Neuroreceptor kinetics in rats repeatedly exposed to quinpirole as a model for OCD

Abstract

Background Obsessive-compulsive disorder (OCD) is a chronic, incapacitating, early onset psychiatric disorder that is characterized by obsessions and compulsions originating from a disturbance in the cortico-striato-thalamico-cortical circuit. We implemented the preclinical quinpirole (QP) rat model for compulsive checking in OCD to analyse the behaviour and visualize the D2R, mGluR5 and GLT1 density in order to contribute to the understanding of the neuroreceptor kinetics. Methods Animals (n = 14) were exposed to either saline (1 mL/kg) or QP (dopamine D2-agonist, 0.5 mg/kg) twice-weekly during 7 weeks. After each injection animals were placed on an open field test. After model setup, animals were placed in a behavioural cage equipped with tracking software and hardware in order to analyse the behaviour. Subsequently, sagittal slides were made of the CP in the right hemisphere and a staining was done with the D2R, mGluR5 and GLT-1 antibody to visualize the corresponding receptor. Results The QP animals displayed a strong increase in travelled distance (+596.70%) and in the number of homebase visits (+1222.90%) compared to the control animals. After chronic exposure to QP, animals had a significantly (p < 0.05) higher percentage of D2R density in the CP (7.92% ± 0.48%) versus 6.66% ± 0.28% in animals treated with saline. There were no differences for mGluR5 and GLT1 receptor density. Conclusions Chronic exposure to QP leads to hyperlocomotion and an increase in D2R density. Furthermore, as mGluR5 and GLT1 density did not seem to be directly affected, decreased levels of glutamate might have influenced the binding potential in earlier reports.

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

“…Next to these compulsive checking behaviors, we also characterized hyperactivity measures and specific behavioral acts the rats performed during a visit at the home-base. Quinpirole-injected adolescent rats travelled over a longer total distance and with higher velocity than control rats, corresponding to hyperactivity, which has also been observed in the adult model ( Servaes et al, 2019 ). In addition, in contrast to control animals showing clear grooming behavior during a home-base visit, quinpiroleinjected adolescent rats did not groom, similar to what has been observed in the adult rat model ( Szechtman et al, 1998 ).…”

“…The clear behavioral effects in quinpirole-injected rats may be a direct result of the preceding quinpirole injection, rather than from a change in the macro-scale functional or structural brain connections. Since previous studies have shown abnormalities at the neurotransmitter and receptor level in the quinpirole model ( Servaes et al, 2019( Servaes et al, , 2017, differences in structural and functional connectivity may be more subtle and at the micro-scale. Differences that are not detectable with macro-scale MRI-based measures.…”

“…The development of compulsive-like behavior after repeated quinpirole injections is believed to reflect modifications in the brain due to the sensitization to the dopamine D2-receptor agonist quinpirole ( Tucci et al, 2014 ), such as an increased D2 receptor density ( Servaes et al, 2019 ). The reduced expression of compulsive checking behavior in the adolescent rat model may be explained by maturational differences in dopaminergic receptors in the striatum between day 40 (adolescence) and day 60 (adulthood) ( Teicher et al, 1995 ), potentially resulting in reduced sensitivity to dopaminergic agonists in young rats ( Bolanos et al, 1998 ;Ulloa et al, 2004 ).…”

Connecting the dots: Structural and functional connections in healthy and diseased brain

“…Next to these compulsive checking behaviors, we also characterized hyperactivity measures and specific behavioral acts the rats performed during a visit at the home-base. Quinpirole-injected adolescent rats travelled over a longer total distance and with higher velocity than control rats, corresponding to hyperactivity, which has also been observed in the adult model (Servaes et al, 2019). In addition, in contrast to control animals showing clear grooming behavior during a homebase visit, quinpirole-injected adolescent rats did not groom, similar to what has been observed in the adult rat model (Szechtman et al, 1998).…”

“…The development of compulsive-like behavior after repeated quinpirole injections is believed to reflect modifications in the brain due to the sensitization to the dopamine D2receptor agonist quinpirole (Tucci et al, 2014a), such as an increased D2 receptor density (Servaes et al, 2019). The reduced expression of compulsive checking behavior in the adolescent rat model may be explained by maturational differences in dopaminergic receptors in the striatum between day 40 (adolescence) and day 60 (adulthood) (Teicher et al, 1995), potentially resulting in reduced sensitivity to dopaminergic agonists in young rats (Bolanos et al, 1998;Ulloa et al, 2004).…”