The endocannabinoid system in guarding against fear, anxiety and stress

Key Points

  • Endocannabinoid (eCB) signalling contributes to activity-dependent modulation of synaptic activity in all brain regions involved in emotional regulation. As such, it is an integral part of the interface between stimulus input and responses at the synaptic level, thereby regulating behavioural responses.

  • eCB signalling exerts a buffering effect on neuronal activity in specific brain circuits within specific limits. Thus, a minimal stimulus is required to activate eCB signalling, and intense stimulation can overwhelm the buffering capacity.

  • The predominant effect of cannabinoid receptor type 1 (CB1R) activation is to reduce anxiety; however, CB1R agonists have bidirectional effects on anxiety-like behaviours. Recent data indicate that CB1R signalling modulates both pro- and anti-anxiety pathways and thus contributes broadly to regulation of anxiety-like behaviours.

  • eCB signalling in the amygdala and other brain regions is essential for several aspects of fear-memory processing, most prominently for extinction of fear responses. Available data suggest that repeated re-exposure to a fear-related stimulus in the absence of the threat increasingly activates eCB signalling, finally contributing to habituation and/or extinction of specific fear responses.

  • The eCB system seems to exert bidirectional control of the choice of coping strategy in response to a threatening stimulus, depending on the neuronal types and circuits involved.

  • eCB signalling is altered by stress and it is centrally involved in the effects of stress and glucocorticoids on synaptic activity.

  • The effect of the eCB system on the processing of anxiety, fear and stress makes it a tantalizing target for the therapeutic treatment of several psychopathologies that occur as a result of inappropriate emotional regulation. However, realizing this potential will not be an easy task, given the complexity of the eCB system.

Abstract

The endocannabinoid (eCB) system has emerged as a central integrator linking the perception of external and internal stimuli to distinct neurophysiological and behavioural outcomes (such as fear reaction, anxiety and stress-coping), thus allowing an organism to adapt to its changing environment. eCB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism's long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders. An understanding of the underlying neural cell populations and cellular processes enables the development of therapeutic strategies to mitigate behavioural maladaptation.

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Figure 1: Architecture of eCB system components in neurons and glia.
Figure 2: Regulation of synaptic excitatory and inhibitory transmission.
Figure 3: Heterosynaptic effects and eCB function in the tripartite synapse.
Figure 4: Dichotomic CB1R function in glutamatergic and GABAergic neurons.

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Acknowledgements

B.L. was supported by the German Research Foundation (SFB TRR 58, CRC 1080 and FOR 926); G.M. by the Institut national de la santé et de la recherche médicale (INSERM), the European Commission Seventh Framework Programme (REPROBESITY, HEALTH-F2-2008-223713, PAINCAGE and HEALTH-2014-603191), the European Research Council (Endofood, ERC–2010–StG−260515, CannaPreg and ERC-2014-PoC-640923), the Fondation pour la Recherche Medicale (DRM20101220445), the Human Frontiers Science Program, Region Aquitaine, Agence Nationale de la Recherche (ANR Blanc NeuroNutriSens ANR-13-BSV4-0006 and BRAIN ANR-10-LABX-0043); R.M. by the grants SAF2014-59648P, RETICS-RTA#RD12/0028/0023, AGAUR#2014-SGR-1547 and Health-F2-2013-602891; and C.J.H. by the US National Institutes of Health grants DA038663, DA026996 and MH102838.

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Glossary

Endocannabinoid

(eCB). A type of lipid signalling molecule derived from arachidonic acid. The eCBs are the endogenous counterparts of the cannabinoids.

Microglia

Immune cells of the brain that are involved in defence.

Anxiety disorders

Mental disorders involving feelings of anxiety and fear, caused by physical or psychological harm. There are different forms, such as general anxiety disorders and specific phobias.

Thigmotaxis

Movement of an organism towards an object (for example, a wall), giving them a sense of increased safety.

Neophobic behaviour

Fear of anything new; unwillingness to try new things and break from routine.

Polymorphism

A genetic variant of a gene, with possible emergence of distinct phenotypes.

Habituation

A form of learning in which an organism reduces its response to a stimulus after repeated presentations of the stimulus.

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Lutz, B., Marsicano, G., Maldonado, R. et al. The endocannabinoid system in guarding against fear, anxiety and stress. Nat Rev Neurosci 16, 705–718 (2015). https://doi.org/10.1038/nrn4036

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