D2 Antidopaminergic Modulation of Frontal Lobe Function in Healthy Human Subjects

Background Although the major principles of dopamine (DA) signaling have been well described previously, its precise modulatory impact on the prefrontal cortex (PFC) in humans is poorly understood. Two major neurophysiological models propose segregated functional circuits on the systems level as well as D1 and D2 receptor-dependent processing states on the cellular level (two-state model). Methods We examined the predictive validity of these models in 10 healthy male volunteers with a haloperidol challenge (HLP). Cortico-striatal-thalamo-cortical (CSTC) motor loop functions were examined during functional magnetic resonance imaging (fMRI) with a sequential finger opposition task. Neuropsychological implications of the two-state model were evaluated with a test battery of D1- or D2-sensitive prefrontal measures. Results Analysis of fMRI data revealed a significant HLP-induced blood oxygen level dependent–signal decrease in the sensorimotor striatum and a lateralized activation loss of ipsilateral higher order motor cortices and contralateral cerebellum. Neuropsychological evaluation demonstrated a preferential impairment of D2-sensitive functions, whereas D1 or non-dopaminergic domains were unaffected. Conclusions Our data support the hypothesis that mesocortical D1 and D2 receptors exert differential influences in the PFC for cognitive function, but the nigrostriatal CSTC network model for the motor domain could not be confirmed. Article Outline