Rafael C Almada1,2, Luiz Luciano Falconi-Sobrinho1,3,4,5, Juliana A da Silva1,3, Carsten T Wotjak6,7, Norberto C Coimbra8,9,10,11. 1. Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. 2. Department of Biological Sciences, School of Science, Humanities and Languages, São Paulo State University (UNESP), Assis, São Paulo, Brazil. 3. Behavioural Neurosciences Institute (INeC), São Paulo, Ribeirão Preto, Brazil. 4. Ophidiarium LNN-FMRP-USP/INeC, Ribeirão Preto Medical School of the University of São Paulo, Ribeirão Preto, São Paulo, Brazil. 5. NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto Medical School of the University of São Paulo, Ribeirão Preto, São Paulo, Brazil. 6. Laboratory of Neuronal Plasticity, Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany. 7. Central Nervous System Diseases Research, Boehringer Ingelheim Pharmaceuticals Gesellschaft Mit Beschränkter Haftung & Compagnie Kommanditgesellschaft, Biberach an der Riß, Germany. 8. Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. nccoimbr@fmrp.usp.br. 9. Behavioural Neurosciences Institute (INeC), São Paulo, Ribeirão Preto, Brazil. nccoimbr@fmrp.usp.br. 10. Ophidiarium LNN-FMRP-USP/INeC, Ribeirão Preto Medical School of the University of São Paulo, Ribeirão Preto, São Paulo, Brazil. nccoimbr@fmrp.usp.br. 11. NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto Medical School of the University of São Paulo, Ribeirão Preto, São Paulo, Brazil. nccoimbr@fmrp.usp.br.
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.
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.
Authors: Rafael Carvalho Almada; Tayllon Dos Anjos-Garcia; Juliana Almeida da Silva; Glauce Regina Pigatto; Carsten T Wotjak; Norberto Cysne Coimbra Journal: Behav Brain Res Date: 2020-11-07 Impact factor: 3.332