Keywords

Introduction

A large body of evidence indicates that the endocannabinoid system is crucially involved in the modulation of memory consolidation for stressful experiences [1–5]. However both impairing and enhancing effects have been reported with respect to cannabinoid effects on memory. Nowadays, the hypothesis is emerging that cannabinoid drugs can induce distinct, and often opposite, effects on behavior depending on the level of stress and/or aversiveness induced by the environmental context [6–9]. In this chapter we will first summarize the different effects induced by endocannabinoid system modulation on learning and memory functions, comparing the results obtained with different methodological approaches. Then we will focus on the fact that cannabinoid effects on cognitive processes are often biphasic, providing evidence that such effects are strongly dependent on the aversiveness of environmental context and on the level of stress at the time of drug administration. Finally, we will provide hypotheses that may help to explain cannabinoid dual effects on emotional memory functions.

The Endocannabinoid System in the Brain

The endocannabinoid system is a neuromodulatory lipid system which consists of the cannabinoid receptor type 1 and type 2 (CB1 and CB2, respectively) [10–12] and the two major endogenous ligands for these receptors, the N-arachidonoyl ethanolamine (anandamide, AEA) [10] and the 2-arachidonoyl glycerol (2-AG) [13]. Endocannabinoids are synthesized on demand from phospholipid precursors on the postsynaptic membrane by Ca2 + -dependent and independent mechanisms [3]. These lipophilic molecules are released directly into the synaptic cleft and act in a retrograde manner on the presynaptic neuron where the cannabinoid receptors are expressed. Activation of the CB1 receptor modulates intracellular transduction pathways through activation/inhibition of several ion channels and kinases, thus inducing the inhibition of further neurotransmitter release [3, 14]. AEA and 2-AG are subsequently taken back into the cell by a still poorly defined uptake process mediated by a transporter mechanism [15, 16] and mainly degraded by the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) [3], respectively.

CB receptors couple to Gi/o proteins which function to inhibit adenylyl cyclase activity, activate potassium channels and inhibit voltage-gated calcium channels [17]. CB1 receptors represent the most abundant class of G-protein-coupled receptors in the central nervous system, but are also present in a variety of peripheral tissues [17], while CB2 receptors are mostly peripherally located on immunological tissues and, only recently, detected in neuronal and glial cells in diverse rat brain areas, including the cerebellum and hippocampus [18, 19]. Within the cortico-limbic system, the most prominent expression of CB1 receptors has been detected in the hippocampus, the basolateral complex of the amygdala (BLA), and the prefrontal cortex (PFC) [20, 21]. Only recently, CB1 mRNA expression has been clearly detected at low levels in the central nucleus of the amygdala (CeA) [22]. Similar to the CB1 receptor, FAAH and MAGL are found in high levels in the BLA, whereas only low levels can be found in the CeA [23]. Several compounds, able to inhibit endocannabinoid transport or degradation, have been characterized and are currently used as pharmacological tools to increase endocannabinoid tone. Among them, the most well characterized compounds are the transport inhibitor AM404 [24], the FAAH inhibitor URB597 [25], the MAGL inhibitor JZL184 [26] and the dual FAAH and MAGL inhibitor JZL195 [27]. Moreover, several extensively used drugs such as acetaminophen [28] and propofol [29, 30] are able to indirectly increase endocannabinoid tone trough inhibition of FAAH.

Within the limbic regions, CB1 receptor is expressed at very high levels in cholecystokinin-positive GABAergic interneurons [31–33] and at moderate to low levels in glutamatergic terminals [3, 34, 35]. Additionally, this receptor has also been detected on serotonergic, noradrenergic and dopaminergic terminals [36–38]. As endocannabinoids and CB1 receptors differentially mediate homeostatic, short- and long-term synaptic plasticity processes [39–41], and neuronal firing [42] throughout the brain, the endocannabinoid system has been reported to be crucially involved in learning and memory processes [1–5].

Cannabinoid Effects on Different Memory Stages

Discrepant findings have been described concerning the role of the endocannabinoid system in the modulation of cognitive processes. Some studies report that cannabis users present short-term memory deficits [43, 44] and impairments in various aspects of executive functioning such as planning, working memory, and mental flexibility [45] after cannabis consumption. However, other studies did not detect any cannabis-related deficit in executive function [46]. Due to the different participant selection strategies used, in terms of poly-drug abuse, pre-existing cognitive and emotional criteria and widely differing methodologies (i.e. chronic vs acute use) it is difficult to draw any clear conclusion from human studies [43, 47].

