Structural and functional MRI of altered brain development in a novel adolescent rat model of quinpirole-induced compulsive checking behavior

Abstract

Obsessive-compulsive disorder (OCD) is increasingly considered to be a neurodevelopmental disorder. However, despite insights in neural substrates of OCD in adults, less is known about mechanisms underlying compulsivity during brain development in children and adolescents. Therefore, we developed an adolescent rat model of compulsive checking behavior and investigated developmental changes in structural and functional measures in the frontostriatal circuitry. Five-weeks old Sprague Dawley rats were subcutaneously injected with quinpirole ( n = 21) or saline ( n = 20) twice a week for five weeks. Each injection was followed by placement in the middle of an open field table, and compulsive behavior was quantified as repeated checking behavior. Anatomical, resting-state functional and diffusion MRI at 4.7T were conducted before the first and after the last quinpirole/saline injection to measure regional

Memantine treatment does not affect compulsive behavior or frontostriatal connectivity in an adolescent rat model for quinpirole-induced compulsive checking behavior

“…Several glutamatergic antagonists effectively reduce OCD symptoms in adults (Pittenger et al 2011 ) and ASD-associated behavior in pediatric patients (Mechler et al 2017 ). Before memantine treatment, quinpirole-injected rats demonstrated clear compulsive-like checking behavior, similar to our earlier study in the adolescent model (Straathof et al 2020 ) and comparable to the adult model (Szechtman et al 1998 ). In line with clinical treatment regimes, we started the memantine treatment after developing compulsive checking behavior (i.e., after the 10th quinpirole/saline injection).…”

“…We used a recently described adolescent rat model of compulsive checking behavior (Straathof et al 2020 ), adapted from an established adult rat model of compulsive checking behavior (Szechtman et al 1998 ).…”

“…The open field area was virtually divided into 25 rectangles of 40 × 40 cm 2 of which the outer zones extended 20 cm outside the open field. For all analyses, we used the last 15 min for the compulsive rats, and the complete 30 min for the control rats (Straathof et al 2020 ). Since the effect of quinpirole is biphasic, i.e., a short inhibition period is followed by extensive excitation, we only included the second half of the observation period for behavioral assessment of the quinpirole rats.…”

“…We calculated hyperactivity measures, including the total traveled distance, average movement velocity, and immobility time (< 0.01 cm movement per video frame). In addition, we manually quantified stereotypic behaviors the rats showed during a stop at their home base (Szechtman et al 1998 ; Straathof et al 2020 ), for the first twenty visits during the observation period. Because control rats were less active, all visits were included when the total amount of home-base visits was below twenty.…”

“…Because of the presence of dopaminergic abnormalities in individuals with OCD (Denys et al 2004 ) and the tight interaction between the glutamatergic and dopaminergic systems in the brain, we used a dopamine-based animal model of compulsivity. To that aim, we measured the behavioral effects of memantine administration in adolescent rats with quinpirole-induced compulsive checking behavior (Straathof et al 2020 ). In addition, we aimed to elucidate memantine’s possible mode of action on the development of structural and functional connectivity and functional activation within the frontostriatal system, which we measured with structural and functional MRI methods.…”