Dissecting the cannabinergic control of behavior: The where matters

Abstract

The endocannabinoid system is the target of the main psychoactive component of the plant Cannabis sativa, the Δ(9)-tetrahydrocannabinol (THC). This system is composed by the cannabinoid receptors, the endogenous ligands, and the enzymes involved in their metabolic processes, which works both centrally and peripherally to regulate a plethora of physiological functions. This review aims at explaining how the site-specific actions of the endocannabinoid system impact on memory and feeding behavior through the cannabinoid receptors 1 (CB1 R). Centrally, CB1 R is widely distributed in many brain regions, different cell types (e.g. neuronal or glial cells) and intracellular compartments (e.g. mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB1 R according to their cell-type localization (e.g. glutamatergic or GABAergic neurons). Thus, understanding the cellular and subcellular function of CB1 R will provide new insights and aid the design of new compounds in cannabinoid-based medicine. Also watch the Video Abstract.

Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation

“…The endocannabinoid system plays a pivotal role both in the modulation of the stress response (13,36) and in the control of cognitive functions (14,18). CB1 receptors modulate HPA feedback inhibition secondary to glucocorticoid receptor activation (15,37), and endocannabinoids can alter both emotional (38) and nonemotional (39) memories.…”

“…The endocannabinoid system is an endogenous neuromodulatory system playing a relevant role in the regulation of the stress response (13)(14)(15)(16)(17)(18). Endocannabinoids, such as 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide; AEA), act mainly at two types of cannabinoid receptors, cannabinoid type-1 (CB1) and type-2 (CB2) receptors.…”

Dorsolateral periaqueductal gray matter CB1 and TRPV1 receptors exert opposite modulation on expression of contextual fear conditioning

“…In addition to different receptors, the bimodal effect of CB compounds could also be explained by modulation of different neurotransmitters (Busquets-Garcia et al, 2015).…”

“…Accordingly, GABAergic neurotransmission is involved in modulation of the eCB system during aversive situations, presenting opposite roles when compared to the glutamatergic system (Busquets-Garcia et al, 2015).…”

Because difficulty is not the same for everyone: the impact of complexity in working memory is associated with cannabinoid 1 receptor genetic variation in young adults

“…This percentage of variance might be related to three facts. First, the position of the rs2180619 on a potential regulatory region (Zhang et al, 2004) might be related to the functional effect of producing differential expression of the CB1 receptor, second, the role of the endocannabinoid system as a neuromodulator of other neurotransmitter systems, via CB1 receptor activation, modulating memory processes (Busquets-Garcia et al, 2015) and third, the extended distribution of CB1 receptor in the human brain (Burns et al, 2007), including related areas participating in WM processes. Our study further supports the notion that CNR1 is one of the candidate genes, among the several genes encoding for signalling molecules (Papassotiropoulos & de Quervain, 2015) to explain the genetics of WM function.…”