In this context, basic research is of critical importance to elucidate the neural mechanisms of cannabinoid effects on cognition. However, also preclinical studies in this field are producing some apparent controversial results.

Early studies, examining the effects of systemic pretraining administration of the cannabinoid agonists ∆9-Tetrahydrocannabinol (∆9-THC) and WIN55,212-2 (WIN) on memory acquisition reported impairing effects on several behavioral tasks in rodents [48–50], whereas other studies reported that intraperitoneal administration of the cannabinoid antagonist rimonabant induces similar effects to those induced by the agonists [51]. Similarly, the exogenous amplification of the endocannabinoid tone induces impairments in memory acquisition in a recognition memory task [6] and in the inhibitory avoidance task [52]. Local infusions into distinct brain regions have given clearer results in this regard. Pretraining administration of a CB1 receptor agonist into the hippocampus has consistently been shown to impair spatial learning [48, 53–55], whereas bilateral blockade of BLA CB1 receptor transmission has been reported to prevent the acquisition of associative fear memory in an olfactory fear conditioning paradigm [56].

Concerning cannabinoid effect on memory consolidation, systemic post-training administration of cannabinoid receptor agonists or of the FAAH inhibitor URB597 have been shown to impair memory consolidation [57–59]. Consistently, systemic post-training injection of cannabinoid receptor antagonists improves the same memory process [60, 61]. Central effects of cannabinoid compound on memory consolidation appear more controversial. Post-training intra-hippocampal administration of the synthetic cannabinoid receptor agonist WIN has been reported to impair memory consolidation [58, 62, 63]. However, other authors reported enhancing effects of anandamide when infused into the hippocampus [64] and of WIN when infused into the BLA [2].

Evidence regarding cannabinoid effects on memory retrieval is still scarce but very consistent. Cannabinoid agonists seem to impair memory retrieval when administered either systemically [65, 66] or in discrete brain areas [67–69].

With regard to memory extinction, literature data have abundantly demonstrated that the cannabinoid system facilitates this memory process. Using a fear conditioning procedure, Marsicano et al. (2002) and subsequent investigators demonstrated that inhibition of endocannabinoid transmission robustly inhibits fear extinction [55, 70–72]. Conversely, stimulation of the endocannabinoid system accelerates fear extinction [71, 73, 74]. Interestingly, Niyuhire and coworkers (2007) reported that rimonabant administration significantly disrupted extinction in two different aversively motivated behavioral tasks (e.g., conditioned freezing and inhibitory avoidance) but failed to affect extinction in an appetitively motivated operant conditioning task [75].

Cannabinoid heterogeneous effects on learning and memory may be due to differences on the dose and route of drug administration, the nature of the task used, the kind of memory (emotional vs non-emotional) [1], the brain areas involved and the memory stage under investigation (acquisition, consolidation, retrieval, and extinction).

However, variations in the stressful conditions employed in the different studies are implicated as well. Recent evidence suggests that the neural processes underlying emotional memory formation seem to be differently sensitive to cannabinoids depending on the levels of emotional arousal associated to the experimental context [9, 76]. In the next paragraph we will briefly describe the interaction between glucocorticoids and arousal-induced norepinephrine in modulating emotional memory, providing evidence which demonstrates how endocannabinoids are crucial mediators of stress effects on memory.

Stress and Endocannabinoids in the Regulation of Memory Function

Memories for emotional events are more persistent and vivid than other memories [77]. Studies examining emotional memory have focused on the highly arousing nature of emotional stimuli or experimental contexts as the key component contributing to enhanced memory [77–80]. The brain regions mainly involved in emotionality are represented by cortico-limbic structures, such as the amygdala, hippocampus, ventral striatum, and medial and orbital regions of the PFC [81]. Among these brain regions, the amygdala represents a key structure for assigning emotional salience to external stimuli and for orchestrating the use of various memory systems in different brain regions, for fear and anxiety responses but also for processing of positive emotions, during periods of emotional arousal [82–86].

