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Endocannabinoids at the synapse and beyond: implications for neuropsychiatric disease pathophysiology and treatment

Abstract

Endocannabinoids (eCBs) are lipid neuromodulators that suppress neurotransmitter release, reduce postsynaptic excitability, activate astrocyte signaling, and control cellular respiration. Here, we describe canonical and emerging eCB signaling modes and aim to link adaptations in these signaling systems to pathological states. Adaptations in eCB signaling systems have been identified in a variety of biobehavioral and physiological process relevant to neuropsychiatric disease states including stress-related disorders, epilepsy, developmental disorders, obesity, and substance use disorders. These insights have enhanced our understanding of the pathophysiology of neurological and psychiatric disorders and are contributing to the ongoing development of eCB-targeting therapeutics. We suggest future studies aimed at illuminating how adaptations in canonical as well as emerging cellular and synaptic modes of eCB signaling contribute to disease pathophysiology or resilience could further advance these novel treatment approaches.

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Fig. 1: Cellular aspects of eCB signaling.
Fig. 2: Stress-induced adaptations in eCB signaling.
Fig. 3: eCB regulation of hypothalamic feeding circuits.
Fig. 4: Altered eCS in a FXS model.

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This work was supported by NIH grants MH107452, MH119817, and AA026186 (SP).

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SP, AFS, FY and SN conceived of content, wrote, and edited the manuscript.

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Scheyer, A., Yasmin, F., Naskar, S. et al. Endocannabinoids at the synapse and beyond: implications for neuropsychiatric disease pathophysiology and treatment. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01438-7

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