Molecular Modeling and Biopharmaceutical Center, University of Kentucky, 789 South Limestone Street, Lexington, Kentucky, 40536, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, Kentucky, 40536, USA.
Addict Biol. 2022 Jul;27(4):e13179. doi: 10.1111/adb.13179.
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.
多巴胺转运体（DAT）在多巴胺能系统中的失调是可卡因暴露的一个重要生物标志物。取决于摄入的可卡因量，单次暴露于大鼠中可能导致大多数（超过总 DAT 的 95%）DAT 易位到多巴胺能神经元的质膜，而正常 DAT 分布为 (~5.7%位于质膜上)。在没有进一步可卡因暴露的情况下，纹状体 DAT 分布的时间过程，就 DAT 的细胞内和质膜部分而言，代表了多巴胺能系统的恢复过程。在这项研究中，我们表明，在单次 20mg/kg（ip）可卡因暴露后，大鼠在第 1 天到第 15 天的初始恢复过程相对较快（从第 1 天的 >95%到第 15 天的约 35.4%）。然而，纹状体 DAT 分布的完全恢复可能需要大约 60 天。在另一种情况下，每天重复一次可卡因暴露，总共给予 17 次 20mg/kg（ip）可卡因（从第 0 天到第 32 天），纹状体 DAT 分布的完全恢复可能需要更长的时间（约 90 天），这代表了慢性可卡因使用的后果。此外，我们表明，一种高效的 Fc 融合可卡因水解酶，CocH5-Fc（M6），通过在大鼠中维持血浆 CocH5-Fc（M6）浓度≥58.7±2.9 nM，有效地阻断了重复可卡因暴露引起的可卡因诱导的多动和 DAT 转运。可卡因水解酶通过防止多巴胺能系统进一步受到可卡因的损伤，保护多巴胺能系统并帮助可卡因改变的 DAT 分布恢复。