Emotional and stressful experiences, via the activation of specific hormonal and brain systems, modulate brain function and regulate memory storage. The response to stress involves the release of epinephrine and glucocorticoids (cortisol in humans; corticosterone in rodents) from the adrenal gland into the bloodstream. Consequently, the peripheral stimulation of the vagal nerve and the activation of the nucleus tractus solitarius (NTS) induce a strong noradrenergic input from the locus coeruleus (LC) to several limbic structures including the amygdala shortly after stress [87]. The same neurons also receive high levels of corticosterone which binds with higher affinity to mineralcorticoid receptors (MRs) and lower affinity to glucocorticoid receptors (GRs) [88], so that during basal conditions only MRs are occupied while during stress conditions both MRs and GRs are occupied and mediate genomic and rapid non-genomic actions [89, 90]. Typically, stress hormones mediate the selective enhancement of consolidation of memory for emotionally significant experiences [89, 91–94]. Conversely, glucocorticoids impair memory retrieval and working memory during emotionally arousing tests [93, 95–98].

Considerable evidence indicates that emotional memory modulation requires activation of the BLA specifically. Lesions of the BLA block the memory enhancing effects of systemic injections of GR agonists on inhibitory avoidance retention, whereas lesions of the CeA are ineffective [99]. During emotionally arousing training, norepinephrine is also released into the amygdala to enhance memory consolidation [77, 100–102], whereas β-adrenoceptor antagonists infused into the BLA, but not into the CeA, block the memory enhancement induced by a glucocorticoid administered either systemically or directly into the BLA [103, 104]. Considerable evidence indicates that glucocorticoids interact with this training-induced noradrenergic activation within the amygdala in enhancing the consolidation of memory of emotionally arousing training experiences [105]. The selective influence of glucocorticoids in modulating memory for emotionally arousing information [106] indicates that glucocorticoid effects on memory processes require concurrent noradrenergic activation in the amygdala [93, 107].

Compelling evidence has been reported in the literature demonstrating a strong bidirectional interaction between endocannabinoids and stress-activated hormones such as glucocorticoids and norepinephrine. For instance, stressful experiences significantly alter endocannabinoid content in limbic brain regions resulting in opposing actions that can both increase and terminate the stress response [108]. Conversely, in the hypothalamus, glucocorticoids induce endocannabinoid signaling [109], which suppresses hypothalamic-pituitary-adrenal (HPA) axis activity by inhibiting the release of glutamate in the paraventricular nucleus [109, 110]. Furthermore, the existence of CB1 receptors in the LC and NTS suggests that cannabinoids may modulate noradrenergic activity [111–115]. Intravenous injection of cannabinoid agonists dose-dependently increases the firing rate of LC noradrenergic neurons via the activation of CB1 receptors [116] as well as noradrenergic release in cortical and limbic brain regions [117, 118]. In concert with this glucocorticoid-noradrenergic interaction, the endocannabinoid system has emerged as a crucial key mediator of stress effects on memory function. Indeed, we and others have shown that the cannabinoid receptor antagonist AM251 is able to block the ability of systemically injected corticosterone (or the synthetic analogue dexamethasone) to enhance memory consolidation of inhibitory avoidance training when directly infused into the BLA (Fig. 1.1) [2] or into the hippocampus [119]. These findings provided the first in vivo evidence in mammals of the existence of this pathway [120]. Additionally, we reported that also the endocannabinoid oleoylethanolamide (OEA) enhances memory consolidation via a norepinephrine-dependent mechanism by demonstrating that the β-adrenoceptor antagonist propranolol, infused into the BLA, blocks the memory enhancing effects induced by systemic administration of OEA [121]. Besides the enhancing effects of glucocorticoids on memory consolidation, many studies demonstrated that such hormones typically impair memory retrieval and working memory during emotionally arousing tests [93, 96–98].

Fig. 1.1
figure 1

Endocannabinoids in the BLA enable glucocorticoid modulation of memory. Immediate post-training bilateral infusions of the CB1 receptor antagonist AM251 (0.14 ng/0.2 µ(micro)l) into the BLA block retention enhancement induced by systemic injection of corticosterone (CORT; 3.0 mg/kg, subcutaneously). Data represent step-through latencies (mean ± SEM) in seconds on the 48-h inhibitory avoidance retention test. *P < 0.05 vs the corresponding vehicle group; ♦  P < 0.05 vs the corresponding AM251 group. (Adapted from [2]; used with permission)

