Stress is most readily defined as any axis is a well-characterized response to stress. CB1 receptors are expressed and both to produce anxiolytic and stress-reducing. CB1 receptor agonists usually promote that stress reduces GABAergic control over. The stress response is a biological cascade of events that occurs in ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors.
Receptors How Stress Response Control Cannabinoid
Before returning to their home cages, animals were kept in the conditioning environment for an additional minute. Twenty-four hours later, all animals were tested for 5 min in the same context. Both stress exposure or dexamethasone i. In order to avoid any association with the grid floor itself, the very few animals less than five that presented freezing behavior during the 3-min habituation phase of the conditioning session before receiving the conditioning shocks were excluded from the analyses.
At the time of infusion, a gauge infusion needle was fitted into the guide cannulae, with its tip protruding 1. A volume of 0. In experiments 1—3 animals were divided into two groups, each receiving one of the following drugs: AM, a selective CB1 antagonist 5. Animals were trained in the CFC with either a strong 0.
Animals were submitted to a stressful event in a different context at different time points, either 0 or 30 min prior to the training session, and then trained in the weak shock protocol 0. Animals were injected i. Experiment 4 was similar to experiment 1, with dexamethasone 0.
Differences between groups receiving intrahippocampal post-training infusions of AM or its vehicle after a weak or a strong footshock were identified by t -test for independent samples experiment 1 ; when more groups were involved, one-way experiments 4 and 5 or two-way experiments 2 and 3 ANOVAs was used and differences sorted by Tukey all-pairwise multiple comparison post-hoc test.
Statistical analysis of the behavioral data was limited to the out of animals with correct cannulae placements Fig. Every effort was made to minimize the number of animals used and their suffering. We acknowledge Zelma Regina V. We also thank Drs. Carla Dalmaz and Sidia Callegari Jacques for their helpful comments and suggestions.
Previous Section Next Section. Effect of intrahippocampal dexamethasone on the levels of amino acid transmitters and neuronal excitability. Factors that determine the non-linear amygdala influence on hippocampus-dependent memory. CrossRef Medline Google Scholar. Differential activation of hippocampus and amygdala following spatial learning under stress. Eur J Neurosci Adrenal steroids and extinction behavior: Antagonism by progesterone, deoxycorticosterone and dexamethasone of a specific effect of corticosterone.
Postreactivation glucocorticoids impair recall of established fear memory. Involvement of the lateral septum and the ventral Hippocampus in the emotional sequelae induced by social defeat: Role of glucocorticoid receptors.
Behav Brain Res Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory.
Proc Natl Acad Sci Endocannabinoids facilitate the induction of LTP in the hippocampus. Cota D Cota D. The role of the endocannabinoid system in the regulation of hypothalamic-pituitary-adrenal axis activity. Functions of cannabinoid receptors in the hippocampus. Amnestic effect of intrahippocampal AM, a CB1-selective blocker, in the inhibitory avoidance, but not in the open field habituation task, in rats.
Neurobiol Learn Mem AM, a selective antagonist of the CB1 receptor, inhibits the induction of long-term potentiation and induces retrograde amnesia in rats. Differential role of the hippocampal endocannabinoid system in the memory consolidation and retrieval mechanisms. Opposite action of hippocampal CB1 receptors in memory reconsolidation and extinction. Stress and glucocorticoids impair retrieval of long-term spatial memory. Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: A fast feedback mechanism.
Glucocorticoids regulate glutamate and GABA synapse-specific retrograde transmission via divergent nongenomic signaling pathways. Formation and inactivation of endogenous cannabinoid anandamide in central neurons.
The biosynthesis, fate and pharmacological properties of endocannabinoids. Handb Exp Pharmacol Dexamethasone reverses the ethanol-induced anxiolytic effect in rats. Pharmacol Biochem Behav Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the conditioning and extinction of inhibitory avoidance. Endocannabinoid signaling and long-term synaptic plasticity. Annu Rev Physiol The silent partner of glucocorticoids in the synapse. An endocannabinoid mechanism for stress-induced analgesia.
