Pro-cognitive effects of the GlyT1 inhibitor Bitopertin in rodents

被引：8

作者：

Deiana, Serena ^{[1
]}

Hauber, Wolfgang ^{[3
,4
]}

Munster, Alexandra ^{[3
,4
]}

Sommer, Susanne ^{[3
,4
]}

Ferger, Boris ^{[1
]}

Marti, Anelise ^{[1
]}

Schmid, Bernhard ^{[2
]}

Dorner-Ciossek, Cornelia ^{[1
]}

Rosenbrock, Holger ^{[1
]}

机构：

[1] Boehringer Ingelheim Pharm GmbH & Co KG, Dept CNS Discovery Res, Biberach An Der Riss, Germany

[2] Boehringer Ingelheim Pharm GmbH & Co KG, Dept Drug Discovery Sci, Biberach An Der Riss, Germany

[3] Univ Stuttgart, Inst Biomat & Biomol Syst, Dept Neurobiol, Stuttgart, Germany

[4] Univ Stuttgart, Syst Neurobiol Res Unit, Stuttgart, Germany

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 2022年 / 935卷

关键词：

Glycine transporter inhibitor; GlyT1; Bitopertin; Cognition; Motivation; Schizophrenia; INDUCED STEREOTYPED BEHAVIOR; GLYCINE REUPTAKE INHIBITORS; SOCIAL-INTERACTION TEST; ADD-ON TREATMENT; NMDA RECEPTOR; ANIMAL-MODELS; NEGATIVE SYMPTOMS; D-SERINE; ACUTE EXACERBATION; N-METHYLGLYCINE;

D O I：

10.1016/j.ejphar.2022.175306

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 alter-nation 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 ef-fects 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.

引用

页数：12

共 56 条

[11] RESERPINE IN THE TREATMENT OF NEUROPSYCHIATRIC DISORDERS [J].

CLOUGH, PW .

ANNALS OF INTERNAL MEDICINE, 1955, 43 (03) :632-637

[12]

Coyle JT, 2017, ADV NEUROBIOL, V15, P255, DOI 10.1007/978-3-319-57193-5_9

[13] SLV330, a cannabinoid CB1 receptor antagonist, ameliorates deficits in the T-maze, object recognition and Social Recognition Tasks in rodents [J].

de Bruin, N. M. W. J. ;

Prickaerts, J. ;

Lange, J. H. M. ;

Akkerman, S. ;

Andriambeloson, E. ;

de Haan, M. ;

Wijnen, J. ;

van Drimmelen, M. ;

Hissink, E. ;

Heijink, L. ;

Kruse, C. G. .

NEUROBIOLOGY OF LEARNING AND MEMORY, 2010, 93 (04) :522-531

[14]

Deiana S., 2014, P MEASURING BEHAV 9, P27

[15] Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-I SSR504734, a potential new type of antipsychotic [J].

Depoortère, R ;

Dargazanli, G ;

Estenne-Bouhtou, G ;

Coste, A ;

Lanneau, C ;

Desvignes, C ;

Poncelet, M ;

Heaulme, M ;

Santucci, V ;

Decobert, M ;

Cudennec, A ;

Voltz, C ;

Boulay, D ;

Terranova, JP ;

Stemmelin, J ;

Roger, P ;

Marabout, B ;

Sevrin, M ;

Vigé, X ;

Biton, B ;

Steinberg, R ;

Françon, D ;

Alonso, R ;

Avenet, P ;

Oury-Donat, F ;

Perrault, G ;

Griebel, G ;

George, P ;

Soubrié, P ;

Scatton, B .

NEUROPSYCHOPHARMACOLOGY, 2005, 30 (11) :1963-1985

[16] The relationship between glycine transporter 1 occupancy and the effects of the glycine transporter 1 inhibitor RG1678 or ORG25935 on object retrieval performance in scopolamine impaired rhesus monkey [J].

Eddins, Donnie ;

Hamill, Terence G. ;

Puri, Vanita ;

Cannon, Christopher E. ;

Vivian, Jeffrey A. ;

Sanabria-Bohorquez, Sandra M. ;

Cook, Jacquelynn J. ;

Morrow, John A. ;

Thomson, Fiona ;

Uslaner, Jason M. .

PSYCHOPHARMACOLOGY, 2014, 231 (03) :511-519

[17] Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management [J].

Fone, Kevin C. F. ;

Watson, David J. G. ;

Billiras, Rodolphe, I ;

Sicard, Dorothee, I ;

Dekeyne, Anne ;

Rivet, Jean-Michel ;

Gobert, Alain ;

Millan, Mark J. .

MOLECULAR NEUROBIOLOGY, 2020, 57 (05) :2144-2166

[18] The emerging role of glutamate in the pathophysiology and treatment of schizophrenia [J].

Goff, DC ;

Coyle, JT .

AMERICAN JOURNAL OF PSYCHIATRY, 2001, 158 (09) :1367-1377

[19] Validation and optimisation of a touchscreen progressive ratio test of motivation in male rats [J].

Hailwood, Jonathan M. ;

Heath, Christopher J. ;

Robbins, Trevor W. ;

Saksida, Lisa M. ;

Bussey, Timothy J. .

PSYCHOPHARMACOLOGY, 2018, 235 (09) :2739-2753

[20] A novel glycine transporter-1 (GlyT1) inhibitor, ASP2535 (4-[3-isopropyl-5-(6-phenyl-3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole), improves cognition in animal models of cognitive impairment in schizophrenia and Alzheimer's disease [J].

Harada, Katsuya ;

Nakato, Kazuhiro ;

Yarimizu, Junko ;

Yamazaki, Mayako ;

Morita, Masahiko ;

Takahashi, Shinji ;

Aota, Masaki ;

Saita, Kyoko ;

Doihara, Hitoshi ;

Sato, Yuichiro ;

Yamaji, Takayuki ;

Ni, Keni ;

Matsuoka, Nobuya .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2012, 685 (1-3) :59-69

← 1 2 3 4 5 6 →