Full size image

Recently, we investigated the interaction between glucocorticoids and the endocannabinoid system in modulating contextual fear memory retrieval. The cannabinoid antagonist AM251 infused into the dorsal hippocampus blocked the impairing effects on memory retrieval of systemic administered corticosterone; such impairing effects were mediated by elevation of hippocampal 2-AG. Moreover, the β-adrenoceptor antagonist propranolol blocked the impairing effect of WIN on memory retrieval and, conversely, the CB1 receptor antagonist AM251 infused into hippocampus together with an impairing dose of norepinephrine failed to abolish the impairing effect of norepinephrine, thus indicating that norepinephrine is functionally located downstream from the endocannabinoid system. [67]. Research from clinical studies demonstrated that exposure to a psychosocial stressor impaired the retrieval of emotional, but not neutral, words learned 24-h before [122]. Other evidence also shows that cannabinoid drugs preferentially modulate memory for emotionally arousing, and not mundane, experiences [123]. Collectively, these findings indicate that endocannabinoids interact with glucocorticoids and, depending on the availability of arousal-induced activation of noradrenergic system, they might differentially modulate memory functions.

In the next paragraphs we report evidence demonstrating how cannabinoid effects on memory can strongly depend on: (i) the level of emotional arousal associated to the experimental context which is originated by elements strikingly related to the cognitive tasks (i.e. footshock intensity on an inhibitory avoidance task); and on (ii) previous stress experiences completely unrelated to the cognitive task; or (iii) to the combination of both factors.

Influence of Emotional Arousal Associated to the Experimental Context

The evidence that CB1 receptor is highly expressed in limbic structures [112, 124] suggests that endocannabinoid signaling has a key role in the control of neuronal responses induced by environmental challenges involving an emotional dimension. We recently demonstrated that exogenously-induced enhancement of endocannabinoid signaling before the training trial, impaired the acquisition of a novel object recognition task in rats tested under high arousal (HA) condition, but had no effect in rats tested under low arousal (LA) condition [6]. Rats under the HA condition were not handled and tested under bright light in an empty arena, whereas animals in the LA condition, were daily handled, habituated to the experimental arena for 1 week and tested under dim red light in an arena with a familiar bedding [6]. Our study demonstrated that cannabinoid effects on memory are dependent on the arousal state at the time of testing. In a subsequent study we investigated the importance of emotional arousal in influencing cannabinoid effects on short- and long-term object recognition memory retention [125]. By following a previous described procedure [106], in order to induce in rats two different levels of emotional arousal, one group of rats received extensive prior habituation to the training apparatus (in the absence of any objects), while a second group was never exposed to the experimental apparatus until the training trial. Unlike the previous study, rats were administered with the CB receptor agonist WIN immediately after the training trial. As shown in Fig. 1.2, WIN induced different effects on short- and long-term memory depending on the level of emotional arousal at the time of training and drug injection. The cannabinoid agonist impaired short-term memory retention in rats not habituated to the experimental arena, while enhanced it in well habituated rats (Fig. 1.2a, b). In contrast, the effects of post-training WIN administration on long-term memory of the object recognition training were different: WIN enhanced long-term retention of object recognition memory in non-habituated rats, but had no effect on long-term memory of extensively habituated animals (Fig. 1.2c, d). WIN effects on memory in not habituated rats were highly comparable to those induced by glucocorticoids in the same experimental protocol [106, 126]. This evidence, together with the fact that cannabinoids closely interact with glucocorticoids, prompted us to explore the possibility that the divergent effects of systemic WIN administration on object recognition memory could be related to differential effects of WIN on training-induced glucocorticoid levels in rats in these two habituation conditions. Confirming our hypothesis, WIN elevated plasma corticosterone levels in non-habituated rats whereas it decreased corticosterone levels in habituated rats. Furthermore, we also demonstrated that adrenocortical suppression with the corticosterone-synthesis inhibitor metyrapone in non-habituated rats altered the effect of post-training WIN administration on both short- and long-term recognition memory in such a way that their cognitive performance became similar to that seen in habituated animals (Fig. 1.3) [125]. It is likely that post-training WIN administration on short-term memory could have influenced memory retrieval, while in the long-term, WIN could have specifically affected memory consolidation. Similarly, de Oliveira Alvares et al. (2010) reported that hippocampal endocannabinoid system is recruited to enhance memory consolidation in a contextual fear conditioning paradigm only under high arousal condition. In this study the cannabinoid antagonist AM251 infused into the dorsal hippocampus impaired the consolidation of a strong conditioning training (0.7 mA) while it did not induce any effect on a weak paradigm (0.3 mA) [119]. Clearly, these findings indicate that some degree of training-associated emotional arousal is essential for enabling glucocorticoid effects on memory acquisition, consolidation and retrieval, supporting the idea that the origin of the altered sensitivity to cannabinoids results from a differential activation of the noradrenergic system during arousing versus low-arousing conditions [117, 118, 127, 128].

