Abstract
Rationale
The contribution of two major endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), in the regulation of fear expression is still unknown.
Objectives
We analyzed the role of different players of the endocannabinoid system on the expression of a strong auditory-cued fear memory in male mice by pharmacological means.
Results
The cannabinoid receptor type 1 (CB1) antagonist SR141716 (3 mg/kg) caused an increase in conditioned freezing upon repeated tone presentation on three consecutive days. The cannabinoid receptor type 2 (CB2) antagonist AM630 (3 mg/kg), in contrast, had opposite effects during the first tone presentation, with no effects of the transient receptor potential vanilloid receptor type 1 (TRPV1) antagonist SB366791 (1 and 3 mg/kg). Administration of the CB2 agonist JWH133 (3 mg/kg) failed to affect the acute freezing response, whereas the CB1 agonist CP55,940 (50 μg/kg) augmented it. The endocannabinoid uptake inhibitor AM404 (3 mg/kg), but not VDM11 (3 mg/kg), reduced the acute freezing response. Its co-administration with SR141716 or SB366791 confirmed an involvement of CB1 and TRPV1. AEA degradation inhibition by URB597 (1 mg/kg) decreased, while 2-AG degradation inhibition by JZL184 (4 and 8 mg/kg) increased freezing response. As revealed in conditional CB1-deficient mutants, CB1 on cortical glutamatergic neurons alleviates whereas CB1 on GABAergic neurons slightly enhances fear expression. Moreover, 2-AG fear-promoting effects depended on CB1 signaling in GABAergic neurons, while an involvement of glutamatergic neurons remained inconclusive due to the high freezing shown by vehicle-treated Glu-CB1-KO.
Conclusions
Our findings suggest that increased AEA levels mediate acute fear relief, whereas increased 2-AG levels promote the expression of conditioned fear primarily via CB1 on GABAergic neurons.
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Acknowledgments
This study is supported by the Instituto de Salud Carlos III, Redes temáticas de Investigación Cooperativa en salud (ISCIII y FEDER): Red de trastornos adictivos RD06/0001/1013 and RD2012/0028/0021; GRUPOS UCM-BSCH (GRUPO UCM 951579); Plan Nacional sobre Drogas: SAS/1250/2009. ALB received a travel grant from Boehringer Ingelheim Fonds. ALBT is supported by a CNPq scholarship (process 290008/2009-3). In addition, this work was supported by the project “CEITEC—Central European Institute of Technology” (CZ.1.05/1.1.00/02.0068) from the European Regional Development Fund (to VM).
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Supplemental Figure 1
Consequences of pharmacological treatment on locomotor activity in C57BL/6N mice. The animals were treated in the same manner as done before re-exposure to the tone at d1-d3 (cf. Fig. 1 + 2), 16 days after fear conditioning. The following behavioral measures were scored during the subsequent 15-min exposure to the activity chambers and analyzed in 3-min bins: (i) movement time (left), distance (middle) and number of vertical explorations (rearings, right). I > II – significant group differences (p < 0.05, ANOVA, followed by Newman-Keuls post-hoc test); * p < 0.05 (significant group x time interval interaction, followed by Newman-Keuls test). (PDF 65 kb)
Supplemental Figure 2
Consequences of JZL184 on locomotor activity in GABA-CB1-KO. GABA-CB1-KO and WT controls were treated with JZL184 (4 mg/kg) or vehicle in the same manner as done before re-exposure to the tone at d1-d3 (cf. Fig. 4A-C), 16 days after fear conditioning. The following behavioral measures were scored during the subsequent 15-min exposure to the activity chambers and analyzed in 3-min bins: (i) movement time (left), distance (middle) and number of vertical explorations (rearings, right). (PDF 32 kb)
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Llorente-Berzal, A., Terzian, A.L.B., di Marzo, V. et al. 2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons. Psychopharmacology 232, 2811–2825 (2015). https://doi.org/10.1007/s00213-015-3917-y
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DOI: https://doi.org/10.1007/s00213-015-3917-y