title: Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus.
abstract: The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction. Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task. This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning. Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning. Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1. Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1.
authors.affiliation: Max Planck Institute of Psychiatry, Dept. Stress Neurobiology & Neurogenetics, Kraepelinstr. 2, D-80804, Munich, Germany; Max Planck Institute of Psychiatry, Dept. Translational Research in Psychiatry, Kraepelinstr. 2, D-80804, Munich, Germany; CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Micale
authors.affiliation: Max Planck Institute of Psychiatry, Dept. Translational Research in Psychiatry, Kraepelinstr. 2, D-80804, Munich, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Stepan
authors.affiliation: Max Planck Institute of Psychiatry, Dept. Stress Neurobiology & Neurogenetics, Kraepelinstr. 2, D-80804, Munich, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Jurik
authors.affiliation: Max Planck Institute of Psychiatry, Dept. Stress Neurobiology & Neurogenetics, Kraepelinstr. 2, D-80804, Munich, Germany.
authors.forename: Fabricio A
authors.initials: FA
authors.lastname: Pamplona
authors.affiliation: Max Planck Institute of Psychiatry, Dept. Stress Neurobiology & Neurogenetics, Kraepelinstr. 2, D-80804, Munich, Germany.
authors.forename: Rudolph
authors.initials: R
authors.lastname: Marsch
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, Medical School, University of Catania, Catania, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
authors.affiliation: Max Planck Institute of Psychiatry, Dept. Stress Neurobiology & Neurogenetics, Kraepelinstr. 2, D-80804, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
authors.affiliation: Max Planck Institute of Psychiatry, Dept. Stress Neurobiology & Neurogenetics, Kraepelinstr. 2, D-80804, Munich, Germany.
authors.forename: Carsten T
authors.initials: CT
authors.lastname: Wotjak
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D007266:Inhibition, Psychological; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics; D000077285:Rimonabant; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; C107594:N-(4-hydroxyphenyl)arachidonylamide
keywords: AM404; Avoidance behavior; CB1 receptors; Dopamine D1 receptors; Response extinction