Antiaversive effects of cannabinoids: is the periaqueductal gray involved?

Abstract

Cannabinoids play an important role in activity-dependent changes in synaptic activity and can interfere in several brain functions, including responses to aversive stimuli. The regions responsible for their effects, however, are still unclear. Cannabinoid type 1 (CB1) receptors are widely distributed in the central nervous system and are present in the periaqueductal gray (PAG), a midbrain structure closely involved in responses related to aversive states. Accordingly, exposure to stressful stimuli increases endocannabinoid (eCB) levels in the PAG, and local administration of CB1 agonists or drugs that facilitate eCB-mediated neurotransmission produces antinociceptive and antiaversive effects. To investigate if these drugs would also interfere in animal models that are sensitive to anxiolytic drugs, we verified the responses to intra-PAG injection of CB1 agonists in rats submitted to the elevated plus-maze, the Vogel punished licking test, or contextual aversive conditioning model. The drugs induced anxiolytic-like effects in all tests. The same was observed with the transient receptor potential vanilloid type 1 (TRPV1) antagonist capsazepine and with cannabidiol, a nonpsychotomimetic phytocannabinoid that produces anxiolytic-like effects after systemic administration in humans and laboratory animals. These results, therefore, suggest that the PAG could be an important site for the antiaversive effects of cannabinoids.

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.