br Anandamide signaling and cardiovascular function The card

Anandamide signaling and cardiovascular function The cardiovascular effects of cannabinoid compounds have been known for a long time. Studies in humans indicate that chronic use of marijuana causes long lasting decrease in blood pressure and heart rate, whereas the acute use increases heart rate without affecting blood pressure (Gorelick et al., 2006, Pacher et al., 2005). The cardiovascular effects of cannabis are largely related to its biphasic effect on the autonomic nervous system, depending on the dose absorbed (Fisher et al., 2005). At low or moderate doses, the phytocannabinoid THC leads to an increase in sympathetic activity and a reduction in parasympathetic activity, producing tachycardia and an increase in cardiac output. At high doses, sympathetic activity is inhibited and parasympathetic activity increased, leading to bradycardia and hypotension. Epidemiological data also indicate that cannabis users are significantly more likely to experience palpitations with the majority being dose-related sinus tachycardia (Petronis and Anthony, 1989). Other reported arrhythmias include sinus bradycardia, second-degree atrioventricular block and atrial fibrillation (Akins and Awdeh, 1981, Singh, 2000). The cardiovascular effects of eCBs have been extensively examined and reviewed (Hillard, 2000, Kunos et al., 2000). Here, the discussion is narrowed down to the results of rodent studies that have explored the cardiovascular effects of AEA signaling enhancement. Importantly, pharmacological approaches that target FAAH and thus selectively enhance AEA neurotransmission might protect from the above reported side effects elicited by high doses of phytocannabinoids.
Conclusions Recent animal model data suggest that inhibition of FAAH activity might represent a novel therapeutic approach for the treatment of the comorbidity between psychological and cardiac disorders. The central mechanisms underlying the mood-enhancing and anti-anxiety effects of AEA are relatively well understood. For example, AEA-mediated CB1 receptor activation has been found to enhance monoaminergic neurotransmission, to suppress stress-induced activation of HPA axis, and to increase neurogenesis in the hippocampus (Fig. 2). Through these and other mechanisms, AEA signaling promotes active coping strategies and 2-APB synthesis to stress, dampening anxiety and regulating mood (Fig. 2). On the other hand, great strides have to be made in order to fully comprehend the mechanistic pathways underlying the cardioprotective action of AEA (Fig. 3). In particular, understanding whether the anti-arrhythmic effects of AEA are due to a central restoration of cardiac autonomic balance and/or to peripheral actions within the heart tissue is of major interest in the framework of arrhythmia vulnerability associated with psychological disturbances (Fig. 3). While emerging evidence indicates that anti-arryhitmic effects of AEA may be due to activation of CB1 receptors, the role of CB2 receptors cannot be ruled out. They have been described to exert a cardioprotective role in chronic heart failure and to decrease tissue damage and arrhythmia after myocardial infarction by direct effects on the heart (Duerr et al., 2014, Hiley, 2009), but they are also present in the prefrontal cortex, hippocampus and brain stem, and are affected by repeated stress (Xing et al., 2014). Also, the possibility that some of the cardiac effects of AEA might be mediated by activation of non-cannabinoid receptor needs to be clarified. In addition, since FAAH targets a variety of other potential fatty acid substrates besides AEA (e.g., palmitoylethanolamide (PEA), oleoylethanolamide (OEA)), more needs to be known about the potential synergistic role of these other agents with respect to the effects of AEA signaling enhancement induced by FAAH inhibitors. For example, given the well-established antinociceptive properties of PEA (Calignano et al., 2001), it may be speculated that the enhancement in this molecule may alleviate cardiodynia associated with angina, atrial fibrillation or other somatoform manifestations of anxiety and panic attacks (Soares-Filho et al., 2014). Importantly, the behavioral and cardiovascular effects of FAAH inhibitors have been so far evaluated exclusively in male rodents, and data using female animals is also required (Fowler, 2015). This is particularly relevant in light of the known sex differences in eCB system functioning and in the behavioral and neurochemical responses to cannabinoid compounds (Rubino and Parolaro, 2011). In conclusion, the preliminary results are promising and prompt further investigation. Given the high availability of rodent models of anxiety and depression that reliably replicate aspects of the human comorbidity between psychological and cardiovascular disorders (Carnevali et al., 2012, Carnevali and Sgoifo, 2014, Carnevali et al., 2014, Carnevali et al., 2013, Carnevali et al., 2015a, Grippo, 2011, Grippo et al., 2011, Sevoz-Couche et al., 2013, Sgoifo et al., 2014, Wood et al., 2012), we believe that it is now timely for preclinical research to investigate in greater detail the potential utility of pharmacological approaches that target FAAH for the treatment of psychological-cardiac comorbidity.