PMID- 36183855
OWN - NLM
STAT- MEDLINE
DCOM- 20221108
LR  - 20221108
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 935
DP  - 2022 Nov 15
TI  - Pro-cognitive effects of the GlyT1 inhibitor Bitopertin in rodents.
PG  - 175306
LID - S0014-2999(22)00567-2 [pii]
LID - 10.1016/j.ejphar.2022.175306 [doi]
AB  - N-methyl-D-aspartate-receptor (NMDAR) hypofunction contributes to cognitive 
      impairments in neuropsychiatric disorders such as schizophrenia. Reduced NMDAR 
      signalling can be enhanced by increasing extracellular levels of the NMDAR 
      co-agonist glycine through inhibition of its transporter (GlyT1). This may be one 
      option to improve cognitive deficits or negative symptoms of schizophrenia. In 
      this preclinical study, we aimed at investigating effects of the GlyT1-inhibitor 
      Bitopertin on cognition, social function and motivation. Central target 
      engagement was assessed by Bitopertin-induced changes in glycine levels in rats' 
      cerebrospinal fluid (CSF) and prefrontal cortex (PFC). Behavioural effects of 
      Bitopertin on recognition memory were evaluated using a social-recognition test 
      in rats, while its effects on working memory were tested in a spontaneous 
      alternation task in mice pre-treated with the NMDAR antagonist MK-801. Bitopertin 
      was further investigated using a social interaction test in rats pre-treated with 
      the NMDAR antagonist phencyclidine, and the effects on effortful motivation were 
      explored in progressive ratio tasks in rats. Results show that Bitopertin 
      increased glycine levels in CSF and PFC. Moreover, it enhanced recognition memory 
      and reduced MK-801-induced working memory deficits. By contrast, Bitopertin had 
      no significant effects on PCP-induced social interaction deficits, and it did not 
      alter effort-related responding. Collectively, our data demonstrate that GlyT1 
      inhibition by Bitopertin increased CSF and extracellular glycine levels and 
      advocated for pro-cognitive effects of GlyT1 inhibition both in intact and NMDAR 
      antagonists-pre-treated rodents. Together, these findings support the use of 
      GlyT1-inhibitors for the treatment of cognitive symptoms in pathologies 
      characterized by NMDR hypofunction, such as schizophrenia.
CI  - Copyright (c) 2022 Elsevier B.V. All rights reserved.
FAU - Deiana, Serena
AU  - Deiana S
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. of CNS Discovery Research, 
      Biberach an der Riss, Germany. Electronic address: 
      serena.deiana@boehringer-ingelheim.com.
FAU - Hauber, Wolfgang
AU  - Hauber W
AD  - Systems Neurobiology Research Unit and Department of Neurobiology, Institute of 
      Biomaterials and Biomolecular Systems, University of Stuttgart, Stuttgart, 
      Germany.
FAU - Munster, Alexandra
AU  - Munster A
AD  - Systems Neurobiology Research Unit and Department of Neurobiology, Institute of 
      Biomaterials and Biomolecular Systems, University of Stuttgart, Stuttgart, 
      Germany.
FAU - Sommer, Susanne
AU  - Sommer S
AD  - Systems Neurobiology Research Unit and Department of Neurobiology, Institute of 
      Biomaterials and Biomolecular Systems, University of Stuttgart, Stuttgart, 
      Germany.
FAU - Ferger, Boris
AU  - Ferger B
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. of CNS Discovery Research, 
      Biberach an der Riss, Germany.
FAU - Marti, Anelise
AU  - Marti A
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. of CNS Discovery Research, 
      Biberach an der Riss, Germany.
FAU - Schmid, Bernhard
AU  - Schmid B
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. of Drug Discovery Science, 
      Biberach an der Riss, Germany.
FAU - Dorner-Ciossek, Cornelia
AU  - Dorner-Ciossek C
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. of CNS Discovery Research, 
      Biberach an der Riss, Germany.
FAU - Rosenbrock, Holger
AU  - Rosenbrock H
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. of CNS Discovery Research, 
      Biberach an der Riss, Germany.
LA  - eng
PT  - Journal Article
DEP - 20220930
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Glycine Plasma Membrane Transport Proteins)
RN  - 0 
      ((4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone)
RN  - 6LR8C1B66Q (Dizocilpine Maleate)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Rats
MH  - *Glycine Plasma Membrane Transport Proteins/physiology
MH  - *Dizocilpine Maleate
MH  - Rodentia
MH  - Receptors, N-Methyl-D-Aspartate/physiology
MH  - Glycine/pharmacology/therapeutic use
MH  - Cognition
OTO - NOTNLM
OT  - Bitopertin
OT  - Cognition
OT  - GlyT1
OT  - Glycine transporter inhibitor
OT  - Motivation
OT  - Schizophrenia
COIS- Declaration of competing interest SD, HR, BF, CDC, BS, AM, are employees of and 
      WH, SS AM have been funded by Boehringer Ingelheim Pharma GmbH & Co. KG. All 
      authors could collegially design the study, analyse and interpret the data 
      without any constraint, write the manuscript and decide to publish their work 
      without any pressure or restriction, whatever the institutional origin.
EDAT- 2022/10/03 06:00
MHDA- 2022/11/09 06:00
CRDT- 2022/10/02 19:34
PHST- 2022/07/31 00:00 [received]
PHST- 2022/09/26 00:00 [revised]
PHST- 2022/09/26 00:00 [accepted]
PHST- 2022/10/03 06:00 [pubmed]
PHST- 2022/11/09 06:00 [medline]
PHST- 2022/10/02 19:34 [entrez]
AID - S0014-2999(22)00567-2 [pii]
AID - 10.1016/j.ejphar.2022.175306 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2022 Nov 15;935:175306. doi: 10.1016/j.ejphar.2022.175306. Epub 
      2022 Sep 30.