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

OBJECTIVE: Cognitive deficits including impaired working memory are a hallmark feature of schizophrenia. Dopamine D1 receptor modulated changes in prefrontal cortex function 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, operationalised by combining the nonselective dopamine agonist L-dopa with the D2-antagonist haloperidol.

METHODS: Fourteen healthy volunteers received placebo or combined carbidopa (25 mg)/L-dopa (100 mg) plus haloperidol (2 mg) orally on two separate occasions according to a within-subjects crossover design. Drug-induced differences in brain activity were assessed during an N-back working memory task in a 3T magnetic resonance imaging environment.

RESULTS: Drug treatment was associated with greater functional connectivity between the dorsolateral prefrontal cortex and areas within the salience network during all N-back trials. Drug treatment was also associated with reduced activation, most prominently in the occipital/temporal brain areas during 2-back performance.

CONCLUSIONS: This 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.