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Propofol is widely used as a short-acting intravenous anaesthetic for the induction and maintenance of anaesthetic sedation. The application of propofol is expanding due to its advantages and the increasing demand for painless diagnosis and treatment. However, accumulating clinical and experimental evidence has shown that propofol can potentially be abused and is prone to causing addiction. To further understand the underlying mechanism of propofol addiction, our review places emphasis on explaining the roles of the mesolimbic, noradrenergic, and nitrergic systems in propofol addiction. We have focused on the role of the gamma-aminobutyric acid, glucocorticoid, N-methyl-D-aspartic acid, adenosine A2A, and corticotropin-releasing factor receptors in the mesolimbic system in forming and maintaining propofol addiction. Furthermore, we have attempted to clarify the relationship between the dopaminergic pathway, extracellular signal-regulated kinase signalling pathway, and the ventral tegmental area-nucleus accumbens circuit in the mesolimbic system. Key Policy Highlights Although propofol is effective in inducing and maintaining anesthesia, it is prone to cause abuse and addiction. The mesolimbic, noradrenergic, and nitrergic systems are involved in propofol addiction. The dopaminergic pathway, extracellular signal-regulated kinase signalling pathway, and the ventral tegmental area-nucleus accumbens circuit in the mesolimbic system may be involved in the maintenance of propofol addiction.