PLG and substance abuse: It has been shown that exogenous tPA administration increases hippocampal BDNF levels61 and the conversion of pro‐BDNF to BDNF by plasmin is essential for LTP late‐phases.62, 63 In addition, a defective tPA/plasmin/PAI‐1‐mediated BDNF maturation has been claimed to be involved in the manifestation of some brain pathologies, such as substance abuse and addiction,64, 65 depression,66 and stress.67