Rationale: The endocannabinoid and endovanniloid anandamide (AEA) exerts biphasic effects when injected into the dorsolateral periaqueductal grey (dlPAG) in rats submitted to threatening situations. Whereas lower doses of AEA induce anxiolytic-like effects by activating cannabinoid CB1 receptors, no effects are observed with higher doses, possibly due to the simultaneous activation of transient receptor potential vanilloid type 1 (TRPV1) receptors. This activation would facilitate glutamatergic neurotransmission.
Objective: Considering that the blockade of TRPV1 or NMDA receptors in the dlPAG induces anxiolytic-like effects, we tested the hypothesis that facilitation of glutamate transmission through TRPV1 is responsible for the lack of anxiolytic-like effect observed with high AEA doses.
Methods: Male Wistar rats with a unilateral cannula aimed at the dlPAG received injections of an ineffective dose of AP7 (an NMDA antagonist, 1 nmol) or capsazepine (CPZ, a TRPV1 antagonist, 10 nmol), followed by a high dose of AEA (50 and 200 pmol) and were exposed to the elevated plus maze (EPM) or the Vogel conflict test (VCT).
Results: AP7, CPZ, or AEA did not induce any significant effects when administered alone. However, AP7 or CPZ prior to AEA significantly increased the percentage of entries and time spent in the open arms of EPM and the number of punished licks in the VCT suggesting an anxiolytic-like effect.
Conclusions: These results suggest that the lack of anxiolytic-like effect of higher AEA doses is due to facilitation of glutamate release in the dlPAG, probably via activation of TRPV1 receptors in this structure.