Cannabinoid CB1 receptor is dispensable for memory extinction in an appetitively motivated learning task. Eur J Pharmacol Endocannabinoids render exploratory behaviour largely independent of the test aversiveness: Role of glutamatergic transmission. Genes Brain Behav doi: Functional actions of corticosteroids in the hippocampus.
Corticosteroid effects on cellular physiology of limbic cells. Cannabinoid CB1 receptor mediates fear extinction via habituation-like processes. Endocannabinoids mediate acute fear adaptation via glutamatergic neurons independently of corticotropin-releasing hormone signaling.
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Springer , Heidelberg, Germany. The endogenous cannabinoid system controls extinction of aversive memories. The disruptive effects of the CB1 receptor antagonist rimonabant on extinction learning in mice are task-specific. Glucocorticoid effects on object recognition memory require training-associated emotional arousal.
WIN —2 impairs contextual fear conditioning through the activation of CB1 cannabinoid receptors. The rat brain in stereotaxic coordinates. Telemetered recording of hormone effects on hippocampal neurons.
Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Cannabinoids reveal importance of spike timing coordination in hippocampal function. Amygdaloid nuclei lesions differentially affect glucocorticoid-induced memory enhancement in an inhibitory avoidance task. Basolateral amygdala noradrenergic influence enables enhancement of memory consolidation induced by hippocampal glucocorticoid receptor activation.
The hippocampus mediates glucocorticoid-induced impairment of spatial memory retrieval: Dependence on the basolateral amygdala. Role of the endocannabinoid system in regulation of the hypothalaic-pituitary-adrenocortical axis. Progress Brain Res Conditional cannabinoid receptor type 1 mutants reveal neuron subpopulation-specific effects on behavioral and neuroendocrine stress responses.
Memory reconsolidation and extinction have distinct temporal and biochemical signatures. Rapid glucocorticoid signaling via membrane-associated receptors. Endocannabinoid system and synaptic plasticity: Implications for emotional responses. Stress impairs reconsolidation of drug memory via glucocorticoid receptors in the basolateral amygdala.
Endocannabinoid signaling in the brain. It also decreased anxiety in the Vogel Conflict Test VCT , a model based on punished-conflict induced by 24 h water deprivation Campos et al. Of note, both the anxiolytic and anxiogenic responses were attenuated by AM It had been previously demonstrated that chronic stress impairs CB 1 receptor-mediated short-term plasticity at GABAergic synapses in the hippocampus Hu et al.
The previous exposure to stressors restraint and water deprivation could down-regulate CB 1 receptors located in GABAergic terminals, facilitating CB 1 -mediated attenuation of glutamate release and resulting in an anxiolytic response Campos et al. It is also possible that stress reduces GABAergic control over hippocampal projection neurons, impairing its control over the HPA axis. However, these stress-dependent effects of AEA in the ventral hippocampus do not seem to extend to its dorsal region, since URB and AM induced anxiolytic-like effects independent of previous stress experience Hakimizadeh et al.
DAGL KO mice present a marked decreased in 2-AG levels in several brains areas, including the hippocampus, together with reduced hippocampal neurogenesis Jenniches et al. Accordingly, inhibition of 2-AG signaling in hippocampal glutamatergic neurons by genetic overexpression of MAGL leads to decreased 2-AG levels and increased anxiety-like behavior, but no change in aversive memory formation Guggenhuber et al.
In slices of entorhinal cortex-hippocampal, Morgan et al. However, the precise mechanism involved in CB 2 -induced change in GABAergic neurotransmission remains to be fully elucidated.
On the other hand, but in the same line of thought, after acute blocked, CB 2 could disturb the balance between GABAergic and glutamatergic neurotransmission or induce the production of other non-classic neurotransmitters such as nitric oxide. On the topic of mood disorders, suppression of endocannabinoid signaling in the hippocampus is sufficient to induce a depressive-like state Hill and Gorzalka, ; Hill et al.
Impairment of CB 1 receptor signaling resulted in increased immobility passive coping behavior in animal models used for the screening of antidepressant drugs, such as the tail suspension TST and the forced swimming FST tests.
