Cocaine preferentially potentiates the fast-releasable vesicle pool in mouse dopaminergic striatum in vivo

Cocaine, an addictive drug of abuse, increases the extracellular dopamine(DA) concentration in the basal ganglia, which is previously assumed to occur mainly through the inhibition of the reuptake activity of DA transporter(DAT). Under physiological in vivo conditions, however, it remains unclear whether cocaine affects DA release as well. Here, we report two kinetically distinct DA releasable vesicle pools, a fast-releasable pool(FRP) and a prolonged-releasable pool(PRP) in mouse striatum following physiological frequency stimulation of the medial forebrain bundle in vivo. Surprisingly, cocaine selectively enhanced the DA release from and vesicle replenishment in FRP. Using a cocaine-insensitive DAT knockin mouse, we found that cocaine-facilitated FRP release was mediated by DAT, the same protein for DA reuptake. In contrast, PRP release was selectively modulated by methamphetamine(m AMPH) and D2 receptor. Finally:FRP had a distinct impact on locomotor behaviors. Thus, following cocaine-DAT-binding, DA overf...Cocaine, an addictive drug of abuse, increases the extracellular dopamine(DA) concentration in the basal ganglia, which is previously assumed to occur mainly through the inhibition of the reuptake activity of DA transporter(DAT). Under physiological in vivo conditions, however, it remains unclear whether cocaine affects DA release as well. Here, we report two kinetically distinct DA releasable vesicle pools, a fast-releasable pool(FRP) and a prolonged-releasable pool(PRP) in mouse striatum following physioAsian Biophysics Association (ABA)、Biophysical Society of China (BSC)、Institute of Biophysics, Chinese Academy of Sciences