Endocannabinoids: The silent partner of glucocorticoids in the synapse

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Abstract
Although it has long been recognized that steroid hormones primarily exert their effects on neuronal function through their ability to modulate gene transcription in the nucleus (1), an array of physiological and behavioral effects of glucocorticoids have been documented to occur in a fashion that cannot be explained by genomic regulation (2). These findings have prompted the hypothesis that glucocorticoids (in addition to all other major classes of steroids) possess membrane-associated receptors through which nongenomic signaling may evoke rapid effects on physiology and behavior (2, 3). Research from Miles Orchinik and Frank Moore (4) in the early 1990s clearly demonstrated the presence of glucocorticoid receptors in the neuronal membrane of an amphibian species that evoked observable effects on neuronal signaling and behavior, but progress in this field has been hampered by a lack of comparable discoveries in mammalian species. However, recent data in a study in this issue of PNAS (5) sheds new light on the rapid effects of glucocorticoids in mammals by revealing a putative nongenomic role of glucocorticoids in regulating emotional learning in rodents through a coordinated induction of endocannabinoid signaling. The report by Campolongo et al. (5) focuses on the role of endocannabinoid signaling in the amygdala in the consolidation of emotionally-aversive memory (5). Previous research has convincingly demonstrated that the consolidation of aversive memories is facilitated by cross-talk between glucocorticoids and noradrenergic signaling in the basolateral nucleus of the amygdala (BLA; ref. 6). The current data add a new player to this game by demonstrating that intra-BLA administration of a cannabinoid CB1 receptor agonist or antagonist immediately after inhibitory avoidance training dose-dependently enhanced or impaired emotional memory consolidation, respectively (5). More interesting, however, was the fact that intra-BLA administration of a CB1 receptor antagonist, at a dose previously ineffective in modulating memory consolidation, …