Nicotinic acetylcholine receptor agonist SIB-1508Y improves cognitive functioning in chronic low-dose MPTP-treated monkeys.
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.
Schneider
J S
JS
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. jay.schneider@mail.tju.edu
Tinker
J P
JP
Van Velson
M
M
Menzaghi
F
F
Lloyd
G K
GK
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000818:Animals; D001288:Attention / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D015259:Dopamine Agents / Q000008:administration & dosage; D005260:Female; D007980:Levodopa / Q000494:pharmacology; D008252:Macaca fascicularis; D008254:Macaca nemestrina; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D010364:Pattern Recognition, Visual / Q000187:drug effects; D011725:Pyridines / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000627:therapeutic use*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013028:Space Perception / Q000187:drug effects
D015259:Dopamine Agents; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; D007980:Levodopa; D009538:Nicotine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C100989:altinicline maleate