The rivers of Lethe and Mnemosyne converge: propofol and memory consolidation.

S INCE its introduction in the 1980s, propofol has become the most widely used intravenous anesthetic in clinical anesthesia. Its success is attributable to its pharmacokinetic advantages and its versatile applications, including the induction and maintenance of general anesthesia and procedural and intensive care sedation. In addition to its well-known sedative and hypnotic actions, propofol is a potent amnestic agent, a desirable action in many of the unpleasant and stressful applications for its use. Modulation of receptors for the inhibitory neurotransmitter -aminobutyric acid is an important molecular mechanism for some of the pharmacologic effects of propofol. Thus, knock-in mice harboring -aminobutyric acid receptor type A 3 subunits rendered insensitive to propofol or etomidate by a single point mutation are resistant to the immobilizing effects of propofol and etomidate in vivo. The molecular mechanism for the amnestic actions of propofol has not been identified directly, but a promising candidate is modulation of the 5 -aminobutyric acid receptor type A subunit. This subunit is expressed in extrasynaptic -aminobutyric acid type A receptors and is responsible for mediating tonic inhibitory currents in many neurons. Knockout of this receptor subunit in mice eliminates the memory-blocking action of etomidate without affecting sedation or hypnosis. Another potential target that has been implicated in the amnestic actions of propofol is the endocannabinoid system, a widespread paracrine cell-signaling mechanism integral to several forms of shortand long-term synaptic plasticity. Now comes a fascinating study published this month in ANESTHESIOLOGY showing that the endocannabinoid system indeed contributes to the effects of propofol on memory but counterintuitively by enhancing retrograde memory consolidation rather than suppressing anterograde memory, the better known effect of propofol on memory. This novel twist in the pharmacology of propofol suggests that a single drug blends the waters from Lethe, the river of forgetfulness, with the waters from Mnemosyne, the river of memory, to block consolidation of anterograde memory and facilitate consolidation of retrograde memory. The endocannabinoid system consists of cannabinoid receptors, of which there are two well-characterized subtypes (CB1 and CB2), endogenous cannabinoids (endocannabinoids) such as anandamide, and the metabolic pathways responsible for endocannabinoid synthesis and degradation. CB1 receptors are highly expressed in brain and mediate most of the psychotropic effects of -tetrahydrocannabinol ( THC), the principal psychoactive component of cannabis. Propofol has been shown to inhibit the activity of fatty acid amide hydrolase, a key enzyme in the degradation of anandamide (fig. 1). Patel et al. reported that sedative doses of propofol, but not of thiopental, increased brain concentrations of anandamide in mice in vivo. Loss of righting reflex, an index of hypnosis in mice, after administration of propofol, but not thiopental, was antagonized by pretreatment with the CB1 receptor antagonist rimonabant, whereas pretreatment with WIN 55212-2, a CB1 receptor agonist, potentiated loss of righting reflex caused by propofol. In addition, propofol, but not thiopental, etomidate, or midazolam, inhibited fatty acid amide hydrolase activity in vitro. These findings implicated the endocannabinoid system in the sedative actions of propofol, but not of the other intravenous general anesthetics tested, through inhibition of the degradation of endogenous CB1 receptor agonists such as anandamide. Interaction with the endocannabinoid system by propofol is an attractive candidate for some of the agent-specific actions of propofol, compared with other general anesthetics, that are shared with cannabinoids including its antiemetic, mood altering, and postoperative dreaming effects. Impaired learning and memory are well-known effects of cannabinoids. These actions can be observed in animal models of memory that depend on the hippocampus, a brain region critical to various forms of memory and known to express high concentrations of CB1 receptors. A role for the endocannabinoid system in anterograde memory is supported by observations that cannabinoid agonists impair, whereas antagonists or CB1 receptor knock-down enhance, performance on hippocampal-dependent memory tasks. However, recent studies demonstrate that cannabinoids can facilitate memory consolidation in specific situations, particularly in memory tasks that involve an emotional component such as fear conditioning. With this in mind, Hauer et al. tested the hypothesis that propofol effects on endocannabinoid signaling are involved in enhanced consolidation of emotionally charged memories. Such an effect could be clinically relevant to posttraumatic stress disorder after intraoperative awareness or stressful intensive care unit events. Accepted for publication March 25, 2011. The authors are not supported by, nor maintain any financial interest in, any commercial activity that may be associated with the topic of this article. The figure in this article was redrawn by Annemarie B. Johnson, C.M. I. , Medical Illustrator, Wake Forest University School of Medicine Creative Communications, Wake Forest University Medical Center, Winston-Salem, North Carolina.