Type‐1 cannabinoid receptors and their ever‐expanding roles in brain energy processes

Abstract

The brain requires large quantities of energy to sustain its functions. At the same time, the brain is isolated from the rest of the body, forcing this organ to develop strategies to control and fulfill its own energy needs. Likely based on these constraints, several brain‐specific mechanisms emerged during evolution. For example, metabolically specialized cells are present in the brain, where intercellular metabolic cycles are organized to separate workload and optimize the use of energy. To orchestrate these strategies across time and space, several signaling pathways control the metabolism of brain cells. One of such controlling systems is the endocannabinoid system, whose main signaling hub in the brain is the type‐1 cannabinoid (CB1) receptor. CB1 receptors govern a plethora of different processes in the brain, including cognitive function, emotional responses, or feeding behaviors. Classically, the mechanisms of action of CB1 receptors on brain function had been explained by its direct targeting of neuronal synaptic function. However, new discoveries have challenged this view. In this review, we will present and discuss recent data about how a small fraction of CB1 receptors associated to mitochondrial membranes (mtCB1), are able to exert a powerful control on brain functions and behavior. mtCB1 receptors impair mitochondrial functions both in neurons and astrocytes. In the latter cells, this effect is linked to an impairment of astrocyte glycolytic function, resulting in specific behavioral outputs. Finally, we will discuss the potential implications of (mt)CB1 expression on oligodendrocytes and microglia metabolic functions, with the aim to encourage interdisciplinary approaches to better understand the role of (mt)CB1 receptors in brain function and behavior.image

Endocannabinoid System Changes throughout Life: Implications and Therapeutic Potential for Autism, ADHD, and Alzheimer’s Disease

“…As a result, these receptors modulate several neuronal functions, such as mood, appetite, and pain signaling [ 7 ]. Also, CB1R expression in different tissues, including the brain, liver, pancreas, skeletal muscle, and adipose tissue, is evidence of its role in energy homeostasis and, consequently, in feeding behavior and energy substrate accumulation [ 8 ]. On the other hand, CB2R is mainly expressed in the peripheral tissues.…”

Anxiety Modulation by Cannabinoids—The Role of Stress Responses and Coping

“…For instance, they regulate energy metabolism [12], body temperature [13], immunity [14], fertility [15], and a wide range of other physiological phenomena. They also control almost all psychological functions, either influencing basic processes such as neurogenesis [16], neuroprotection [17] and neural energetics [18], or by putatively direct effects on anxiety, depression, cognition, reward, etc. [19,20].…”

Informing the Cannabis Conjecture: From Life’s Beginnings to Mitochondria, Membranes and the Electrome—A Review

“…This led to the idea that THC could disrupt cellular respiration to limit neuronal activity via mitochondrial CB-1R interacting with complex 1 [114] and, later, the publication of data indicating that its inhibitory effects on mitochondrial function and bioenergetics could have adverse effects during post-natal development [115]. In fact, it is now being suggested that mitochondrial CB-1Rs could be playing a much wider role in brain energy processes than previously thought [116]. Another group also showed that THC could disrupt neuronal cell mitochondrial function, affecting complexes I, II and III, decreasing coupling and enhancing ROS, suggesting that this could be important in cannabis-related strokes [117].…”