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Psychopharmacology

, Volume 232, Issue 15, pp 2811–2825 | Cite as

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

  • Alvaro Llorente-Berzal
  • Ana Luisa B. Terzian
  • Vincenzo di Marzo
  • Vincenzo Micale
  • Maria Paz Viveros
  • Carsten T. WotjakEmail author
Original Investigation

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.

Keywords

Fear extinction TRPV1 CB1 CB2 URB597 JZL184 AM404 Anandamide 

Notes

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).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

213_2015_3917_MOESM1_ESM.pdf (66 kb)
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)
213_2015_3917_MOESM2_ESM.pdf (32 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)
213_2015_3917_MOESM3_ESM.rtf (93 kb)
Suppl. Tab. 01 (RTF 93 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Alvaro Llorente-Berzal
    • 1
    • 6
  • Ana Luisa B. Terzian
    • 2
    • 3
  • Vincenzo di Marzo
    • 4
  • Vincenzo Micale
    • 2
    • 5
  • Maria Paz Viveros
    • 1
    • 6
  • Carsten T. Wotjak
    • 2
    Email author
  1. 1.Departamento de Fisiología (Fisiología Animal II), Facultad de BiologíaUniversidad Complutense de MadridMadridSpain
  2. 2.RG “Neuronal Plasticity”, Department of Stress Neurobiology and NeurogeneticsMax Planck Institute of PsychiatryMunichGermany
  3. 3.Graduate School of Systemic NeuroscienceLudwig-Maximilians-UniversitätMunichGermany
  4. 4.Endocannabinoid Research Group, Institute of Biomolecular ChemistryC.N.R.PozzuoliItaly
  5. 5.CEITEC—Central European Institute of TechnologyMasaryk UniversityBrnoCzech Republic
  6. 6.Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC)MadridSpain

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