Fig. 1.2
figure 2

Effects of the CB receptor agonist WIN on short- and long-term retention of object recognition training are influenced by the level of training-associated emotional arousal. Rats were either habituated for 7 days (WITH) or not habituated (WITHOUT) to the training context. On day 8, they were given a 3-min training trial during which they could freely explore two identical objects, and training was followed by an intraperitoneal (i.p.) administration of WIN (0.1, 0.3 or 1 mg/kg,). Retention was tested 1 h or 24 h later. Data represent discrimination index (%) at the retention trial, expressed as mean ± SEM. The discrimination index was calculated as the difference in the time spent exploring the novel and the familiar object, expressed as a ratio of the total time spent exploring both objects. Post-training WIN dose-dependently impaired 1-h object recognition performance of non-habituated rats (a) but enhanced performance of habituated rats (b). In contrast, post-training administration of WIN, at a dose that impaired 1-h retention, enhanced 24-h object recognition performance of non-habituated rats (c) but not of habituated rats (d). *P < 0.05 vs. vehicle. (Adapted from [125]; used with permission)

Full size image
Fig. 1.3
figure 3

Effects of the CB receptor agonist WIN on short- and long-term retention of object recognition in rats trained under high arousal conditions and pretreated with the corticosterone synthesis inhibitor metyrapone (Mety). Metyrapone (35 mg/kg, i.p.) administered to non-habituated rats 40 min before training reverted the impairing effect of post-training WIN (0.3 mg/kg, i.p.) on 1-h retention performance (a) and the enhancing effect of WIN (0.3 mg/kg, i.p.) on 24-h retention performance (b) in such a way that their performances became similar to that seen in habituated animals. Data are expressed as means ± SEM. *P < 0.05; **P < 0.01 vs. the corresponding vehicle group; ##P < 0.01 vs. WIN alone group. (Adapted from [125]; used with permission)

Full size image

Influence of Stress Unrelated to the Behavioral Task

Few studies have been reported in the literature investigating the effects of stress experience completely unrelated to the experimental context and its interaction with endocannabinoid system in modulating cognitive functions. De Oliveira Alvares and coworkers (2010) showed that intra-hippocampal infusions of the cannabinoid antagonist AM251 had no effect per se on memory consolidation of a weak contextual fear conditioning paradigm (i.e. 0.3 mA footshock intensity) but reverted the memory enhancing effects of a stressor (i.e. two 0.1 mA footshocks in a different context) administered immediately before conditioning [119]. It has been reported that exposure to an out-of-context stressor (i.e. elevated platform) after an object recognition training enhances long-term memory only in rats that were not previously habituated to the experimental apparatus [129]. The same group has recently shown that intra-BLA infusions of the cannabinoid agonist WIN inhibit the increase in plasma corticosterone levels in rats exposed for 30 min to a stressor (i.e. elevated platform) [130]. Moreover, they demonstrated that WIN infusion did not have any effect by itself but prevented the memory enhancing effects on the acquisition and the impairment on the extinction of an inhibitory avoidance task induced by the elevated platform stress exposure [130]. In a separate study, they also reported that WIN (5 µ(micro)g/side) infused into the BLA did not show any effect on memory consolidation by itself. Conversely, when administered before stress exposure (i.e. elevated platform for 30 min), it blocked the enhancing effects on memory consolidation induced by stress [131]. This evidence appears to be at odd with our finding that intra-BLA infusions of WIN (50 ng/side) immediately after the training trial of an inhibitory avoidance task enhanced memory consolidation [2]. It is likely that differences in doses or/and in the behavioral task used may account for such discrepancy. In a very recent study Segev et al. (2014) reported that 3 days of WIN administration during a 21-day exposure to a chronic mild stress (a common paradigm for stress-induced depression) prevents the stress-induced alterations in memory extinction via CB1 receptor activation [132].

Taken together, these findings give evidence that factors related to arousal, stress, and emotional state at the time of training may differentially influence cannabinoid effects on memory.

