Vol. 290, Issue 2, 731-739, August 1999

Nicotinic Acetylcholine Receptor Agonist SIB-1508Y Improves Cognitive Functioning in Chronic Low-Dose MPTP-Treated Monkeys¹

J. S. Schneider, John P. Tinker, Maria Van Velson, Frederique Menzaghi and G. Kenneth Lloyd

Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University (J.S.S., J.P.T., M.V.V.), Philadelphia, Pennsylvania and SIBIA Neurosciences, Inc., (F.M., G.K.L.), La Jolla, California

Monkeys that receive chronic low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration have difficulty performing numerous cognitive tasks. This study further examines the extent to which chronic low-dose MPTP exposure affects performance of a visual memory task [variable delayed response (VDR)] with both attentional and short-term memory components and assesses the effects of the novel neuronal nicotinic acetylcholine receptor agonist SIB-1508Y and levodopa on cognitive task performance. Before MPTP treatment, these monkeys displayed a delay-dependent decrement in performance on the VDR task and performed well on delayed matching-to-sample and visual pattern discrimination tasks. Chronic low-dose MPTP treatment caused a shift to a delay-independent pattern of responding on the VDR task, such that short-delay trials were performed as poorly as long-delay trials. There were also deficits in performing the delayed matching-to-sample task, whereas visual discrimination performance remained intact. SIB-1508Y normalized the pattern of response on the VDR task by significantly improving performance on short-delay trials and on the delayed matching-to-sample task. These effects lasted up to 24 to 48 h after SIB-1508Y administration. Neither levodopa nor nicotine significantly improved task performance. These results suggest that chronic low-dose MPTP exposure results in a cognitive disturbance that can be corrected by the nicotinic acetylcholine receptor agonist SIB-1508Y but not by levodopa. Thus, SIB-1508Y may be useful in the treatment of the cognitive deficits in Parkinson's disease.