Nicotinic acetylcholine receptor agonist SIB-1508Y improves cognitive functioning in chronic low-dose MPTP-treated monkeys

J Pharmacol Exp Ther. 1999 Aug;290(2):731-9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine* / administration & dosage
  • Animals
  • Attention / drug effects
  • Cognition Disorders / chemically induced
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / psychology
  • Conditioning, Operant / drug effects
  • Discrimination Learning / drug effects
  • Dopamine Agents* / administration & dosage
  • Female
  • Levodopa / pharmacology
  • Macaca fascicularis
  • Macaca nemestrina
  • Male
  • Memory, Short-Term / drug effects
  • Nicotine / pharmacology
  • Nicotinic Agonists / pharmacology
  • Nicotinic Agonists / therapeutic use*
  • Pattern Recognition, Visual / drug effects
  • Pyridines / therapeutic use*
  • Pyrrolidines / therapeutic use*
  • Receptors, Nicotinic / drug effects*
  • Space Perception / drug effects

Substances

  • Dopamine Agents
  • Nicotinic Agonists
  • Pyridines
  • Pyrrolidines
  • Receptors, Nicotinic
  • Levodopa
  • Nicotine
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • altinicline maleate