Opposing local effects of endocannabinoids on the activity of noradrenergic neurons and release of noradrenaline: relevance for their role in depression and in the actions of CB(1) receptor antagonists.

There is strong evidence that endocannabinoids modulate signaling of serotonin and noradrenaline, which play key roles in the pathophysiology and treatment of anxiety and depression. Most pharmacological and genetic, human and rodent studies suggest that the presence of under-functioning endocannabinoid type-1 (CB(1)) receptors is associated with increased anxiety and elevated extracellular serotonin concentration. In contrast, noradrenaline is presumably implicated in the mediation of depression-type symptoms of CB(1) receptor antagonists. Evidence shows that most CB(1) receptors located on axons and terminals of GABA-ergic, serotonergic or glutamatergic neurons stimulate the activity of noradrenergic neurons. In contrast, those located on noradrenergic axons and terminals inhibit noradrenaline release efficiently. In this latter process, excitatory ionotropic or G protein-coupled receptors, such as the NMDA, alpha1 and beta1 adrenergic receptors, activate local endocannabinoid synthesis at postsynaptic sites and stimulate retrograde endocannabinoid neurotransmission acting on CB(1) receptors of noradrenergic terminals. The underlying mechanisms include calcium signal generation, which activates enzymes that increase the synthesis of both anandamide and 2-arachidonoylglycerol, while G(q/11) protein activation also increases the formation of 2-arachidonoylglycerol from diacylglycerol during the signaling process. In addition, other non-CB(1) receptor endocannabinoid targets such as CB(2), transient receptor potential vanilloid subtype, peroxisome proliferator-activated receptor-alpha and possibly GPR55 can also mediate some of the endocannabinoid effects. In conclusion, both neuronal activation and neurotransmitter release depend on the in situ synthesized endocannabinoids and thus, local endocannabinoid concentrations in different brain areas may be crucial in the net effect, namely in the regulation of neurons located postsynaptically to the noradrenergic synapse.