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

Deng, Jing; Zhang, Ting; Zheng, Xirong; Shang, Linyue; Chen, Zhan; Zheng, Fang

doi:10.1111/adb.13179

Cited by 8 publications

(34 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Striatum samples were quickly isolated on ice and immediately treated using our previously reported procedure. 49,55 The treated striatum samples were analyzed for striatal DAT distribution, particularly the intracellular and plasma membrane fractions of DAT using a protocol described previously in detail. 49 Statistical Analysis.…”

Section: Methodsmentioning

confidence: 99%

“…For dopamine transporter (DAT) trafficking analysis, at 24 h after IP administration of 60 mg/kg cocaine, rats ( n = 4) were decapitated under deep anesthesia with CO 2 (40% chamber replacement rate, 3–4 min) to collect the brain samples. Striatum samples were quickly isolated on ice and immediately treated using our previously reported procedure. , The treated striatum samples were analyzed for striatal DAT distribution, particularly the intracellular and plasma membrane fractions of DAT using a protocol described previously in detail …”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Development of a Highly Efficient Long-Acting Cocaine Hydrolase Entity to Accelerate Cocaine Metabolism

et al. 2022

Self Cite

View full text Add to dashboard Cite

It is particularly challenging to develop a truly effective pharmacotherapy for cocaine use disorder (CUD) treatment. Accelerating cocaine metabolism via hydrolysis at cocaine benzoyl ester using an efficient cocaine hydrolase (CocH) is known as a promising pharmacotherapeutic approach to CUD treatment. Preclinical and clinical studies on our first CocH (CocH1), in its human serum albumin-fused form known as TV-1380, have demonstrated the promise of a general concept of CocH-based pharmacotherapy for CUD treatment. However, the biological half-life of TV-1380 (t 1/2 = 8 h in rats, associated with t 1/2 = 43−77 h in humans) is not long enough for practical treatment of cocaine dependence, which requires enzyme injection for no more than once weekly. Through protein fusion of a human butyrylcholinesterase mutant (denoted as CocH5) with a mutant (denoted as Fc(M6)) of Fc from human IgG1, we have designed, prepared, and tested a new fusion protein (denoted as CocH5-Fc(M6)) for its pharmacokinetic profile and in vivo catalytic activity against (−)-cocaine. CocH5-Fc(M6) represents the currently most efficient long-acting cocaine hydrolase with both the highest catalytic activity against (−)-cocaine and the longest elimination half-life (t 1/2 = 229 ± 5 h) in rats. As a result, even at a single modest dose of 3 mg/kg, CocH5-Fc(M6) can significantly and effectively accelerate the metabolism of cocaine in rats for at least 60 days. In addition, ∼70 nM CocH5-Fc(M6) in plasma was able to completely block the toxicity and physiological effects induced by intraperitoneal injection of a lethal dose of cocaine (60 mg/kg).

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Development of a Highly Efficient Long-Acting Cocaine Hydrolase Entity to Accelerate Cocaine Metabolism

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…administration of 20 mg/kg cocaine for 17 times in male rats was upregulated from $5.7% (negative control) to 97.1 ± 0.2% on Day 1 and decreased to 40.8 ± 3.1% on Day 30, 15.3 ± 1.2% on Day 60 and then 12.3 ± 1.3% on Day 90 after the last exposure of 20 mg/kg cocaine (i.p.). 17 According to the data in Figure 4, the initial recovery process during the first 30 days was relatively faster (from 91.7 ± 0.8% on Day 1 to 31.4 ± 2.3% on Day 30) and then slowed down afterward. Remarkably, the plasma membrane fraction (9.0 ± 2.6%) on Day 60 was not significantly different from the negative control (4.5 ± 1.0%).…”

Section: Recovery Of the Dopaminergic System In Female Rats After Coc...mentioning

confidence: 90%

“…that were found important for male rats. 17 Likewise, rat brain samples were collected at 24 h after i.p. administration of cocaine or saline.…”

