CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity

Abstract

Endocannabinoids (eCBs) are amongst the most ubiquitous signaling molecules in the nervous system. Over the past few decades, observations based on a large volume of work, first examining the pharmacological effects of exogenous cannabinoids, and then the physiological functions of eCBs, have directly challenged long-held and dogmatic views about communication, plasticity and behavior in the central nervous system (CNS). The eCBs and their cognate cannabinoid receptors exhibit a number of unique properties that distinguish them from the widely studied classical amino-acid transmitters, neuropeptides, and catecholamines. Although we now have a loose set of mechanistic rules based on experimental findings, new studies continue to reveal that our understanding of the eCB system (ECS) is continuously evolving and challenging long-held conventions. Here we will briefly summarize findings on the current canonical view of the ‘ECS’ and will address novel aspects that reveal how a nearly ubiquitous system can determine highly specific functions in the brain. In particular, we will focus on findings that push for an expansion of our ideas around long-held beliefs about eCB signaling that, while clearly true, may be contributing to an oversimplified perspective on how cannabinoid signaling at the microscopic level impacts behavior at the macroscopic level.

POMC neurons functional heterogeneity relies on mTORC1 signaling

“…Then, to confirm that lack of CB1R on POMC neurons alters POMC/GABAergic transmission, we evaluated miniature inhibitory post-synaptic currents (mIPSCs) frequency onto PVN parvocellular neurons. In agreement with the inhibitory role of CB1R activation on neurotransmitter release (Busquets-Garcia et al, 2018;Castillo et al, 2012), bath application of the CB1R agonist WIN 55,212-2 inhibited mIPSCs frequency in control littermates, but not in POMC-CB1-KO mice (Figure S7 C-E).…”

“…Indeed, AgRP neurons seem physiologically relevant for the search of food rather than food intake, while POMC neurons may actually be the ones in charge of controlling the whole feeding sequence, from its start to its termination, as suggested by recently published evidence (Brandt et al, 2018;Chen et al, GABAergic and glutamatergic transmission, including in brain areas targeted by POMC neurons, is regulated by specific mechanisms (Dietrich and Horvath, 2013). Among these, the retrograde suppression of neurotransmitter release through endocannabinoids acting at the presynaptic cannabinoid type 1 receptor (CB1R) is well described (Busquets-Garcia et al, 2018;Castillo et al, 2012). Brain CB1R activation generally stimulates food intake (Mazier et al, 2015) and it offsets a-MSH effects in the PVN (Mazier et al, 2019;Monge-Roffarello et al, 2014;Verty et al, 2004).…”

Localization of the cannabinoid type‐1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus

“…This system is widely distributed in the central and peripheral nervous system (Katona & Freund, ; Lu & Mackie, ), and also in peripheral organs (Piazza, Cota, & Marsicano, ), where the CB 1 receptors are also localized in mitochondria of striated and heart muscles (Mendizabal‐Zubiaga et al, ). The eCB system regulates brain functions by acting on different cell types and cellular compartments (Busquets‐Garcia, Bains, & Marsicano, ; Gutiérrez‐Rodríguez et al, ; Katona & Freund, ; Lu & Mackie, ). The activation of CB 1 receptors in astrocytes promotes astroglial differentiation (Aguado et al, ) and mediates neuron‐astrocyte communication that plays a role in synaptic plasticity, memory and behavior (Araque et al, ; Gómez‐Gonzalo et al, ; Han et al, ; Metna‐Laurent & Marsicano, ; Navarrete & Araque, ; Navarrete, Diez, & Araque, ; Oliveira da Cruz, Robin, Drago, Marsicano, & Metna‐Laurent, 2015).…”

The effects of cannabidiol on cue- and stress-induced reinstatement of cocaine seeking behavior in mice are reverted by the CB1 receptor antagonist AM4113

“…Given that CBD shows important molecular and behavioral anti-anxiety effects (Campos et al, 2017;Skelley et al, 2019), it is difficult to propose a possible mechanism underlying these results. However, the structural and functional ubiquity of CB1 receptors in the central nervous system (Busquets-Garcia et al, 2018) allows CBD to interfere in unexpected ways with different brain structures, in certain environmental situations leading to drug relapse. In this sense, it is possible that the diverse effects of CBD over CB1-expressing, heterogeneous neuronal populations may lead to both undesirable and protective consequences.…”