Memantine treatment does not affect compulsive behavior or frontostriatal connectivity in an adolescent rat model for quinpirole-induced compulsive checking behavior
Authors: Straathof Milou , Blezer Erwin L. A. , Smeele Christel E. , van Heijningen Caroline , van der Toorn Annette , Buitelaar Jan K. , Glennon Jeffrey C. , Otte Willem M. , Dijkhuizen Rick M. ,   TACTICS Consortium, Buitelaar Jan , de Ruiter Saskia , Naaijen Jilly , Akkermans Sophie , Mennes Maarten , Zwiers Marcel , Ilbegi Shahrzad , Hennissen Leonie , Glennon Jeffrey , van de Vondervoort Ilse , Kapusta Katarzyna , Bielczyk Natalia , Amiri Houshang , Havenith Martha , Franke Barbara , Poelmans Geert , Bralten Janita , Heskes Tom , Sokolova Elena , Groot Perry , Williams Steven , Murphy Declan , Lythgoe David , Bruchhage Muriel , Dud Iulia , Voinescu Bogdan , Dittmann Ralf , Banaschewski Tobias , Brandeis Daniel , Mechler Konstantin , Berg Ruth , Wolf Isabella , Häge Alexander , Landauer Michael , Hohmann Sarah , Boecker-Schlier Regina , Ruff Matthias , Dijkhuizen Rick , Blezer Erwin , Straathof Milou , van der Marel Kajo , Pullens Pim , Mol Wouter , van der Toorn Annette , Otte Willem , van Heijningen Caroline , Durston Sarah , Mensen Vincent , Oranje Bob , Mandl René , Joel Daphna , Cryan John , Petryshen Tracey , Pauls David , Saito Mai , Heckman Angelique , Bahn Sabine , Schwalber Ameli , Florea Ioana 
Published: April 2022

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 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.