RT Journal Article
T1 2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons
A1 Llorente Berzal, Álvaro
A1 Terzian, Ana Luisa B.
A1 Di Marzo, Vincenzo
A1 Micale, Vincenzo
A1 Viveros, María Paz
A1 Wotjak, Carsten T.
AB 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.
PB springer
SN 0033-3158, ESSN: 1432-2072
YR 2015
FD 2015-08
LK https://hdl.handle.net/20.500.14352/23325
UL https://hdl.handle.net/20.500.14352/23325
LA eng
NO Instituto de Salud Carlos III, Redes temáticas de Investigación Cooperativa en salud (ISCIII y FEDER): Red de trastornos adictivos
NO Universidad Complutense de Madrid-Banco de Santander
NO Plan Nacional sobre Drogas (España)
NO CNPq (Brasil)
NO European Regional Development Fund
NO Boehringer Ingelheim Fonds (Germany)
DS Docta Complutense
RD 27 abr 2025