Pharmacological MRI responses of raclopride in rats: The relationship with D2 receptor occupancy and cataleptic behavior.

Abstract

Pharmacological magnetic resonance imaging (phMRI) allows the visualization of brain pharmacological effects of drugs using functional MRI (fMRI). phMRI can help us facilitate central nervous system (CNS) drug development. However, there have been few studies demonstrating the dose relationship of the fMRI response induced by CNS drugs to underlying target engagement or behavioral efficacy. To clarify these relationships, we examined receptor occupancy measurements using positron emission tomography (PET) (n=3~5), fMRI (n=5~8) and a cataleptic behavior (n=6) with raclopride, a dopamine D2 receptor antagonist (8, 20, and 200μg/kg) on Wistar rats. Dopamine D2 receptor occupancy was increased dose dependently by raclopride (41.8±2.7%, 8μg/kg; 64.9±2.8%, 20μg/kg; 83.1±3.0%, 200μg/kg). phMRI study revealed significant positive responses to raclopride at 200μg/kg specifically in the striatum and nucleus accumbens, related to dopaminergic system. Slight fMRI responses were observed at 20μg/kg in some areas corresponding to the striatum and nucleus accumbens. There were no noticeable fMRI responses at 8μg/kg raclopride administration. Raclopride at 200μg/kg significantly increased the cataleptic score, although, at 8 and 20μg/kg, raclopride had no significant effects. These findings showed that raclopride-induced fMRI responses were observed at doses inducing cataleptic behavior and high D2 receptor occupancy, suggesting that phMRI can be useful for dose selection in clinical trial as an evaluation method of brain activity, which reflects behavioral responses induced by target engagements.