Effects of nicotinic therapies on attention and executive functions in chronic low-dose MPTP-treated monkeys.
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.
Decamp
E
E
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, 521 JAH, Philadelphia, PA 19107, USA.
Schneider
J S
JS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000704:Analysis of Variance; D000818:Animals; D001288:Attention / Q000187:drug effects*; D001522:Behavior, Animal; D004195:Disease Models, Animal; D020267:MPTP Poisoning / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D008253:Macaca mulatta; D008297:Male; D009483:Neuropsychological Tests; D009538:Nicotine / Q000627:therapeutic use*; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D010636:Phenols / Q000627:therapeutic use; D011340:Problem Solving / Q000187:drug effects*; D011759:Pyrrolidines / Q000627:therapeutic use; D011930:Reaction Time / Q000187:drug effects
C119207:4-((2-(1-methyl-2-pyrrolidinyl)ethyl)thio)phenol hydrochloride; D018722:Nicotinic Agonists; D010636:Phenols; D011759:Pyrrolidines; D009538:Nicotine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine