Deciphering the scopolamine challenge rat model by preclinical functional MRI

Gergely Somogyi,Dávid Hlatky,András Czurkó,Zsófia Spisák,Tamás Spisák,Gabriella Nyitrai

doi:10.1038/s41598-021-90273-9

Abstract

During preclinical drug testing, the systemic administration of scopolamine (SCO), a cholinergic antagonist, is widely used. However, it suffers important limitations, like non-specific behavioural effects partly due to its peripheral side-effects. Therefore, neuroimaging measures would enhance its translational value. To this end, in Wistar rats, we measured whisker-stimulation induced functional MRI activation after SCO, peripherally acting butylscopolamine (BSCO), or saline administration in a cross-over design. Besides the commonly used gradient-echo echo-planar imaging (GE EPI), we also used an arterial spin labeling method in isoflurane anesthesia. With the GE EPI measurement, SCO decreased the evoked BOLD response in the barrel cortex (BC), while BSCO increased it in the anterior cingulate cortex. In a second experiment, we used GE EPI and spin-echo (SE) EPI sequences in a combined (isoflurane + i.p. dexmedetomidine) anesthesia to account for anesthesia-effects. Here, we also examined the effect of donepezil. In the combined anesthesia, with the GE EPI, SCO decreased the activation in the BC and the inferior colliculus (IC). BSCO reduced the response merely in the IC. Our results revealed that SCO attenuated the evoked BOLD activation in the BC as a probable central effect in both experiments. The likely peripheral vascular actions of SCO with the given fMRI sequences depended on the type of anesthesia or its dose.

Highlights

IntroductionThe systemic administration of scopolamine (SCO), a cholinergic antagonist, is widely used
During preclinical drug testing, the systemic administration of scopolamine (SCO), a cholinergic antagonist, is widely used
SCO and peripherally acting analogue BSCO were used as a pretreatment and BOLD activation were measured to air-puff stimulation of the whisker pad with GE echo-planar imaging (EPI) sequence and with functional arterial spin labeling (ASL) in isoflurane anesthesia

Summary

Introduction

The systemic administration of scopolamine (SCO), a cholinergic antagonist, is widely used. By emphasizing the peripheral vascular action of SCO as a primary mechanism, a SCO provocation-based pharmaco-MRI model was proposed as a test for procognitive agents[5,14]. In this case, another non-blood–brain barrier-penetrating anticholinergic drug, butylscopolamine (BSCO) was used. SCO and peripherally acting analogue BSCO were used as a pretreatment and BOLD activation were measured to air-puff stimulation of the whisker pad with GE echo-planar imaging (EPI) sequence and with functional ASL in isoflurane anesthesia

Methods

Results

Conclusion