Kivonat:
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 (CB1) receptors
is associated with increased anxiety and elevated extracellular
serotonin concentration. In contrast, noradrenaline
is presumably implicated in the mediation of depressiontype
symptoms of CB1 receptor antagonists. Evidence
shows that most CB1 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 CB1 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 Gq/11 protein activation also increases
the formation of 2-arachidonoylglycerol from
diacylglycerol during the signaling process. In addition,
other non-CB1 receptor endocannabinoid targets such as
CB2, 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.
