Integrating endocannabinoid signaling in the regulation of anxiety and depression

Abstract

Brain endogenous cannabinoid (eCB) signaling seems to harmonize appropriate behavioral responses, which are essential for the organism's long-term viability and homeostasis. Dysregulation of eCB signaling contributes to negative emotional states and increased stress responses. An understanding of the underlying neural cell populations and neural circuit regulation will enable the development of therapeutic strategies to mitigate behavioral maladaptation and provide insight into the influence of eCB on the neural circuits involved in anxiety and depression. This review focuses on recent evidence that has added a new layer of complexity to the idea of targeting the eCB system for therapeutic benefits in neuropsychiatric disease and on the future research direction of neural circuit modulation.

Keywords: anxiety; cannabinoid 1 receptor (CB1R); depression; endocannabinoid (eCB); neural circuits.

Fig. 1

Architecture of eCB system components in neurons and astrocytes. Endocannabinoid (eCB) system shows a distinct anatomical distribution in the central nervous system. On depolarization of the postsynaptic terminal, 2-arachidonoylglycerol (2-AG) is present at the postsynaptic terminal and synthesized “on-demand” by diacylglycerol lipase-α (DAGLα). 2-AG travels to the presynaptic CB₁R to inhibit neurotransmitter release, especially when the postsynaptic terminal is strongly activated. The 2-AG-degrading enzyme monoacylglycerol lipase (MAGL) is located at the presynaptic terminal or in astrocytes. The N-arachidonoylethanolamine (AEA)-degrading enzyme fatty acid amide hydrolase (FAAH) is present at the postsynaptic terminal. The cannabinoid receptor type 1 (CB₁R) is typically present at the presynaptic terminal. Its stimulation by 2-AG or AEA leads to the inhibition of neurotransmitter release from the presynaptic terminal. CB₁R is also present in the astrocytes, and activation of the CB₁R leads to an increase in intracellular Ca²⁺ concentration. AEA can also activate the postsynaptic transient receptor potential cation channel subfamily V member 1 (TRPV1), leading to an increase in the postsynaptic current. CB₂R is present on microglial cells and is involved in immune reactions