Differential contributions of prefrontal and hippocampal dopamine D ₁ and D₂ receptors in human cognitive functions

Dopamine D₁ receptors in the prefrontal cortex (PFC) are important for prefrontal functions, and it is suggested that stimulation of prefrontal D₁ receptors induces an inverted U-shaped response, such that too little or too much D₁ receptor stimulation impairs prefrontal functions. Less is known of the role of D₂ receptors in cognition, but previous studies showed that D₂ receptors in the hippocampus (HPC) might play some roles via HPC-PFC interactions.Wemeasured both D₁ and D₂ receptors in PFC and HPC using positron emission tomography in healthy subjects, with the aim of elucidating how regional D₁ and D₂ receptors are differentially involved in frontal lobe functions and memory. We found an inverted U-shaped relation between prefrontal D₁ receptor binding and Wisconsin Card Sorting Test performance. However, prefrontal D₂ binding has no relation with any neuropsychological measures. Hippocampal D₂ receptor binding showed positive linear correlations not only with memory function but also with frontal lobe functions, but hippocampal D₁ receptor binding had no association with any memory and prefrontal functions. Hippocampal D₂ receptors seem to contribute to local hippocampal functions (long-term memory) and to modulation of brain functions outside HPC ("frontal lobe functions"), which are mainly subserved by PFC, via the HPC-PFC pathway. Our findings suggest that orchestration of prefrontal D₁ receptors and hippocampal D₂ receptors might be necessary for human executive function including working memory.