Memantine treatment does not affect compulsive behavior or frontostriatal connectivity in an adolescent rat model for quinpirole-induced compulsive checking behavior
TACTICS Consortium
(2022) Psychopharmacology, volume 239, issue 8, pp. 2457 - 2470
(Article)
Abstract
Rationale: Compulsivity often develops during childhood and is associated with elevated glutamate levels within the frontostriatal system. This suggests that anti-glutamatergic drugs, like memantine, may be an effective treatment. Objective: Our goal was to characterize the acute and chronic effect of memantine treatment on compulsive behavior and frontostriatal network structure
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and function in an adolescent rat model of compulsivity. Methods: Juvenile Sprague–Dawley rats received repeated quinpirole, resulting in compulsive checking behavior (n = 32; compulsive) or saline injections (n = 32; control). Eight compulsive and control rats received chronic memantine treatment, and eight compulsive and control rats received saline treatment for seven consecutive days between the 10th and 12th quinpirole/saline injection. Compulsive checking behavior was assessed, and structural and functional brain connectivity was measured with diffusion MRI and resting-state fMRI before and after treatment. The other rats received an acute single memantine (compulsive: n = 12; control: n = 12) or saline injection (compulsive: n = 4; control: n = 4) during pharmacological MRI after the 12th quinpirole/saline injection. An additional group of rats received a single memantine injection after a single quinpirole injection (n = 8). Results: Memantine treatment did not affect compulsive checking nor frontostriatal structural and functional connectivity in the quinpirole-induced adolescent rat model. While memantine activated the frontal cortex in control rats, no significant activation responses were measured after single or repeated quinpirole injections. Conclusions: The lack of a memantine treatment effect in quinpirole-induced compulsive adolescent rats may be partly explained by the interaction between glutamatergic and dopaminergic receptors in the brain, which can be evaluated with functional MRI.
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Keywords: Compulsive behavior, Diffusion magnetic resonance imaging, Frontostriatal circuitry, Functional magnetic resonance imaging, NMDA antagonist, Pharmacology
ISSN: 0033-3158
Publisher: Springer Verlag
Note: Funding Information: The TACTICS consortium consists of Jan Buitelaar, Saskia de Ruiter, Jilly Naaijen, Sophie Akkermans, Maarten Mennes, Marcel Zwiers, Shahrzad Ilbegi, Leonie Hennissen, Jeffrey Glennon, Ilse van de Vondervoort, Katarzyna Kapusta, Natalia Bielczyk, Houshang Amiri, Martha Havenith, Barbara Franke, Geert Poelmans, Janita Bralten, Tom Heskes, Elena Sokolova, Perry Groot from Radboud University Medical Center Nijmegen, the Netherlands; Steven Williams, Declan Murphy, David Lythgoe, Muriel Bruchhage, Iulia Dud, Bogdan Voinescu from King’s College London, United Kingdom; Ralf Dittmann, Tobias Banaschewski, Daniel Brandeis, Konstantin Mechler, Ruth Berg, Isabella Wolf, Alexander Häge, Michael Landauer, Sarah Hohmann, Regina Boecker-Schlier, Matthias Ruff from Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany; Rick Dijkhuizen, Erwin Blezer, Milou Straathof, Kajo van der Marel, Pim Pullens, Wouter Mol, Annette van der Toorn, Willem Otte, Caroline van Heijningen, Sarah Durston, Vincent Mensen, Bob Oranje, René Mandl from University Medical Center Utrecht, Utrecht, the Netherlands; Daphna Joel from Tel Aviv University, Tel Aviv, Israel; John Cryan from University College Cork, Cork City, Ireland; Tracey Petryshen, David Pauls, Mai Saito from Massachusetts General Hospital, Boston, MA, USA; Angelique Heckman from Genoway, Lyon, France; Sabine Bahn from University of Cambridge, Cambridge, United Kingdom; Ameli Schwalber from concentris research management GmbH, Fürstenfeldbruck, Germany; and Ioana Florea from Lundbeck, Valby, Denmark. Funding Information: This work was supported by the Netherlands Organization for Scientific Research (NWO-VICI 016.130.662 to dr. R.M. Dijkhuizen, NWO-VENI 016.168.038 to dr. W.M. Otte), and the Dutch Brain Foundation (F2014(1)-06 to dr. W.M. Otte). The research leading to these results has received funding from the European Community’s Seventh Framework Program (FP7/2007–2013) TACTICS under grant agreement no. 278948. The funding sources had no role in the study design. Publisher Copyright: © 2022, The Author(s).
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