A large body of evidence supports a contribution

A large body of evidence supports a contribution of the endocannabinoid (eCB) system in the regulation of stress and emotional behavior (Gorzalka and Hill, 2011, Hill and Patel, 2013, Morena et al., 2016). General findings from this work indicate that eCB anandamide signaling is critical for buffering the physiological effects of the stress response, dampening anxiety and regulating mood. Moreover, anandamide has been reported to exhibit cardioprotective abilities, including potential anti-arrhythmic actions (Hiley, 2009). The present review summarizes the results of rodent studies that have explored the involvement of anandamide signaling in the regulation of stress-response physiology, emotional behavior and cardiac function. Moreover, recent promising findings on the effects of pharmacological enhancement of anandamide signaling in rodent models that reproduce aspects of human psychological/cardiac comorbidity are discussed.
The endocannabinoid system Endocannabinoids (eCBs) are endogenous lipid mediators generated by almost all cell types both in the brain and in the peripheral tissues that mimic most of the effects of Δ9-tetrahydrocannabinol (THC), the active ingredient of the marijuana plant Cannabis sativa. The two best characterized eCBs are arachidonoyl ethanolamide (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), although this family of bioactive lipids includes other fatty arachidonic NPI-0052 australia derivatives with putative cannabimimetic properties (e.g., virodhamine, noladin ether, N-acyl dopamines). ECBs exert biological actions predominantly via activation of two Gi/o protein-coupled cannabinoid receptors, the type-1 (CB1) and type-2 (CB2) (Fig. 1) (Howlett, 2002). The CB1 receptor is highly expressed in the brain (Moldrich and Wenger, 2000) but also present at much lower yet functionally relevant concentrations in various peripheral districts, including the cardiovascular system (Batkai et al., 2004, Bonz et al., 2003, Pertwee et al., 2010). The CB2 receptor was initially thought to be expressed only in immune and hematopoietic cells (Howlett, 2002), but subsequent studies have established its presence also in the brain and myocardium (Pertwee et al., 2010). ECBs interact also with non-CB1/non-CB2 targets, such as (i) the transient potential vanilloid type 1 (TRPV1) receptor, which is activated by both AEA and 2-AG (Di Marzo and De Petrocellis, 2010), (ii) the peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ (Pistis and Melis, 2010), and (iii) the orphan G protein-coupled receptor GPR55 (Moriconi et al., 2010). The concentration of eCBs at target receptors is tightly controlled by enzymes regulating their synthesis and degradation. AEA is preferentially degraded in vivo by the enzyme fatty acid amide hydrolase (FAAH), while monoacylglycerol lipase (MGL) is responsible for the degradation of 2-AG (Fig. 1) (for detailed information regarding eCBs synthesis and/or metabolism the reader is referred to (Basavarajappa, 2007, Ligresti et al., 2005)).
Endocannabinoid system, stress and emotional behavior Cannabis sativa has long been known by humans for its stress-reducing and mood-elevating properties. Despite this, the idea that the eCB system may be involved in the regulation of stress and emotional behavior dates back only to 2005 (Hill and Gorzalka, 2005a). Since then the literature on this topic has accumulated pointing to eCB signaling as a stress-buffering system. In the central nervous system, eCBs are believed to be synthesized “on demand” in post-synaptic neurons during times of increased neuronal activity and are released into the synapse where they act in a retrograde manner to activate pre-sinaptically located CB1 receptors (Kano et al., 2009, Piomelli, 2003). Activation of CB1 receptors leads to inhibition of adenylyl cyclase activity and calcium influx and augmentation of inward potassium currents: these actions reduce excitability of the pre-synaptic neuron, inhibit neurotransmitter release, and hence reduce synaptic input to the post-synaptic neuron (Freund and Hajos, 2003, Schlicker and Kathmann, 2001). ECB synthetic enzymes and CB1 receptors are highly expressed in stress-responsive brain regions including the prefrontal cortex, amygdala, hippocampus, and hypothalamus (Hill and Patel, 2013). This positions eCB/CB1 signaling as an important system involved in the modulation of synaptic transmission within corticolimbic neurocircuitry. Compromised CB1-mediated eCB signaling is thought to lead to poor habituation to stress, which in turn could contribute to the development of stress-related psychological disorders (Gorzalka and Hill, 2011, Hill and Patel, 2013) (Fig. 2). Probably the most striking clinical evidence supporting this view has been the discovery that chronic use of the CB1 antagonist rimonabant as an antiobesity agent induced symptoms of anxiety and depression in a significant proportion of individuals, including those who had no history of mental illness prior to drug treatment (Christensen et al., 2007). Consequently, the drug was withdrawn from the market. Preclinical studies have generally shown that stress evokes bidirectional changes in AEA and 2-AG, with stress exposure reducing AEA levels and increasing 2-AG levels (Morena et al., 2016). The decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic–pituitary–adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity and to the expression of conditioned fear (Hohmann et al., 2005, Lim et al., 2015, Llorente-Berzal et al., 2015, Morena et al., 2016). In the next subchapters we will briefly discuss preclinical evidence that strongly supports a role for CB1-mediated AEA neurotransmission in regulating the activation of stress responsive systems and related behavioral manifestations, and we will summarize the results of rodent studies demonstrating anxiolytic- and antidepressant-like effects of pharmacological facilitation of AEA-mediated signaling.