The Rivers of Lethe and Mnemosyne Converge

Abstract

Propofol and Memory Consolidation S INCE its introduction in the 1980s, propofol has be-come the most widely used intravenous anesthetic in clinical anesthesia. Its success is attributable to its pharmaco-kinetic 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 po-tent amnestic agent, a desirable action in many of the un-pleasant and stressful applications for its use. Modulation of receptors for the inhibitory neurotransmitter ␥-aminobu-tyric 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. 1 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 recep-tors and is responsible for mediating tonic inhibitory cur-rents in many neurons. Knockout of this receptor subunit in mice eliminates the memory-blocking action of etomidate without affecting sedation or hypnosis. 2 Another potential target that has been implicated in the amnestic actions of propofol is the endocannabinoid system, a widespread para-crine cell-signaling mechanism integral to several forms of short-and long-term synaptic plasticity. 3 Now comes a fas-cinating study published this month in ANESTHESIOLOGY 4 showing that the endocannabinoid system indeed contrib-utes to the effects of propofol on memory but counterintui-tively by enhancing retrograde memory consolidation rather than suppressing anterograde memory, the better known ef-fect of propofol on memory. This novel twist in the pharma-cology 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 consolida-tion of anterograde memory and facilitate consolidation of retrograde memory. The endocannabinoid system consists of cannabinoid re-ceptors, of which there are two well-characterized subtypes (CB1 and CB2), endogenous cannabinoids (endocannabi-noids) such as anandamide, and the metabolic pathways re-sponsible for endocannabinoid synthesis and degradation. CB1 receptors are highly expressed in brain and mediate most of the psychotropic effects of ⌬ 9 -tetrahydrocannabinol (⌬ 9 THC), the principal psychoactive component of canna-bis. Propofol has been shown 5 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 concen-trations of anandamide in mice in vivo. 5 Loss of righting reflex, an index of hypnosis in mice, after administration of propofol, but not thiopental, was antagonized by pretreat-ment 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 mida-zolam, 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. In-teraction 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 alter-ing, 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.