Assumption to Explain Biphasic Cannabinoid Effects on Memory: A Putative Model

To summarize the findings reported above, the role of the endocannabinoid system on memory modulation is strictly dependent on the aversiveness of the environmental condition and on the level of emotional arousal at the time of training. Therefore, the interaction with glucocorticoids and norepinephrine is of crucial importance in determining the impairing or enhancing effects of cannabinoids on memory. Stress effects on both consolidation and retrieval of emotionally arousing experiences require concurrent glucocorticoid and noradrenergic activity [107, 133]. Corticosterone rapidly elevates endocannabinoid levels in the amygdala [134], conversely, cannabinoid administration can both activate and inhibit the HPA axis [130, 135] and a blockade of CB1 receptor activity in the BLA prevents corticosterone-induced memory enhancement [2]. Extensive evidence indicates that the BLA preferentially modulates memory of emotionally arousing training experiences [77]. In the BLA, CB1 receptors are expressed in GABAergic cells, thus, an activation of CB1 receptors can suppress the release of GABA [136–138]. It is well established that the amygdala GABAergic transmission is involved in memory modulation [133] and that inhibition of GABAergic activity within the BLA enhances memory consolidation by increasing the release of norepinephrine [139]. Thus, in view of this evidence, we and others previously proposed a model: glucocorticoids via a rapid, non-genomic effect [140], bind to a membrane bound receptor in the BLA that activates a G-protein signaling cascade to stimulate the synthesis of endocannabinoids. Therefore, endocannabinoids might increase BLA neuronal activity by decreasing GABAergic neurotransmission, leading to increased noradrenergic activity within the same brain region (Fig. 1.4). Nevertheless, it is possible that glucocorticoid-induced memory effects might be also a result of the endocannabinoid-mediated changes in glutamatergic signaling [141].

Fig. 1.4
figure 4

Putative Model of role of the endocannabinoid system in the modulation of memory consolidation within the BLA. Stress hormones (i.e. CORT and epinephrine) are released into the bloodstream during training. CORT binds metabotropic GRs within the BLA, activating the Gs–cAMP/PKA pathway to induce endocannabinoid (eCB) synthesis. Endocannabinoids are released into the synaptic cleft where they bind CB1 receptors on GABAergic terminals, thereby inhibiting GABA release. Suppression of GABAergic transmission results in the disinhibition of noradrenergic neurons and increases noradrenergic activation of postsynaptic β-adrenoceptors, enhancing the consolidation of emotionally arousing memories. (Adapted from [76]; used with permission)

Full size image

Several characteristics of the endocannabinoid system may also account to the opposing effects of cannabinoids on memory functions. Endocannabinoids are synthesized on demand and, as a result, they are released only in those brain regions where and when there is an active endocannabinoid signaling. As a consequence, depending on the pharmacological tool used for a certain experiment, it is possible to appreciate different effects. For instance, direct agonists can bind all cannabinoid receptors both in the brain and in the periphery regardless of their specific involvement in a particular process. In contrast, drugs inducing an amplification of endocannabinoid response act only in those brain areas where and when the signaling is already active. Furthermore, CB1 receptors can suppress the release of neurotransmitters such as GABA and glutamate [3, 31, 32, 34] which often act in an opposite way in the control of several neurophysiological processes related to memory and emotional responses [39, 142–144]. Besides CB1-dependent effects, endocannabinoids also activate CB2 receptors, the peroxisome proliferator-activated nuclear receptor (PPAR) and the transient receptor potential vanilloid type 1 (TRPV1) which have been shown to modulate both emotional responses [145] and aversive memory processes [19, 52, 121].

Conclusions

The evidence summarized in this chapter indicates that the endocannabinoid system plays a key role in mediating emotional arousal and stress effects on memory, shedding light on the neurobiological mechanism involved in the differential impact of stress on memory processes.

The endocannabinoid system modulates cognitive function in a manner strictly dependent on the aversiveness of the environmental condition and on the level of emotional arousal at the time of testing, thus making it possible to hypothesize that the interaction with stress hormones is of crucial importance in determining modulatory effects of cannabinoid compounds on memory processes. It is likely that, depending on the availability of stress hormones, the subsequent interplay between endocannabinoids and glucocorticoids and/or norepinephrine might result in opposing effects on memory processes.

Further research is warranted to disentangle the complex neurobiological mechanisms involved in the unique endocannabinoid modulatory action on memory.

Role of Funding Source

P.C.’s research is supported by grants from Human Frontier Science Program (RGY0077/2012), the Italian Ministry of Education MIUR [FIRB Futuro in Ricerca (RBFR10XKHS_003), and PRIN 2010–2011 (2010BN3MXM_003].