Impact of a highly potent and long-acting cocaine hydrolase on recovery of dopaminergic system after cocaine exposure

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 our lab’s studies, 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 from days 0 to 32, the complete recovery of striatal DAT distribution may take an even longer time (~90 days), which represents a consequence of chronic cocaine use. Further, we demonstrated that one of our highly efficient Fc-fused cocaine hydrolases, CocH5-Fc(M6), effectively blocked cocaine-induced DAT trafficking and associated behavioral effects with repeated cocaine exposures by maintaining a plasma CocH5-Fc(M6) concentration ≥58.7±2.9 nM in rats. CocH5-Fc(M6) protected dopaminergic system and helped the cocaine-altered DAT distribution to recover by preventing the dopaminergic system from further damage by cocaine in both male and female rats.