Detection of heroin addiction- and relapse-induced axonal transport dysfunction in the brain in vivo by MRI

Abstract

Purpose Heroin is a highly addictive drug that causes axonal damage. Here, manganese-enhanced magnetic resonance imaging (MEMRI) was used to dynamically monitor axonal transport in different stages after heroin addiction.Methods Rodent models of heroin addiction (HA) and heroin relapse (HR) were established by injection of different doses of heroin solution at different times. Heroin-induced learning and memory deficits were evaluated by the Morris water maze (MWM). MEMRI was used to dynamically evaluate axonal transport through the olfactory pathway. The expression of proteins related to axonal structure and function were assessed by western blotting. Transmission electron microscopy (TEM) was used to observe ultrastructural changes. Neurofilament heavy chain (NF-H) protein levels were analyzed by immunofluorescence staining.Result HA model rats and especially HR model rats showed worse spatial learning and memory abilities than control rats. Compared with HA model rats and control rats, HR model rats exhibited a significant increase in escape latency and significant decreases in the number of platform location crossings and time spent in the target quadrant. Mn2+ transport was accelerated in HA model rats. HR model rats exhibited a severely insufficient capacity for Mn2+ transport, and the axonal transport rate (ATR) was significantly reduced in these rats compared to control rats (P<0.001). The levels of cytoplasmic dynein and KIF5 in rats in the HR group were significantly decreased (P<0.001), and the levels of energy-related proteins, including COX IV and ATPB, were lower in the HR group than the control group (P<0.001). The brains of heroin-exposed rats showed an abnormal ultrastructure, exhibiting neuronal apoptosis and mitochondrial dysfunction. Heroin decreased the expression of NF-H, with the staining intensity being significantly reduced in tissues from HA and HR model rats (P<0.05).Conclusion MEMRI can detect axonal transport dysfunction caused by long-term repeated exposure to heroin, and decreases in the levels of motor proteins and mitochondrial dysfunction may be the main causes of this axonal transport impairment. Thus, the study shows that MEMRI is a potential tool for visualizing axonal transport in individuals experiencing drug addiction, providing a new direction for the evaluation of addictive drug withdrawal.