title: Facilitation of fear extinction by the 5-HT(1A) receptor agonist tandospirone: possible involvement of dopaminergic modulation.
abstract: Fear extinction-based exposure treatment is an important component of psychotherapy for anxiety disorders such as posttraumatic stress disorder (PTSD). Recent studies have focused on pharmacological approaches combined with exposure therapy to augment extinction. In this study, we elucidated the therapeutic potential of the serotonin 1A (5-HT(1A) ) receptor agonist tandospirone compared with the effects of the N-methyl-D-aspartate partial agonist D-cycloserine (DCS), focusing on the possible involvement of dopaminergic mechanisms. We used a rat model of juvenile stress [aversive footshock (FS)] exposure during the third postnatal week (3wFS). The 3wFS group exhibited extinction deficit reflected in sustained fear-related behavior and synaptic dysfunction in the hippocampal CA1 field and medial prefrontal cortex (mPFC), which are responsible for extinction processes. Tandospirone administration (5 mg/kg, i.p.) before and after the extinction trials ameliorated both the behavioral deficit and synaptic dysfunction, i.e., synaptic efficacy in the CA1 field and mPFC associated with extinction training and retrieval, respectively, was potentiated in the tandospirone-treated 3wFS group. Extracellular dopamine release in the mPFC was increased by extinction retrieval in the non-FS control group. This facilitation was not observed in the 3wFS group; however, tandospirone treatment increased cortical dopamine levels after extinction retrieval. DCS (15 mg/kg, i.p.) also ameliorated the extinction deficit in the 3wFS group, but impaired extinction in the non-FS control group. These results suggest that tandospirone has therapeutic potential for enhancing synaptic efficacy associated with extinction processes by involving dopaminergic mechanisms. Pharmacological agents that target cortical dopaminergic systems may provide new insights into the development of therapeutic treatments of anxiety disorders, including PTSD.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Science, Health Sciences University of Hokkaido, Ishikari-Tobetsu 061-0293, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Machiko
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hiraide
authors.forename: Sumiyoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kubo
authors.forename: Kei-Ichi
authors.initials: K
authors.lastname: Shimamura
authors.forename: Hiroko
authors.initials: H
authors.lastname: Togashi
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003214:Conditioning, Classical; D003523:Cycloserine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000187:drug effects*; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D054833:Isoindoles / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D058825:Serotonin 5-HT1 Receptor Agonists; C055267:tandospirone; D003523:Cycloserine; D004298:Dopamine