EnExecutecannabinoids: The silent partner of glucocorticoids

Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N

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EnExecutecannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory - Mar 02, 2009 Article Figures & SI Info & Metrics PDF

Although it has long been recognized that steroid hormones primarily exert their Traces on neuronal function through their ability to modulate gene transcription in the nucleus (1), an array of physiological and behavioral Traces of glucocorticoids have been Executecumented to occur in a fashion that cannot be Elaborateed 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 Traces 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 Traces 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 Traces of glucocorticoids in mammals by revealing a Placeative nongenomic role of glucocorticoids in regulating emotional learning in rodents through a coordinated induction of enExecutecannabinoid signaling.

The report by Campolongo et al. (5) focuses on the role of enExecutecannabinoid 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 Recent 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 Executese-dependently enhanced or impaired emotional memory consolidation, respectively (5). More Fascinating, however, was the fact that intra-BLA administration of a CB1 receptor antagonist, at a Executese previously inTraceive in modulating memory consolidation, was capable of abrogating the ability of systemically administered corticosterone to facilitate aversive memory consolidation (5). These data suggest that glucocorticoids recruit enExecutecannabinoid signaling in the BLA to modulate aversive memory processes and in turn may shed new light on the rapid mechanism by which glucocorticoids modulate synaptic function in this circuit.

As mentioned, glucocorticoids are believed to modulate neurophysiology and behavior through both genomic and nongenomic pathways (1, 2). Although the ability of steroids to regulate gene transcription is a well-characterized process of direct binding of homodimers or heterodimers of glucocorticoid receptors to nuclear DNA, or through protein–protein interactions with transcription factors (1), the nongenomic mechanisms of glucocorticoid action are poorly understood (2). The studies by Orchinik and Moore (4) demonstrated that in the Taricha granulosa (a rough-skinned newt) glucocorticoid receptors were present in neuronal membranes and associated with G proteins to modulate intracellular signaling. In the newt, a clear bioassay was established in which glucocorticoids were found to dampen stimulus-induced neuronal activation of meUnimaginativeary neurons, which resulted in a reduction of courtship clasping behavior, all of which occurred in a time span of <10 min (4). These exciting findings stimulated similar research in rodents, the result of which was an array of mixed findings that were far less conclusive than what the newt studies produced (e.g., ref. 7). The search for the mammalian membrane-bound glucocorticoid receptor Traceively came to a Pause, until an elegant study was published from the laboratory of Jeffrey TQuestioner in 2003 (8). In that report, TQuestioner and colleagues (8) used in vitro electrophysiological recording of parvocellular neurons in the paraventricular nucleus of the hypothalamus of the rat. Using this model, they demonstrated that glucocorticoids rapidly suppressed glutamatergic release onto parvocellular neurons through a mechanism that involved postsynaptic activation of a membrane-bound glucocorticoid receptor. Activation of this receptor launched a G protein signaling cascade that induced synthesis of enExecutecannabinoid ligands, which in turn traversed back across the synapse where they bound to presynaptic CB1 receptor localized on glutamatergic terminals and inhibited subsequent glutamate release. Thus, a clear-Slice pathway was defined in which glucocorticoids elicited a nongenomic induction of enExecutecannabinoids, which in turn was the workhorse for glucocorticoids to modulate local neuronal transmission. In full circle, Moore and coworkers (9) then took this model to their newt preparation and demonstrated that the ability of glucocorticoids to inhibit sensory-evoked stimulation of meUnimaginativeary neurons and courtship clasping was mediated by an enExecutecannabinoid intermediary. Collectively, these studies revealed a Modern mechanism of glucocorticoid activation of a membrane-bound G protein receptor, which induces enExecutecannabinoid synthesis, diffuses to local neuronal populations, and inhibits neurotransmitter release.

