Ultra‐high‐field pharmacological functional MRI of dopamine D1 receptor‐related interventions in anesthetized rats

Abstract

The dopamine D1 receptor (D1R) is associated with schizophrenia, Parkinson's disease, and attention deficit hyperactivity disorder. Although the receptor is considered a therapeutic target for these diseases, its neurophysiological function has not been fully elucidated. Pharmacological functional MRI (phfMRI) has been used to evaluate regional brain hemodynamic changes induced by neurovascular coupling resulting from pharmacological interventions, thus phfMRI studies can be used to help understand the neurophysiological function of specific receptors. Herein, the blood oxygenation level‐dependent (BOLD) signal changes associated with D1R action in anesthetized rats was investigated by using a preclinical ultra‐high‐field 11.7‐T MRI scanner. PhfMRI was performed before and after administration of the D1‐like receptor agonist (SKF82958), antagonist (SCH39166), or physiological saline subcutaneously. Compared to saline, the D1‐agonist induced a BOLD signal increase in the striatum, thalamus, prefrontal cortex, and cerebellum. At the same time, the D1‐antagonist reduced the BOLD signal in the striatum, thalamus, and cerebellum by evaluating temporal profiles. PhfMRI detected D1R‐related BOLD signal changes in the brain regions associated with high expression of D1R. We also measured the early expression of c‐fos at the mRNA level to evaluate the effects of SKF82958 and isoflurane anesthesia on neuronal activity. Regardless of the presence of isoflurane anesthesia, c‐fos expression level was increased in the region where positive BOLD responses were observed with administration of SKF82958. These findings demonstrated that phfMRI could be used to identify the effects of direct D1 blockade on physiological brain functions and also for neurophysiological assessment of dopamine receptor functions in living animals.

New clues for the role of cerebellum in schizophrenia and the associated cognitive impairment

“…Cerebellar D1R is a promising therapeutic target for CIAS going beyond the more common D2R antagonists (Goldman-Rakic et al, 2004). D1R agonists were found to enhance blood oxygenation leveldependent (BOLD) signals in the cerebellum in addition to striatum, thalamus, and PFC, while D1R antagonists did the opposite (Kimura et al, 2023). This observation suggests revisiting the Weinberger's view that D1Rs are principally located in PFC where they are hypoactivated causing negative symptoms (Weinberger, 1987;Slifstein et al, 2015;Rao et al, 2018;, by integrating cerebellar D1R hypofunction as a potential cause of CIAS.…”

“…( 5) Whole brain level: The cerebellum controls the functioning and rhythms of the cerebral cortex (Popova and Naumenko, 2013;Margarint et al, 2020), which show relevant alterations in CIAS. (6) Neuromodulation systems: The cerebellum is emerging as part of complex regulatory systems that subtend CIAS and are based on dopamine (Ikai et al, 1994;Carta et al, 2019;D'Angelo, 2019;Cutando et al, 2022;Kimura et al, 2023), Ach (Jaarsma et al, 1997;Zhang et al, 2016;Okkels et al, 2023;Zhao et al, 2023), and 5HT ( Oostland and van Hooft, 2013;Saitow et al, 2013). Moreover, the cerebellum hosts among the most important NMDA receptor-dependent neurotransmission and plasticity mechanisms in the brain, addressing the glutamatergic hypothesis of CIAS (Hansel et al, 2001;Contestabile, 2002;Bouvier et al, 2016;Mapelli L. et al, 2022).…”