title: 2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons.
abstract: BACKGROUND
  The contribution of two major endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), in the regulation of fear expression is still unknown.
  
  
  OBJECTIVE
  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.
authors: Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid, C/ Jose Antonio Novais 12, 28040, Madrid, Spain.
authors: Alvaro
authors: A
authors: Llorente-Berzal
authors: Ana Luisa B
authors: AL
authors: Terzian
authors: Vincenzo
authors: V
authors: di Marzo
authors: Vincenzo
authors: V
authors: Micale
authors: Maria Paz
authors: MP
authors: Viveros
authors: Carsten T
authors: CT
authors: Wotjak
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology; D004644:Emotions / Q000187:drug effects; D063388:Endocannabinoids / Q000378:metabolism*; D005239:Fear / Q000187:drug effects*; D059330:GABAergic Neurons / Q000187:drug effects* / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism*; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant
chemical_list: D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids; D063388:Endocannabinoids; D005989:Glycerides; C462953:N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide