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Brain interstitial fluid drainage and extracellular space are closely related to waste clearance from the brain.Different anesthetics may cause different changes of brain interstitial fluid drainage and extracellular space but these still remain unknown.Herein,effects of the inhalational isoflurane,intravenous sedative dexmedetomidine and pentobarbital sodium on deep brain matters' interstitial fluid drainage and extracellular space and underlying mechanisms were investigated.When compared to intravenous anesthetic dexmedetomidine or pentobarbital sodium,inhalational isoflurane induced a restricted diffusion of extracellular space,a decreased extracellular space volume fraction,and an increased norepinephrine level in the caudate nucleus or thalamus with the slowdown of brain interstitial fluid drainage.A local administration ofnorepinephrine receptor antagonists,propranolol,atipamezole and prazosin into extracellular space increased diffusion of extracellular space and interstitial fluid drainage whilst norepinephrine decreased diffusion of extracellular space and interstitial fluid drainage.These findings suggested that restricted diffusion in brain extracellular space can cause slowdown of interstitial fluid drainage,which may contribute to the neurotoxicity following the waste accumulation in extracellular space under inhaled anesthesia per se.