Antiaversive Effects of Cannabinoids: Is the Periaqueductal Gray Involved?
Figure 1
Possible effects of cannabinoids in the dlPAG.
Glutamatergic inputs from forebrain structures such as the dorsomedial part of
the ventromedial hypothalamic nucleus (dmVMH) and dorsal premammilary
hypothalamic nucleus (PmD) activate a local neural substrate that mediates
defensive responses [88]. This substrate is under GABAergic and serotonergic
inhibitory influence [26]. Activation of CB1 receptors by cannabinoids such as
AEA interferes with presynaptic glutamate (Glu) and GABA (Ga) neurotransmitter
release. CB1-mediated decrease of glutamate release would promote
anxiolytic-like effects. Activation of TRPV1 presynaptic receptors, on the
other hand, would produce opposite effects. The anxiolytic effects of
cannabidiol (CBD), a nonpsychotomimetic cannabinoid, in the dlPAG are not
mediated by CB1 receptors, but probably involve activation of postsynaptic
5HT1A receptors. The bell-shaped dose-response curves observed with AEA and CBD
may depend on activation of TRPV1 receptors. Regarding AEA, a presynaptic
decrease of GABA release could also be related to this effect.