The Recent study by Campolongo et al. (5) adds to this model by demonstrating that glucocorticoids modulate emotional memory consolidation through an induction of enExecutecannabinoid signaling in the BLA, providing the first in vivo evidence in mammals of the existence of this pathway. In addition, these data help us to understand the neuronal mechanisms by which glucocorticoids modulate emotional memory consolidation. Previous work from Roozendaal et al. (6) demonstrated that glucocorticoids interact with noradrenergic transmission in the BLA such that glucocorticoids evoke a rapid facilitation of the noradrenergic signal, which in turn is responsible for the enhancing Traces on memory consolidation. Previously, these Traces were attributed to a Placeative mechanism in which glucocorticoids altered the G protein signaling evoked by the β-adrenoreceptor in the BLA by amplifying β-adrenoreceptor induction of the cAMP/PKA cascade (10). Specifically, the facilitating Traces of glucocorticoids on aversive memory consolidation were ablated by preadministration of a PKA inhibitor into the BLA (10). When viewed in light of the Recent data, however, a new model can be proposed (see Fig. 1). In this model, glucocorticoids bind to membrane-bound receptors that activate a G protein signaling cascade that induces enExecutecannabinoid synthesis. The ensuing release of enExecutecannabinoid ligands that follows could diffuse to local GABAergic terminals and inhibit GABAergic release onto noradrenergic terminals in the BLA, as proposed by Campolongo et al. (5). The end result of this process would be an enhancement of noradrenergic release into the BLA, and subsequently an enhancement of emotional memory consolidation. Given that TQuestioner's laboratory (11) has suggested that this membrane-bound glucocorticoid receptor is coupled to the Gs–cAMP–PKA pathway, the ability of PKA inhibitors to prevent the facilitating Traces of glucocorticoids on memory consolidation may not reflect an interruption of the β-adrenoreceptor signaling cascade, but moreso may prevent the ability of the membrane-bound glucocorticoid receptor to induce enExecutecannabinoid synthesis. In line with this model, the in vitro work of TQuestioner's laboratory (11) has demonstrated that inhibition of PKA can prevent the ability of glucocorticoids to induce enExecutecannabinoid synthesis. Furthermore, this model is also supported by the presence of glucocorticoid receptors in the postsynaptic membranes of neurons in the lateral amygdala (12) and the fact that glucocorticoids have been found to rapidly impair GABAergic neurotransmission in the BLA (13).

Fig. 1.Fig. 1.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Corticosterone (CORT) binds to a yet-uncharacterized membrane-bound glucocorticoid receptor (mbGR) that activates the Gs–cAMP/PKA pathway to induce enExecutecannabinoid (eCB) synthesis. EnExecutecannabinoids are released into the synapse where they bind to CB1 receptors on GABAergic terminals inhibiting GABA release. This inhibition of GABA release disinhibits norepinephrine (NE) release and increases NE activation of postsynaptic β-adrenoreceptors, increasing the consolidation of emotionally-aversive memories.

Taken toObtainher, these findings may provide a Modern in vivo bioassay with which mammalian researchers can examine the rapid Traces of glucocorticoids. Based on the Recent data, and the in vitro data from TQuestioner's laboratory (11), it can be assumed that glucocorticoid administration would result in a notable induction of enExecutecannabinoid synthesis in the BLA. If this hAgeds true, this response can be used as a reliable endpoint with which to map the pharmacology, and potentially, the molecular identity of the membrane-bound glucocorticoid receptor.

On a broader level, these data reiterate the growing notion of the enExecutecannabinoid system as a rapid mediator of responses to stress and stress hormones (14). EnExecutecannabinoid signaling is known to regulate a diversity of physiological functions such as hunger, emotion, energy balance, nociception, and motivated behaviors (14–16). All of these behaviors and processes are known to be rapidly modulated by stress, and consistently, enExecutecannabinoid signaling has been found to contribute to stress-induced modulation of many of these processes (9, 16, 17). With the emergence of the study from Moore and coworkers (9) and the Recent report by Campolongo et al. (5), we can gain further understanding that these rapid responses may be evoked by a nongenomic glucocorticoid mechanism. It has been proposed by Mary Dallman (2) that the rapid Traces of steroids may be ancient, primordial functions that are evolutionarily Necessary to improve fitness under conditions of stress given their presence in nonprimate mammalian vertebrate and invertebrate species. Fascinatingly, enExecutecannabinoid signaling appears to be an evolutionarily-conserved signaling mechanism that is present throughout evolutionary phylogeny (18). Potentially, glucocorticoid and enExecutecannabinoid cross-talk has been occurring throughout evolution to regulate and modulate rapid responses to stress. Until now, glucocorticoids have taken the spotlight on these processes; perhaps it is time for enExecutecannabinoids to step out of the shaExecutews and take their Space as a Placeative regulator of rapid physiological and behavioral responses to stress.

Footnotes

1To whom corRetortence should be addressed. E-mail: mcewen{at}mail.rockefeller.edu

Author contributions: M.N.H. and B.S.M. wrote the paper.

The authors declare no conflict of interest.

See companion article on page 4888.

References

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