A proof-of-principle study of the effect of combined haloperidol and levodopa administration on working memory-related brain activation in humans

Background and PurposeCognitive deficits including impaired working memory are a hallmark feature of schizophrenia. Changes in prefrontal cortex function modulated by dopamine D1 receptors, play a potentially important role in the pathology underlying such deficits. However, pharmacological interventions that selectively engage the D1 receptor are severely restricted for research in humans. The present study is a proof-of-principle for enhancing cognitive performance and associated brain activation via indirect D1 stimulation. Here, we combine the non-selective dopamine agonist L-dopa with the D2-antagonist haloperidol, theoretically producing increased stimulation at the D1 receptor.\n\nExperimental ApproachFourteen healthy volunteers received placebo or combined carbidopa (125 mg, 100mg L-dopa) plus haloperidol (2 mg) orally on two separate occasions according to a within-subjects cross-over design. Drug-induced differences in brain activity were assessed during an N-back working memory task in a 3T magnetic resonance imaging environment.\n\nKey ResultsDrug treatment was associated with a reduction in activity in a large number of brain areas, most prominently occipital/temporal brain areas during 2-back performance, which may be due to the effects of haloperidol specifically. Drug treatment was also associated with greater functional connectivity within parts of the salience network during all N-back trials.\n\nConclusion and ImplicationsThis preliminary study provides initial evidence for combined L-dopa/haloperidol modulation in cognition-related brain areas and networks, which is relevant for the treatment of cognitive impairments in mental illness.