Dopamine D2 receptor occupancy levels of acute sulpiride challenges that produce working memory and learning impairments in healthy volunteers

Abstract

Rationale: In humans, the effects of dopaminergic agents administered systemically are less clear-cut than studies in experimental animals where agents can be applied locally in the brain. DA receptor occupancy could clearly contribute to the variance in findings, although this is typically not known.

Objectives: The objective of the study was to measure the DA D2 receptor occupancy of sulpiride 200 and 400 mg and relate this to changes in task performance.

Materials and methods: Positron emission tomography scans were acquired in ten healthy volunteers with [11C]-raclopride. Striatal drug occupancy was calculated as the percentage change in binding potential between placebo and drug scans. All volunteers received placebo and sulpiride 400 mg, with four receiving 200 mg on a third session. Immediate post-scan neuropsychological assessment included working memory and learning tasks.

Results: Striatal sulpiride occupancy was approximately 17% (200 mg) and approximately 28% (400 mg), with similar occupancy within the midbrain. Neuropsychological data analysis was restricted to the higher dose (n = 10). Accuracy on the spatial working memory and spatial learning tasks was impaired after the drug, and the former was inversely related to occupancy.

Conclusion: Doses of sulpiride typically used in human cognitive studies produced low levels of DA D2 receptor occupancy compared to that considered efficacious in the treatment of schizophrenia. The levels of occupancy were sufficient to replicate impairments on a spatial working memory task and impair spatial learning. The relationship between occupancy and working memory was suggestive of presynaptic effects, although the precise mechanism underlying the impairment will require studies of wider ranges of occupancy within and outside of the striatum.