Moreover, increased HPA axis activity following exposure to stress is also reported after CB 1 receptors signaling blocked Aso et al. Chronic pharmacological activation of CB 1 receptors by HU induces anxiolytic and antidepressant effects and facilitates adult hippocampal neurogenesis Jiang et al.
Likewise, local activation of CB 1 receptors within the dentate gyrus of the hippocampus elicited antidepressant-like behavior in socially isolated animals McLaughlin et al.
Of note, Wistar Kyoto WKY rat, a well-accepted model of depressive-like behavior, expresses high levels of CB 1 receptors in the hippocampus. This increase of CB 1 receptor binding sites could be a compensatory mechanism in response to diminished AEA tone in the hippocampus Vinod et al.
In the case of CB 2 receptors, few data are available, and the results are not always consistent. In an animal model based on the surgical removal of the olfactory bulbs bulbectomy—an animal model of depression , decreased levels of AEA and CB 2 expression in the hippocampus were reported Smaga et al. Furthermore, overexpression of CB 2 receptors induced a depression-resilient phenotype after chronic stress, but no alterations in hippocampal BDNF levels.
Chronic stress produces behavioral and neurochemical changes in rodents that resemble those found in human depression. CUS induced depressive-like behavior, reduced hippocampal activation of mTOR signaling, decreased neurogenesis and impaired LTP induction in the hippocampus, whereas repeated injections of a MAGL inhibitor prevented CUS-induced biochemical, cellular and behavioral abnormalities Zhong et al. It is worthy to mention that, in some studies, the gene deletion or the chronic treatment with a high-dose of a MAGL inhibitor induces a pro-depressant phenotype, attributable to CB 1 receptor downregulation Schlosburg et al.
Also, DAGL-deficient mice or other manipulations that reduce 2-AG signaling in the hippocampus increased behavioral despair and reduced hippocampal neurogenesis in mice Jenniches et al.
A single injection of a FAAH inhibitor decreased passive behavioral coping responses to acute inescapable stress but failed in producing an antidepressant effect in chronically stressed mice Xu et al. Furthermore, manipulations of the CB system FAAH KO mice and prolonged treatment with THC increased the firing rate of dorsal raphe nucleus neurons and enhanced hippocampal 5-HT 1A receptor activity, all hallmarks of classical antidepressant mechanism of action Bambico et al.
Finally, it has been suggested that the available treatments for major depressive disorder modulate cannabinoid signaling Bambico et al. Similar to the actions of conventional antidepressants, both exogenous cannabinoids and eCBs seem to regulate serotonergic and noradrenergic systems. Moreover, the inhibition of anandamide hydrolysis by URB in rats submitted to an acute swim stress procedure resulted in increased release of noradrenaline in the prefrontal cortex and the basolateral amygdala Bedse et al.
In mice lacking the FAAH enzyme, an increased firing rate of serotonergic neurons accompanied by desensitization of inhibitory serotonergic receptors in the hippocampus was reported Bambico et al. Similar results were reported by Bambico et al. An interrelationship between conventional antidepressants and cannabinoids also come from the similarity of their neuroplastic effects, with both affecting synaptic plasticity, neurogenesis and neurotrophin expression in the hippocampus Aguado et al.
Emotional learning is essential for survival. Stress and arousal events activate neurobiological systems that play a crucial role in memory consolidation, ensuring that the strength of memories occurs according to their emotional significance McGaugh, Cannabinoids can modulate the different phases of memory processes, namely acquisition, consolidation, retrieval, reconsolidation and extinction Da and Takahashi, ; de Oliveira Alvares et al.
For instance, THC impaired the performance of rodents in a working memory task and the acquisition of spatial learning in the water maze, whereas consolidation and retrieval of a previously learned task were not affected. Pre-treatment with a CB 1 receptor antagonist prevented these learning deficits Da and Takahashi, Additionally, THC activation the CB 1 receptors found mainly in GABAergic interneurons stimulated the mTOR pathway in the hippocampus through a glutamatergic mechanism, which could be responsible for the characteristic long-term memory impairment induced by cannabinoids Puighermanal et al.
