Melatonin Protects Against Cocaine‐Induced Blood−Brain Barrier Dysfunction and Cognitive Impairment by Regulating miR‐320a‐Dependent GLUT1 Expression

ABSTRACT Cocaine abuse has been strongly linked to blood−brain barrier (BBB) dysfunction, though the exact mechanism by which cocaine disrupts the BBB remains unclear. In this study, we found that cocaine treatment reduces the expression of glucose transporter 1 (GLUT1) in brain microvascular endothelial cells, a key factor in cocaine‐induced brain glucose uptake, BBB leakage, and cognitive impairment. Mechanistically, our results show that cocaine upregulates miR‐320a, which in turn suppresses GLUT1 expression via the beta 2‐adrenergic receptor (ADRB2). Notably, the administration of adeno‐associated viruses encoding full‐length GLUT1 or miR‐320a inhibitors to the brain microvascular endothelium significantly mitigated cocaine‐induced BBB leakage and cognitive deficits. Additionally, we discovered that melatonin, a well‐known neuroprotective hormone, alleviates cocaine‐induced BBB disruption and cognitive impairment. This protective effect of melatonin was mediated through the upregulation of miR‐320a‐dependent GLUT1 expression in brain endothelial cells via MT 1 receptor‐mediated inhibition of the cAMP/PKA/CREB signaling pathway. In conclusion, our findings demonstrate that cocaine downregulates brain microvascular GLUT1, leading to BBB dysfunction, and highlight melatonin as a potential therapeutic agent for treating cocaine‐related complications.