Endocannabinoids, stress signaling, and the locus coeruleus-norepinephrine system

Abstract

The endocannabinoid (eCB) system has been implicated in a variety of physiological functions due to abundant expression of its receptors and endogenous ligands in the central nervous system. Substantial progress has been made in understanding how the eCB system influences the brain norepinephrine (NE) system, an important neurochemical target in the continued development of new therapies for stress-induced psychiatric disorders. We, and others, have characterized the neuroanatomical, biochemical and pharmacological effects of cannabinoid receptor modulation on brain noradrenergic circuitry and defined how molecular elements of the eCB system are positioned to directly impact the locus coeruleus (LC)-prefrontal cortex pathway, a neural circuit well recognized for contributing to symptoms of hyperarousal, a key pathophysiological feature of stress-related disorders. We also described molecular and electrophysiological properties of LC noradrenergic neurons and NE release in the medial prefrontal cortex under conditions of cannabinoid type 1 receptor deletion. Finally, we identified how stress influences cannabinoid modulation of the coeruleo-cortical pathway. A number of significant findings emerged from these studies that will be summarized in the present review and have important implications for clinical studies targeting the eCB system in the treatment of stress-induced psychiatric disorders.

Early life stress and development of the endocannabinoid system: A bidirectional process in programming future coping

“…The ECS also plays a specific role in neural development, controlling the establishment of cortical–subcortical connections especially by densities of its receptors in the corticolimbic system (Belue, Howlett, Westlake, & Hutchings, 1995; de Fonseca, Ramos, Bonnin, & Fernández‐Ruiz, 1993; Mato, Olmo, & Pazos, 2003). In addition, there are many reports supporting ECS regulation of stress responsivity and emotional behavior from young to old ages; thus, this system is a promising therapeutic target for anxiety‐ and stress‐related disorders (Hillard, Beatka, & Sarvaideo, 2016; Katzman, Furtado, & Anand, 2016; Micale & Drago, 2018; Patel, Hill, Cheer, Wotjak, & Holmes, 2017; Vangopoulou et al, 2018; Wyrofsky et al, 2019).…”

Crosstalk between Bone and Nerves within Bone

“…[ 19–23 ] α ‐AR signaling can upregulate proteins related to osteogenesis in MC3T3‐E1 osteoblastic cells and promotes bone formation. [ 24 ] The intensity and duration of NE signals are regulated by feedback mechanisms through presynaptic α ‐ARs, norepinephrine transporter, [ 25 ] the cannabinoid system, [ 26,27 ] and neuropeptide Y. [ 28,29 ]…”

Reviewing the Role of the Endocannabinoid System in the Pathophysiology of Depression

“…Particularly, CB1 blockade leads to increased plasma corticosterone ( Wade et al, 2006 ). Furthermore, the activation of CB1 on noradrenergic signaling represents an important mechanism for stress adaptation ( Wyrofsky et al, 2019 ). Chronic HPA-axis-induced stimulation of noradrenergic areas such as the locus coeruleus increases anxiety and depressive-like behavior ( Valentino and Van Bockstaele, 2008 ).…”