Similar to the anxiety data, it seems that the degree of aversiveness is a crucial contributor to the influence of cannabinoid signaling on memory processes for review, see Morena and Campolongo, Regarding memory acquisition, systemic injection of an AEA transport inhibitor AM modified cognitive parameters depending on the level of emotional arousal.
In a high aversive condition the drug impaired the memory acquisition of the novel object in a recognition task while, in a lower stressful environment, AM did not reduce memory performance Campolongo et al. Additionally, acute administration of WIN55, disrupted the acquisition of contextual-fear conditioning, which is a hippocampal-dependent learning and memory task Pamplona et al.
On the other hand, regarding memory consolidation, Morena et al. This effect was prevented by a CB 1 antagonist. Indeed, intrahippocampal infusion of a CB 1 receptor antagonist disrupted long-term memory consolidation, possibly by inhibiting LTP de Oliveira Alvares et al.
The conflicting findings regarding the influence of cannabinoids in memory modulation could be reflecting differences on the aversiveness of the experimental conditions or the memory phase being tested Barros et al. For example, a CB 1 antagonist injected into the hippocampus, for example, promoted contextual fear memory formation Lin et al. On the other hand, facilitation of CB 1 receptor signaling in this brain area impaired contextual fear memory formation Lin et al.
Recently, Micale et al. The data revised here indicate that the hippocampal eCB signaling contributes to emotional and behavioral flexibility during the exposure to aversive stimuli, functioning as a regulatory buffer system for emotional responses. This proposal, however, has its limitations. Another critical point is that most of the available data in the literature associating hippocampus, eCB, and stress arrive from preclinical studies and sometimes seem to depend on the animal model being used.
Although stressful experiences are definite risk factors for the precipitation of psychiatric disorders, caution must be taken to translate the preclinical data directly into human pathology. Moreover, besides the hippocampus, other brain regions such as the prefrontal cortex, amygdala Hill et al. These regions are modulated by eCBs and, therefore, are also potential therapeutic targets for cannabinoid drugs For additional information about this topic, please read the excellent reviews by Gorzalka and Hill , Riebe and Wotjak , Hillard et al.
The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We thank our research group for keeping such interactive and comprehensible scientific environment. We apologize to all authors whose studies were not cited here, due to space limitations. National Center for Biotechnology Information , U. Journal List Front Mol Neurosci v. Published online Dec Detoni , Nilson C.
Ferreira-Junior , Francisco S. Author information Article notes Copyright and License information Disclaimer. Received Sep 28; Accepted Nov The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract Exposure to stressful situations is one of the risk factors for the precipitation of several psychiatric disorders, including Major Depressive Disorder, Posttraumatic Stress Disorder and Schizophrenia.
Cannabinoid Signaling Humankind has been using Cannabis sativa for therapeutic and recreational purposes since ancient times Mechoulam and Parker, Open in a separate window. Interplay between Glucocorticoids and Cannabinoid Neurotransmission Considering that stress-induced HPA axis activation and consequent corticosterone release modulate the production of eCB and CB 1 function Hillard et al.
Stress Induces Changes in Cannabinoid-Mediated Hippocampal Neuroplasticity Probably reflecting its role in several brain functions such as learning, memory and affective processing, the hippocampus is a very plastic brain structure. Implications for Stress Coping and Defensive Behaviors A large number of pharmacological and genetic studies support the proposal that the eCB system is an essential regulator of cognition, mood and anxiety for review, see Ruehle et al.
Conclusion The data revised here indicate that the hippocampal eCB signaling contributes to emotional and behavioral flexibility during the exposure to aversive stimuli, functioning as a regulatory buffer system for emotional responses.
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How Endocannabinoids Limit Stress
CB1 receptor-endocannabinoid signaling is activated by stress and .. reducing both the endocrine and neuronal responses to stress. CB1 Receptors Control Stress-Induced Impairment of Memory . of the peripheral stress response in stress-induced memory impairment using. Marijuana may hijack cannabinoid receptors in the amygdala to reduce The natural endocannabinoid system regulates anxiety and the response to stress by for reducing anxiety—but they are a drug-free way to lower the stress hormone .