarker of cocaine exposure. Depending on cocaine amount in-taken, one-time exposure in rats could lead to most (>95% of total) of DAT translocating to plasma membrane of the dopaminergic neurons compared to normal DAT distribution ($5.7% on the plasma membrane). Without further cocaine exposure, the time course of striatal DAT distribution, in terms of intracellular and plasma membrane fractions of DAT, represents a recovery process of the dopaminergic system. In this study, we demonstrated that after an acute cocaine exposure of 20 mg/kg (i.p.), the initial recovery process from days 1 to 15 in rats was relatively faster (from >95% on day 1 to $35.4% on day 15). However, complete recovery of the striatal DAT distribution may take about 60 days. In another situation, with repeated cocaine exposures for once every other day for a total of 17 doses of 20 mg/kg cocaine (i.p.) from days 0 to 32, the complete recovery of striatal DAT distribution may take an even longer time (about 90 days), which represents a consequence of chronic cocaine use. Further, we demonstrated that a highly efficient Fc-fused cocaine hydrolase, CocH5-Fc(M6), effectively blocked cocaine-induced hyperactivity and DAT trafficking with repeated cocaine exposures by maintaining a plasma CocH5-Fc (M6) concentration ≥58.7 ± 2.9 nM in rats. The cocaine hydrolase protected dopaminergic system and helped the cocaine-altered DAT distribution to recover by preventing the dopaminergic system from further damage by cocaine.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recovery of dopaminergic system after cocaine exposure and impact of a long‐acting cocaine hydrolase

et al. 2022

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“…Particularly for treatment of cocaine abuse, previous studies 20,23,30,37,41,43 demonstrated that an exogenous CocH (known as a BChE mutant with at least 1000‐fold improved catalytic efficiency against cocaine compared to wild‐type BChE) can powerfully rescue rats by rapidly detoxifying cocaine and its toxic metabolites 25,27,29,44 at any time point as long as rats are still alive, and also effectively block cocaine‐induced hyperactivity 23,28,30,37,45 . However, it was unknown whether an enzyme can also effectively block cocaine‐induced DAT trafficking to plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

“…[19][20][21][22] Further, we have also designed and discovered a long-acting form of the CocH (denoted as CocH-Fc) 23,24 through protein fusion with the Fc fragment (wild-type or mutant) of human immunoglobulin G1 (IgG1). It has been demonstrated that these CocHs and CocH-Fc proteins are capable of accelerating cocaine metabolism, rapidly detoxifying cocaine and its toxic metabolites, [25][26][27][28][29] and that a single dose of the CocH-Fc protein can effectively block the physiological, discriminative stimulus and reinforcing effects of cocaine for a long period of time (weeks). 23,28,30 It would be interesting to know whether a CocH-Fc protein can also block cocaine-induced DAT trafficking while blocking cocaine's physiological effects.…”

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confidence: 99%

Cocaine hydrolase blocks cocaine‐induced dopamine transporter trafficking to the plasma membrane

et al. 2021

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Cocaine blocks dopamine uptake via dopamine transporter (DAT) on plasma membrane of neuron cells and, as a result, produces the high and induces DAT trafficking to plasma membrane which contributes to the drug seeking or craving. In this study, we first examined the dose dependence of cocaine-induced DAT trafficking and hyperactivity in rats, demonstrating that cocaine at an intraperitoneal dose of 10 mg/kg or higher led to redistribution of most DAT to the plasma membrane while inducing significant hyperactivity in rats. However, administration of 5-mg/kg cocaine (ip) did not significantly induce DAT trafficking or hyperactivity in rats. So the threshold (intraperitoneal) dose of cocaine that can significantly induce DAT trafficking or hyperactivity should be between 5 and 10 mg/kg. These data suggest that when a cocaine dose is high enough to induce significant hyperactivity, it can also significantly induce DAT trafficking to the plasma membrane. Further, the threshold brain cocaine concentration required to induce significant hyperactivity and DAT trafficking was estimated to be $2.0 ± 0.8 μg/g. Particularly, for treatment of cocaine abuse, previous studies demonstrated that an exogenous cocainemetabolizing enzyme, for example, CocH3-Fc(M3), can effectively block cocaineinduced hyperactivity. However, it was unknown whether an enzyme could also effectively block cocaine-induced DAT trafficking to the plasma membrane. This study demonstrates, for the first time, that the enzyme is also capable of effectively blocking cocaine from reaching the brain even with a lethal dose of 60-mg/kg cocaine (ip) and, thus, powerfully preventing cocaine-induced physiological effects such as the hyperactivity and DAT trafficking.

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“…In chronic users, the maximum time for detection of benzoylecgonine in urine is 22 days after the last use [Verstraete 2004]. Norcacaine, a metabolite known for its vasoconstrictive effects, has also been shown to be highly cardiotoxic [Kovacic et al 1988;Zheng et al 2019].…”

Section: мEtabolites Of Cocaine With Expressed Cardiotoxicitymentioning

confidence: 99%

Oxidative Stress and Cocaine Intoxication as Start Points in the Pathology of Cocaine-Induced Cardiotoxicity. A Systematic Review

Georgieva

Karamalakova

Nikolova

2021

Preprint

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Background: Psychomotor stimulants are the most commonly used prohibited substances after cannabis. Globally, their use reaching epidemiological proportions and is one of the most common causes of death in many countries. In recent years, more research, define drug use as the leading cause of serious cardiovascular pathologies ranging from abnormal heart rhythms to heart attack and sudden cardiac death. The reactive oxygen species generation, toxic metabolites formation and oxidative stress play a significant role in cocaine-induced cardiotoxicity. Main body: In the present review, we discuss various studies related to dopamine neurotransmission and oxidative stress, with a focus on the cardiotoxicity of the cocaine molecule and the cardiovascular complications that occur after cocaine use. Conclusion: Hypothetically, this study can serve as a basis for developing a rapid and effective method for determining oxidative stress levels by monitoring changes in the redox status of patients with cocaine intoxication.

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In vivo characterization of toxicity of norcocaethylene and norcocaine identified as the most toxic cocaine metabolites in male mice

Cited by 18 publications

References 21 publications

Recovery of dopaminergic system after cocaine exposure and impact of a long‐acting cocaine hydrolase

Recovery of dopaminergic system after cocaine exposure and impact of a long‐acting cocaine hydrolase

Cocaine hydrolase blocks cocaine‐induced dopamine transporter trafficking to the plasma membrane

Oxidative Stress and Cocaine Intoxication as Start Points in the Pathology of Cocaine-Induced Cardiotoxicity. A Systematic Review

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