Review

Cannabinoids and glucocorticoids modulate emotional memory after stress

• Irit Akirav^, , 

• Department of Psychology, University of Haifa, Haifa 31905, Israel

• http://dx.doi.org/10.1016/j.neubiorev.2013.08.002, How to Cite or Link Using DOI

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  Highlights

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  Glucocorticoid and endocannabinoid systems cross-talk after stress.

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  Exogenous cannabinoid agonists decrease HPA axis activity after stress.

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  Stress and glucocorticoids modulate endocannabinoid levels in limbic areas.

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  Cannabinoid receptor agonists ameliorate the effects of stress on emotional memory.

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  Cannabinoids decrease HPA axis activity in the amygdala via the GABAergic system.

   

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  Abstract

  Bidirectional and functional relationships between glucocorticoids and the endocannabinoid system have been demonstrated. Here, I review the interaction between the endocannabinoid and glucocorticoid/stress systems. Specifically, stress is known to produce rapid changes in endocannabinoid signaling in stress-responsive brain regions. In turn, the endocannabinoid system plays an important role in the downregulation and habituation of hypothalamic–pituitary–adrenocortical (HPA) axis activity in response to stress. Glucocorticoids also recruit the endocannabinoid system to exert rapid negative feedback control of the HPA axis during stress.

  It became increasingly clear, however, that cannabinoid CB1 receptors are also abundantly expressed in the basolateral amygdala (BLA) and other limbic regions where they modulate emotional arousal effects on memory. Enhancing cannabinoids signaling using exogenous CB1 receptor agonists prevent the effects of acute stress on emotional memory. I propose a model suggesting that the ameliorating effects of exogenously administered cannabinoids on emotional learning after acute stress are mediated by the decrease in the activity of the HPA axis via GABAergic mechanisms in the amygdala.

  Keywords

  • Endocannabinoids;
  • Glucocorticoids;
  • Stress;
  • HPA axis;
  • Emotional memory;
  • WIN55,212-2

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  Figures and tables from this article:

  

  Fig. 1. Blocking GRs in the BLA and hippocampus prevents the effects of WIN55,212-2 on extinction after exposure to single prolonged stress. We microinjected a combination of WIN55,212-2 (WIN; 5 μg/side) and the GR antagonist RU486 (RU; 10 ng/side) into the BLA (A) or the hippocampus (B) immediately after exposure to single prolonged stress (SPS), and examined their effects on contextual fear retrieval (Retrieval/Ext1) and extinction (Ext2-Ext3) tested a week later. (A) Mixed ANOVA (groups × days (5 × 3)) revealed a significant difference between the groups in freezing levels (F_(4,40) = 3.94; p = 0.009). Post-hoc comparisons revealed that on Ext2 rats that were exposed to SPS and microinjected with vehicle into the BLA (SPS + V) or with RU (SPS + RU) demonstrated increased freezing compared with rats that were not exposed to SPS and injected with Vehicle (no SPS + V) or rats that were exposed to SPS and injected with WIN (SPS + WIN) (a, p < 0.05). On Ext3, the no SPS + V group demonstrated decreased freezing compared with the SPS + V, SPS + RU (b, p < 0.01), and SPS + RU + WIN (c, p < 0.05) groups. Also, the SPS + WIN group demonstrated decreased freezing compared with the SPS + V group (d, p = 0.052). (B) Mixed ANOVA (groups × days (5 × 3)) revealed a significant difference between the groups in freezing levels (F_(4,37) = 6.09; p = 0.001). Post-hoc comparisons revealed that on Ext2 the no SPS + V and SPS + WIN groups demonstrated decreased freezing compared with the SPS + V and SPS + RU groups (a, p < 0.05). On Ext3, the no SPS + V group demonstrated decreased freezing compared with the SPS + V and SPS + RU groups (b, p < 0.05) as well as with the SPS + WIN + RU group (c, p < 0.01). The SPS + WIN group demonstrated decreased freezing compared with all groups (d, p < 0.01).
  Data published by Ganon-Elazar and Akirav (2013) in Psychoneuroendocrinology.

  Figure options

  

  Fig. 2. Intra-BLA CB1 agonist immediately after stress exposure and HPA axis activation reduces the stress response via GABAergic mechanism. The lateral amygdala (LA) is connected to basolateral amygdala (BLA) and central amygdala (CeA). A sub-population of LA neurons innervates inhibitory interneurons, which in turn are connected to CeA by inhibitory synapses. The CeA represents a main output station of the amygdala to the brain stem and hypothalamus (and the HPA axis). A most dominant distribution of CB1 receptor is found in GABAergic (full arrow) and glutamatergic (empty arrow) neurons in the BLA and CeA. Intra-BLA CB1 agonist administered immediately after stress exposure reduces GABA release in BLA interneurons, thereby reducing their inhibition of the GABAergic neurons of the intercalated nuclei, which, in turn, increases their inhibition of the pyramidal neurons of the CeA. Hence CB1 agonists can reduce HPA axis activation (and corticosterone release) and modulate the effects of stress on emotional memory. Hence, cannabinoid receptor activation after stress exposure prevents the stress-induced increase in corticosterone levels. The BLA is reciprocally connected with the hippocampal formation. Hence the amygdala may modulate hippocampal-dependent memory processes directly or indirectly via its effects on the HPA axis (e.g. as corticosterone readily enters the brain and binds to GRs in the hippocampus to affect memory).

  Figure options

  Table 1. The effects of exogenous cannabinoid administration on stress-induced HPA axis activity.

  

  BLA, basolateral amygdala; CA1, CA1 area of the hippocampus; CORT, corticosterone; GR, glucocorticoid receptors; HPA, hypothalamic–pituitary–adrenal; Single prolonged stress, consists of three different stress paradigms (restraint for 2 h, forced swim for 20 min, and anesthesia).

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  Table 2. The effects of stress exposure on eCB content in limbic structures.

  

  AEA, narachidonylethanolamine [anandamide]; 2-AG, 2-arachidonoyl-glycerol; mA, milliamp; PFC, prefrontal cortex.

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  Table 3. The effects of glucocorticoids on eCB content in limbic structures.

  

  AEA, narachidonylethanolamine [anandamide]; 2-AG, 2-arachidonoyl-glycerol; CORT, corticosterone; eCB, endocannabinoids FAAH, fatty acid amide hydrolases; s.c., subcutaneously.

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  Table 4. WIN55,212-2 prevents the effects of stress on emotional learning.

  

  BLA, basolateral amygdala; single prolonged stress, restraint for 2 h, forced swim for 20 min, and anesthesia.

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