Where does the Endocannabinoid System fit?

I have a question. Are the endocannabinoid system and the dopamine system two key elements of the central nervous system?

The popular press has been busy of late drafting, publishing, and republishing articles on the structure and function of the endocannabinoid system (ECS). These articles discuss:

  • the discovery of the CB1 receptor and the binding of THC (a phyto-cannabinoid),
  • the elucidation of the endocannabinoids (cannabinoids produced by the body) anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), and
  • the interaction of CBD with the CB2 receptor.

The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system development, synaptic plasticity (the adaptability of the CNS to changing environments), and the response to internal and environmental insults. The ECS comprises cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids.

The discovery of the endocannabinoid system and the CB1 and CB2 receptors was a significant milestone in the study of neuropharmacology and the central nervous system. This initial discovery has led to hundreds of new research programs which have been focused not only on expanding the knowledgebase on the interactions of the system with internal and external cannabinoids, but also how the ECS interacts with other systems within the body. THC has the most significant impact on the human body through its interactions with the CB1 and CB2 receptors. Our endocannabinoids, anandamide and 2-AG, also bind to the CB1 and CB2 receptors and have been isolated from several different cell types including monocytes, macrophages, basophils, lymphocytes, and dendritic cells (nerve cells). Anandamide and 2-AG are produced and released by these cells on demand through an abbreviated and rapid cell process (Cabral et al., 2015) in response to infection and injury. CBD and CBN also bind to the CB1 and CB2 receptors and have been demonstrated to moderate immune functions.

Cannabinoids also bind to other receptors (Breivogel, 2001), suggesting an additional level of complexity within the ECS. One receptor, GPR55, is activated by THC and CBD and results in increases of intracellular calcium by activating signaling pathways quite distinct from those used by CB1 and CB2 (Lauckner et al., 2008). GPR55 may be considered a cannabinoid receptor whose distinct signaling profile enlarges the cellular repertoire of cannabinoid action. These research programs also demonstrate a complexity within the ECS that is yet to be fully understood. To fully understand to complexity of the ECS, its structure and function needs to be understood within the greater context of the central nervous system (CNS). The endocannabinoid system regulates the neural transmitters’ release of glutamate and gaba and, indirectly, dopamine, and is activated on demand as a significant neural system modulator.

Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. In this context, the endocannabinoid system is a mediator between the internal and external world with participation in appropriate behavioral responses to external stimuli (such as sensory inputs) and internal stimuli (such as endocrine, paracrine, metabolic and neuronal signals) that are vital for an organism’s survival (Lutz et al., 2015). Thus, a growing body of work indicates that the ECS is an integral regulator of the stress response. Recent data demonstrates stress-induced regulation of ECS signaling and the impact that ECS signaling has on many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two ECS molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG). Stress exposure reduces AEA levels and increases 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in the ECS signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including an increase in anxiety behavior, while the increased 2-AG signaling contributes to changes in pain perception, memory and synaptic plasticity. ECS signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions such as depression and post-traumatic stress disorder. Collectively, these data create a compelling argument that ECS signaling is an important component of the CNS which has a significant role in the regulation of brain systems that largely functions to buffer against many of the effects of stress and that dynamic changes in the ECS contribute to different aspects of the stress response (Morena et al., 2016).

The ECS is also implicated in the mediation of both reward and reinforcement. This is evidenced by the ability of exogenous cannabinoid drugs to influence behavior and maintain self-administration in both human and animal subjects. The ECS similarly facilitates behaviors motivated by reward through indirect interaction with the mesolimbic dopamine (DA) and endogenous opioid systems. DA transmission mediates several aspects of reinforced behavior, such as motivation, incentive salience, and cost-benefit calculations. However, much research suggests that endogenous opioid signaling underlies the hedonic aspects of reward. The ECS and their receptors functionally interact with opioid systems to support reward, most likely through augmenting DA release.

Given the abundance of research demonstrating the interactions between the ECS and the overarching CNS, it seems that one can’t discuss one without discussing the other.

What do you think?

 

Cabral, G., Rogers, T., and Lichtman, A. 2015. Turning Over a New Leaf: Cannabinoid and Endocannabinoid Modulation of Immune Function. J. Neuroimmune Pharmacol 10:193-203.
Breivogel, C., Griffin, G., Di Marzo, V., Martin, B. 2001. Evidence for a new G protein-coupled cannabinoid receptor in mouse brain.  Mol. Pharmacol 60(1): 155-163
Lauckner, J., Jensen, J., Chen, H., Lu, H., Hille, B., Mackie, K. 2008. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. PNAS. Vol 105; No. 7 2699-2704.
M., Patel, S., Bains, J., and Hill, M. 2016. Neurobiological Interactions Between Stress and the Endocannabinoid System. Neuropsychopharmacology. Jan;41(1):80-102
Lutz, B., Marsicano, G., Maldonado, R., Hillard, C.J., 2015.  The endocannabinoid system in guarding against fear, anxiety, and stress.  Nat. Rev. Neurosci.

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