Altered regional cerebral glucose utilization (rCMRglu) by acute administration of antipsychotic drugs in the rat brain: A FDG PET study with arterial blood sampling

Objectives Haloperidol (HAL) and clozapine (CLZ) both block dopamine D₂ receptors resulted in increased subcortical dopamine concentration for relieving the symptoms of schizophrenia, but differences in pharmacodynamics cause varied clinical aspects such as the presence of extrapyramidal syndrome, determining the typicality of antipsychotic drugs. In an attempt to characterize metabolic response to typical and atypical antipsychotic drugs, we investigated changes in rCMRglu by acute administration of HAL and CLZ using FDG PET.

Methods Anesthetized (2% isoflurane) Sprague-Dawley rats underwent dynamic FDG PET studies after the intravenous injection of vehicle, HAL (ED₅₀ = 13 µg/kg) or CLZ (ED₅₀ = 250 µg/kg). Whole-blood input function was measured using femoral arteriovenous shunt and a coincidence detector system during the PET scan. Additional blood samples were withdrawn at 2, 5, 10, 30, 60 min after the scan start to calculate whole-blood to plasma radioactivity ratio. rCMRglu in cortical and subcortical regions were estimated by Patlak graphical analysis using tissue time-activity curves and the whole-blood to plasma ratio-corrected input function. Statistical differences of rCMRglu between drug administration conditions were tested by Two-way ANOVA with Bonferroni post-hoc analysis.

Results Increased rCMRglu by the acute administration of HAL and CLZ were found across cortical and subcortical regions (F(4, 20) = 5.6, P < 0.01) and drugs (F(3, 20) = 12.4, P < 0.01). HAL induced the highest increase of rCMRglu in the thalamus (t = 3.486, P < 0.05), followed by the hippocampus (t = 3.128, P < 0.05) compared to the vehicle. And the greatest increase of rCMRglu by acute administration of CLZ was found in the hippocampus.

Conclusions Data demonstrated that acute administration of HAL and CLZ increased rCMRglu in the rat brain and results suggest that those antipsychotic drugs may have comparable pharmacodynamic characteristics for regional cerebral metabolism regardless of its typicality.