title: Fear erasure in mice requires synergy between antidepressant drugs and extinction training.
abstract: Antidepressant drugs and psychotherapy combined are more effective in treating mood disorders than either treatment alone, but the neurobiological basis of this interaction is unknown. To investigate how antidepressants influence the response of mood-related systems to behavioral experience, we used a fear-conditioning and extinction paradigm in mice. Combining extinction training with chronic fluoxetine, but neither treatment alone, induced an enduring loss of conditioned fear memory in adult animals. Fluoxetine treatment increased synaptic plasticity, converted the fear memory circuitry to a more immature state, and acted through local brain-derived neurotrophic factor. Fluoxetine-induced plasticity may allow fear erasure by extinction-guided remodeling of the memory circuitry. Thus, the pharmacological effects of antidepressants need to be combined with psychological rehabilitation to reorganize networks rendered more plastic by the drug treatment.
authors.affiliation: Sigrid Jusélius Laboratory, Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Nina N
authors.initials: NN
authors.lastname: Karpova
authors.forename: Anouchka
authors.initials: A
authors.lastname: Pickenhagen
authors.forename: Jesse
authors.initials: J
authors.lastname: Lindholm
authors.forename: Ettore
authors.initials: E
authors.lastname: Tiraboschi
authors.forename: Natalia
authors.initials: N
authors.lastname: Kulesskaya
authors.forename: Arna
authors.initials: A
authors.lastname: Agústsdóttir
authors.forename: Hanna
authors.initials: H
authors.lastname: Antila
authors.forename: Dina
authors.initials: D
authors.lastname: Popova
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Akamine
authors.forename: Amine
authors.initials: A
authors.lastname: Bahi
authors.forename: Regina
authors.initials: R
authors.lastname: Sullivan
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.forename: Liam J
authors.initials: LJ
authors.lastname: Drew
authors.forename: Eero
authors.initials: E
authors.lastname: Castrén
mesh_terms: D000679:Amygdala / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology / Q000627:therapeutic use*; D001008:Anxiety Disorders / Q000628:therapy*; D001521:Behavior Therapy; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003131:Combined Modality Therapy; D003214:Conditioning, Classical; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005108:Extinction, Psychological; D005239:Fear; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use*; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008297:Male; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D018687:Antidepressive Agents, Second-Generation; D019208:Brain-Derived Neurotrophic Factor; D005473:Fluoxetine