Physiological and neurobehavioral effects of cholinesterase inhibition in healthy adults

• Tested acute neurobehavioral effects of cholinesterase inhibitors in healthy adults
• Hourly assessments of RBC cholinesterase, reaction time, and declarative memory
• Unlike donepezil, huperzine A and galantamine selectively inhibited AChE.
• Despite AChE inhibition, neurobehavioral performance neither improved nor diminished.
• Maintenance of neurocognitive function under reduced cholinergic tone is discussed.

IntroductionBased on common pharmacodynamic mechanisms, recent efforts to develop second generation alternatives for organophosphate (OP) prophylaxis have expanded to include cholinesterase (ChE) inhibiting compounds traditionally approved for use in the treatment of Alzheimer’s disease (AD). The primary purpose of this study was to determine the extent to which low-dose huperzine A, galantamine, or donepezil selectively inhibited acetylcholinesterase (AChE) versus butyrylcholinesterase (BChE) activity in healthy adults and whether such inhibition impacted neurobehavioral performance.MethodsIn addition to hourly red blood cell cholinesterase sampling, neurobehavioral function was assessed before and after a single oral dose of huperzine A (100 or 200 μg), galantamine (4 or 8 mg), donepezil (2.5 or 5 mg), or placebo (n = 12 subjects per drug/dose).ResultsCompared to placebo, both dosages of huperzine A and galantamine inhibited circulating AChE but not BChE. With the exception of huperzine A (200 μg), which maintained declarative recall performance across sessions, compounds did not improve neurobehavioral performance. Some aspects of neurobehavioral performance correlated with AChE activity, although associations may have reflected time of day effects.DiscussionAlthough huperzine A and galantamine significantly inhibited AChE (and likely increased central acetylcholine levels), neither compound improved neurobehavioral performance. The latter was likely due to ceiling effects in this young, healthy test population. Under conditions of reduced cholinergic activity (e.g., Alzheimer's disease), AChE inhibition (and corresponding maintenance of cholinergic tone) could potentially maintain/augment some aspects of neurobehavioral function.