title: Involvement of the strychnine-sensitive glycine receptor in the anxiolytic effects of GlyT1 inhibitors on maternal separation-induced ultrasonic vocalization in rat pups.
abstract: Several studies have shown that glycine transporter 1 (GlyT1) inhibitors have anxiolytic actions. There are two types of glycine receptor: the strychnine-sensitive glycine receptor (GlyA) and the strychnine-insensitive glycine receptor (GlyB); however, which receptor is the main contributor to the anxiolytic actions of GlyT1 inhibitors is yet to be determined. Here, we clarified which glycine receptor is the main contributor to the anxiolytic effects of GlyT1 inhibitors by using maternal separation-induced ultrasonic vocalization (USV) by rat pups as an index of anxiety. We confirmed that administration of the benzodiazepine diazepam or the selective serotonin reuptake inhibitor escitaloplam, which are both clinically proven anxiolytics, or the GlyT1 inhibitor SSR504734 (2-chloro-N-[(S)-phenyl[(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide), decreases USV in rat pups. In addition, we showed that another GlyT1 inhibitor, ALX5407 ((R)-N-[3-(4'-fluorophenyl)-3(4'-phenylphenoxy)propyl]sarcosine) also decreases USV in rat pups. SSR504734- or ALX5407-induced decreases in USV were dose-dependently reversed by administration of the GlyA antagonist strychnine, whereas the diazepam- or escitalopram-induced decreases in USV were not. Furthermore, GlyT1-induced decreases in USV were not reversed by administration of the GlyB antagonist L-687,414. Together, these results suggest that GlyA activation is the main contributor to the anxiolytic actions of GlyT1 inhibitors and that the anxiolytic actions of diazepam and escitalopram cannot be attributed to GlyA activation. Our findings provide new insights into the importance of the activation of GlyA in the anxiolytic effects of GlyT1 inhibitors.
authors.affiliation: Department of Clinical Neuroscience, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-0001, Japan; Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. Electronic address: h2-komatsu@hhc.eisai.co.jp.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Komatsu
authors.affiliation: Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Furuya
authors.affiliation: Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sawada
authors.affiliation: Department of Clinical Neuroscience, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-0001, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Asada
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D001010:Anxiety, Separation / Q000188:drug therapy* / Q000209:etiology; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008426:Maternal Deprivation; D049990:Membrane Transport Modulators / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D058990:Molecular Targeted Therapy; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D012521:Sarcosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D013331:Strychnine / Q000494:pharmacology; D014465:Ultrasonics; D014828:Vocalization, Animal / Q000187:drug effects*
chemical_list: C510369:(R)-(N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl))sarcosine; C507205:2-chloro-N-((S)-phenyl((2S)-piperidin-2-yl)methyl)-3-trifluoromethyl benzamide; D014151:Anti-Anxiety Agents; D001549:Benzamides; D050487:Glycine Plasma Membrane Transport Proteins; D049990:Membrane Transport Modulators; D010880:Piperidines; D011760:Pyrrolidinones; D018009:Receptors, Glycine; C493266:Slc6a9 protein, rat; C027822:strychnine receptor; C084173:L 687414; D013331:Strychnine; D012521:Sarcosine
keywords: Anxiety; Glycine transporter 1 inhibitor (GlyT1); Maternal separation; Strychnine-sensitive glycine receptor; Ultrasonic vocalization (USV)