Abstract
Rationale
Direct activation of the cannabinoid CB1 receptor in the dorsolateral periaqueductal gray (dlPAG) inhibits anxiety- and panic-related behaviours in experimental animals. It has remained unclear, however, whether the local endocannabinoid signalling is recruited as a protective mechanism against aversive stimuli.
Objectives
The present study tested the hypothesis that the endocannabinoid system counteracts aversive responses in the dlPAG-stimulation model of panic attacks.
Methods
All drugs were infused into the dlPAG of rats. Local chemical stimulation with N-methyl-d-aspartate (NMDA, 1 nmol) was employed to induce panic-like behavioural and cardiovascular responses in freely moving and anaesthetized animals, respectively. The neuronal activity in the dlPAG was investigated by c-Fos immunohistochemistry.
Results
The selective CB1 receptor agonist, ACEA (0.005–0.5 pmol), prevented the NMDA-induced panic-like escape responses. More interestingly, increasing the local levels of endogenous anandamide with a fatty acid amide hydrolase (FAAH) inhibitor, URB597 (0.3–3 nmol), prevented both the behavioural response and the increase in blood pressure induced by NMDA. The effect of URB597 (3 nmol) was reversed by the CB1 receptor antagonist, AM251 (0.1 nmol). Moreover, an otherwise ineffective and sub-threshold dose of NMDA (0.5 nmol) was able to induce a panic-like response if local CB1 receptors were previously blocked by AM251 (0.1 nmol). Finally, URB597 prevented the NMDA-induced neuronal activation of the dlPAG.
Conclusions
The endocannabinoid system in the dlPAG attenuates the behavioural, cellular and cardiovascular consequences of aversive stimuli. This process may be considered for the development of additional treatments against panic and other anxiety-related disorders.
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Acknowledgments
TGV was a master degree student and recipient of a CAPES fellowship. FAM is a recipient of a CNPq Productivity Fellowship (level 2). This work was supported by grants from FAPEMIG (Universal APQ-01038-11 and PRONEM APQ-04625-10) and FAPESP (2012/17626-7).
Conflict of interest
The authors have no financial interests to disclose.
Ethical disclosure
The experiments were performed in accordance with the Brazilian Society of Neuroscience and Behaviour guidelines for the care and use of laboratory animals. All protocols were approved by the Committee for Ethics in Animal Experiments (CEUA, protocol number 059/11).
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Viana, T.G., Hott, S.C., Resstel, L.B. et al. Anti-aversive role of the endocannabinoid system in the periaqueductal gray stimulation model of panic attacks in rats. Psychopharmacology 232, 1545–1553 (2015). https://doi.org/10.1007/s00213-014-3793-x
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DOI: https://doi.org/10.1007/s00213-014-3793-x