Chronic administration of low doses of the
neurotoxin MPTP to nonhuman primates induces cognitive deficits similar to those seen in early
Parkinson's disease (PD) patients, without the confounding effect of significant motor impairment. The present study assessed the extent to which specific attentional and central executive deficits in chronic low dose (CLD)
MPTP-treated monkeys could be modified by nicotinic
therapies. Four adult male rhesus monkeys were trained to perform attention and executive function tasks and were then administered low doses of
MPTP (dose range: 0.025-0.1 mg/kg, i.v.) over 98-158 days until stable cognitive deficits appeared. Results showed that both
nicotine and the alpha4beta4 subtype-selective nAChR agonist
SIB-1553A could improve certain aspects of attentional and central executive functioning in this model of early
Parkinsonism.
Nicotine failed to improve performance of CLD-
MPTP-treated animals on an attention set-shifting task while
SIB-1553A significantly improved at least some aspects of performance, suggesting that the compound increased the animals' ability to maintain a previously formed response set and restored cognitive flexibility. Both
nicotine and
SIB-1553A caused a dose-dependent enhancement of performance on the focused attention (cued reaction time) task, decreasing reaction times on both cued and noncued trials.
Nicotine caused a significant reduction in reaction times but did not alter the error profile on an impulse (motor readiness) task.
SIB-1553A reduced reaction times but caused an increase in bar release (i.e. impulsivity) errors. These data suggest that nicotinic drugs may have therapeutic potential for treating
cognitive dysfunction in PD.