title: Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction.
abstract: Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory.
authors.affiliation: Department of Pharmacology and Toxicology, Center for Chemistry and Biomedicine, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Whittle
authors.affiliation: Department of Pharmacology and Toxicology, Center for Chemistry and Biomedicine, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: V
authors.initials: V
authors.lastname: Maurer
authors.affiliation: Department of Pharmacology and Toxicology, Center for Chemistry and Biomedicine, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Murphy
authors.affiliation: Division of Molecular Pathophysiology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Rainer
authors.affiliation: Division of Molecular Pathophysiology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Bindreither
authors.affiliation: Department of Pharmacology and Toxicology, Center for Chemistry and Biomedicine, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: M
authors.identifier: 0000-0003-3539-7661
authors.initials: M
authors.lastname: Hauschild
authors.affiliation: Department of Pharmacology and Toxicology, Center for Chemistry and Biomedicine, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Scharinger
authors.affiliation: Department of Pharmacology and Toxicology, Center for Chemistry and Biomedicine, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Oberhauser
authors.affiliation: Department of Pharmacology and Toxicology, Center for Chemistry and Biomedicine, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Keil
authors.affiliation: Department of Pharmacology and Toxicology, Center for Chemistry and Biomedicine, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Brehm
authors.affiliation: Division of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Valovka
authors.affiliation: Department of Pharmacology and Toxicology, Center for Chemistry and Biomedicine, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Striessnig
authors.affiliation: Department of Pharmacology and Toxicology, Center for Chemistry and Biomedicine, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Singewald
mesh_terms: D000679:Amygdala / Q000502:physiology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D003131:Combined Modality Therapy; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D051548:Histone Acetyltransferases / Q000502:physiology*; D007171:Implosive Therapy; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D017397:Prefrontal Cortex / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D001549:Benzamides; D011725:Pyridines; C118739:entinostat; D007980:Levodopa; D051548:Histone Acetyltransferases; D004298:Dopamine