Differential Contributions of Prefrontal and Hippocampal Dopamine D1 and D2 Receptors in Human Cognitive Functions

Dopamine D-1 receptors in the prefrontal cortex (PFC) are important for prefrontal functions, and it is suggested that stimulation of prefrontal D-1 receptors induces an inverted U-shaped response, such that too little or too much D-1 receptor stimulation impairs prefrontal functions. Less is known of the role of D-2 receptors in cognition, but previous studies showed that D-2 receptors in the hippocampus (HPC) might play some roles via HPC-PFC interactions. We measured both D-1 and D-2 receptors in PFC and HPC using positron emission tomography in healthy subjects, with the aim of elucidating how regional D-1 and D-2 receptors are differentially involved in frontal lobe functions and memory. We found an inverted U-shaped relation between prefrontal D-1 receptor binding and Wisconsin Card Sorting Test performance. However, prefrontal D-2 binding has no relation with any neuropsychological measures. Hippocampal D-2 receptor binding showed positive linear correlations not only with memory function but also with frontal lobe functions, but hippocampal D-1 receptor binding had no association with any memory and prefrontal functions. Hippocampal D-2 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 D-1 receptors and hippocampal D-2 receptors might be necessary for human executive function including working memory.