Facilitation of serotonergic activity and amnesia in rats caused by intravenous anesthetics

Midazolam and propofol often provoke retrograde amnesia after recovery from anesthesia in humans. Because an increase in central serotonergic activity impairs learning and memory, the authors examined the relation between changes in the serotonergic activity caused by intravenous anesthetics and memory.

Changes in extracellular concentrations of monoamines and their metabolites were investigated in rat striatum by a microdialysis procedure, and the effects of intraperitoneal injections of midazolam (5 mg/kg), propofol (60 mg/kg), and pentobarbital (15 mg/kg) were then examined. To evaluate the behavioral alteration with these agents, the authors used a step-through passive avoidance test.

Midazolam and propofol slightly increased the extracellular concentration of 5-hydroxytryptamine in the striatum, although pentobarbital did not produce any changes. Midazolam and propofol increased the extracellular concentration of 5-hydroxyindoleacetic acid, a metabolite of 5-hydroxytryptamine, with the peak values each 138% and 138% of that in saline-injected animals, respectively. However, pentobarbital decreased the 5-hydroxyindoleacetic acid concentration to 61% of that in the saline group. Administration of midazolam or propofol immediately after the completing the passive avoidance learning reduced step-through latencies after 24 h, although pentobarbital-injected animals maintained a consistent performance. The effects of midazolam and propofol on step-through latencies were completely antagonized by intracerebroventricular administration of spiroxatrine (5 microg), a 5-hydroxytryptamine 1A antagonist, 30 min before training.

Midazolam and propofol increased central serotonergic activity and provoked retrograde amnesia. Because amnesia was completely diminished by a 5-hydroxytryptamine antagonist, facilitation of the serotonergic system may be involved in retrograde amnesia caused by these agents.