Mechanisms of endocannabinoid transport in the brain

Abstract

The endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide are among the best studied lipid messengers in the brain. By activating cannabinoid receptors in the CNS, endocannabinoids tune synaptic function, thereby influencing a variety of physiological and behavioural processes. Extensive research conducted over the last few decades has considerably enhanced our understanding of the molecular mechanisms and physiological functions of the endocannabinoid system. It is now well-established that endocannabinoids are synthesized by postsynaptic neurons and serve as retrograde messengers that suppress neurotransmitter release at central synapses. While the detailed mechanisms by which endocannabinoids gate synaptic function and behavioural processes are relatively well characterized, the mechanisms governing endocannabinoid transport at central synapses remain ill defined. Recently, several studies have begun to unravel the mechanisms governing intracellular and intercellular endocannabinoid transport. In this review, we will focus on new advances in the mechanisms of intracellular and synaptic endocannabinoid transport in the CNS.

Cannabinoid Modulation of Dopamine Release During Motivation, Periodic Reinforcement, Exploratory Behavior, Habit Formation, and Attention

“…Because many reviews already exist that describe endocannabinoid (eCB) signaling (Toczek and Malinowska, 2018;Zou and Kumar, 2018;Cristino et al, 2020;Kaczocha and Haj-Dahmane, 2021), the risks of cannabis abuse (Ferland and Hurd, 2020;Hindley et al, 2020), and the potential cannabinoids may offer in psychiatric medicine (Amar, 2006;Black et al, 2019;Navarrete et al, 2020), our goal in the present manuscript is to describe how exogenous cannabinoids and eCBs influence dopamine (DA) signaling and behavior. While we will emphasize our own observations, we will also consider how they fit into the context of the general literature on reinforcement, appetitive behavior, adjunctive behavior, habit formation, and attentional processes.…”

Fatty Acid-Binding Protein 5 Modulates Brain Endocannabinoid Tone and Retrograde Signaling in the Striatum

“…The lipophilic nature of eCBs necessitates a mechanism(s) that enables their translocation across the synaptic cleft from their site of synthesis to CB1Rs. Several mechanisms have been proposed to account for synaptic eCB transport, including FABP5 and extracellular vesicles (Kaczocha and Haj-Dahmane, 2021 ). We have previously shown that FABP5 is necessary for retrograde 2-AG signaling at glutamate synapses of DRn neurons (Haj-Dahmane et al, 2018 ).…”

Microglial Endocannabinoid Signalling in AD

“…Although there is strong indirect evidence for the existence of this transmembrane transport, the molecular identity of the protein(s) involved remains to be assessed. In this context, several lipid-carrier proteins, which assist the movement of eCBs within and outside cells, have been identified, confirming that, despite the current controversy, the eCBs transport system should be further characterized in the future [ 71 , 72 ].…”