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2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons

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Llorente Berzal, Álvaro and Terzian, Ana Luisa B. and Di Marzo, Vincenzo and Micale, Vincenzo and Viveros, María Paz and Wotjak, Carsten T. (2015) 2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons. Psychopharmacology, 232 (15). pp. 2811-2825. ISSN 0033-3158, ESSN: 1432-2072

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Official URL: https://link.springer.com/article/10.1007/s00213-015-3917-y



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.


Item Type:Article
Uncontrolled Keywords:Fear extinction; TRPV1; CB1; CB2; URB597; JZL184; AM404; Anandamide
Subjects:Medical sciences > Biology > Animal physiology
Medical sciences > Biology > Neurosciences
Medical sciences > Pharmacy > Pharmacology
ID Code:42558
Deposited On:05 May 2017 11:07
Last Modified:05 May 2017 11:38

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