Section: Dat Trafficking Induced By Acute Cocaine Administration In F...mentioning

confidence: 99%

Gender differences in cocaine‐induced hyperactivity and dopamine transporter trafficking to the plasma membrane

et al. 2022

Self Cite

View full text Add to dashboard Cite

As well known, cocaine induces stimulant effects and dopamine transporter (DAT) trafficking to the plasma membrane of dopaminergic neurons. In the present study, we examined cocaine‐induced hyperactivity along with cocaine‐induced DAT trafficking and the recovery rate of the dopaminergic system in female rats in comparison with male rats, demonstrating interesting gender differences. Female rats are initially more sensitive to cocaine than male rats in terms of both the DAT trafficking and hyperactivity induced by cocaine. Particularly, intraperitoneal (i.p.) administration of 5 mg/kg cocaine induced significant hyperactivity and DAT trafficking in female rats but not in male rats. After repeated cocaine exposures (i.e., i.p. administration of 20 mg/kg cocaine every other day from Day 0 to Day 32), cocaine‐induced hyperactivity in female rats gradually became a clear pattern of two phases, with the first phase of the hyperactivity lasting for only a few minutes and the second phase lasting for over an hour beginning at ~30 min, which is clearly different from that of male rats. It has also been demonstrated that the striatal DAT distribution of female rats may recover faster than that of male rats after multiple cocaine exposures. Nevertheless, despite the remarkable gender differences, our recently developed long‐acting cocaine hydrolase, known as CocH5‐Fc(M6), can similarly and effectively block cocaine‐induced DAT trafficking and hyperactivity in both male and female rats.

show abstract

“…5,7 It has also been demonstrated in rats that CocH5-Fc(M6) can effectively protect the dopaminergic system and help the cocaine-altered dopamine transporter (DAT) distribution to recover by preventing the dopaminergic system from further damage by cocaine. 5,6 Further, we wanted to know whether CocH5-Fc(M6) can also effectively accelerate further metabolism of norcocaine (as it is even more toxic than cocaine 17 ) and benzoylecgonine (as it might be responsible for the long-term toxicity of cocaine 11 ). This is particularly important for treatment of cocaine toxicity (overdose conditions).…”

Section: Introductionmentioning

confidence: 99%

Catalytic activities of a highly efficient cocaine hydrolase for hydrolysis of biologically active cocaine metabolites norcocaine and benzoylecgonine

Shang

Jin

Wei

et al. 2022

Preprint

View full text Add to dashboard Cite

Cocaine is a widely abused, hepatotoxic drug without an FDA-approved pharmacotherapy specific for cocaine addiction or overdose. It is recognized as a promising therapeutic strategy to accelerate cocaine metabolism which can convert cocaine to pharmacologically inactive metabolite(s) using an efficient cocaine-metabolizing enzyme. Our previous studies have successfully designed and discovered a highly efficient cocaine hydrolase, denoted as CocH5-Fc(M6), capable of rapidly hydrolyzing cocaine at the benzoyl ester moiety. In the present study, we determined the kinetic parameters of CocH5-Fc(M6) against norcocaine (kcat = 9,210 min-1, KM = 20.9 µM, and kcat/KM = 1.87 × 105 min-1 M-1) and benzoylecgonine (kcat = 158 min-1, KM = 286 µM, and kcat/KM = 5.5 × 105 min-1 M-1) for the first time. Further in vivo studies have demonstrated that CocH5-Fc(M6) can effectively accelerate clearance of not only cocaine, but also norcocaine (known as a cocaine metabolite which is more toxic than cocaine itself) and benzoylecgonine (known as an unfavorable long-lasting metabolite with some long-term toxicity concerns) in rats. Due to the desired high catalytic activity against norcocaine, CocH5-Fc(M6) is capable of quickly detoxifying both cocaine and its more toxic metabolite norcocaine after intraperitoneally administering lethal dose of 60 or 180 mg/kg cocaine. In addition, the ability of CocH5-Fc(M6) to accelerate clearance of benzoylecgonine should also be valuable for the use of CocH5-Fc(M6) in treatment of cocaine use disorder.

show abstract

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

Cited by 8 publications

References 50 publications

Development of a Highly Efficient Long-Acting Cocaine Hydrolase Entity to Accelerate Cocaine Metabolism

Development of a Highly Efficient Long-Acting Cocaine Hydrolase Entity to Accelerate Cocaine Metabolism

Gender differences in cocaine‐induced hyperactivity and dopamine transporter trafficking to the plasma membrane

Catalytic activities of a highly efficient cocaine hydrolase for hydrolysis of biologically active cocaine metabolites norcocaine and benzoylecgonine

Contact Info

Product

Resources

About