Abstract
Rationale
The endocannabinoid modulation of fear and anxiety due to the on-demand synthesis and degradation is supported by a large body of research. Although it has been proposed that anandamide (AEA) in the substantia nigra pars reticulata (SNpr) seems to be important for the organisation of innate fear-related behaviours, a role for endogenous AEA has yet to be clarified.
Methods
Mice were treated with the fatty acid amide hydrolase (FAAH) selective inhibitor URB597 at different concentrations (0.01, 0.1, 1 nmol/0.1 µL) in the SNpr and confronted by rattlesnakes (Crotalus durissus terrificus). The most effective dose of URB597 (1 nmol) was also preceded by microinjections of the CB1 receptor antagonist AM251 (0.1 nmol) into the SNpr, and mice were then confronted by the venomous snake.
Results
URB597 (0.1 and 1 nmol) in the SNpr decreased the expression of defensive behaviours such as defensive attention, escape, and time spent inside the burrow of mice confronted by rattlesnakes. Moreover, pretreatment of SNpr with AM251 suppressed these antiaversive effects of URB597 in this midbrain structure.
Conclusion
Overall, these data clearly indicate that the panicolytic consequences of endogenous AEA enhancement in the SNpr are mediated by CB1 receptor signalling.
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Acknowledgements
R.C. Almada was supported by FAPESP (postdoctoral fellowship process 2012/22681-7, young investigator program: research grant process 2018/03898-1 and researcher fellowship process 2019/01713-7) and CAPES (postdoctoral fellowship process PNPD20131680-33002029012P3). L.L. Falconi-Sobrinho was supported by FAPESP (M.Sc. process 2013/10984-8) and CNPq (M.Sc. fellowship process 134267/2013-3; Sc.D. fellowship process 145258/2015-7). J.A. da Silva was a recipient of a Scientific Initiation scholarship from CNPq (PIBIC process 2005.1.891.17.3) and was also supported by FAPESP and CNPq PostGraduation fellowships (CNPq M.Sc. process 130170/2009-7/FAPESP M.Sc. process 2009/02458-9; CNPq Sc.D. process 142844/2011-0; FAPESP Postdoctoral process 2015/10313-1). N.C. Coimbra was a researcher (level 1A) from CNPq (processes 301905/2010-0 and 301341/2015-0). Each organisation had no further role in the study design; the collection, analysis, and interpretation of the data; the writing of the report; or the decision to submit the paper for publication.
Funding
This work was supported by the Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico (CNPq) (Research Grants 470119/2004–7 and 427397/2018–9), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Research Grants 2007/01174–1, 2012/03798–0, 2017/11855–8, and 2020/15050–7), and a Pro-Rectory of the University of São Paulo (USP) Research Grant (NAP-USP-NuPNE; process IaPq2012-156-USP-12.1.25440.01.6). This work was also supported by the German-Israeli Foundation for Scientific Research and Development (GIF grant I-1442–421.13/2017 to CTW). Each organisation played no further role in the design of the study; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication.
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Almada, R.C., Falconi-Sobrinho, L.L., da Silva, J.A. et al. Augmented anandamide signalling in the substantia nigra pars reticulata mediates panicolytic-like effects in mice confronted by Crotalus durissus terrificus pit vipers. Psychopharmacology 239, 2753–2769 (2022). https://doi.org/10.1007/s00213-022-06127-3
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DOI: https://doi.org/10.1007/s00213-022-06127-3