The subtype-selective nicotinic acetylcholine receptor agonist SIB-1553A improves both attention and memory components of a spatial working memory task in chronic low dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys.
Monkeys that receive chronic low dose (CLD) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration develop deficits in spatial delayed-response task performance. The present study examined the extent to which SIB-1553A [(+/-)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride], a novel neuronal nicotinic acetylcholine receptor (nAChR) agonist with selectivity for beta4 subunit-containing nAChRs, could counteract this cognitive deficit produced by CLD MPTP exposure. Prior to MPTP treatment, monkeys displayed a delay-dependent decrement in performance on a variable delayed response task. CLD MPTP treatment caused a shift to a delay-independent pattern of responding on this task, such that short-delay trials were performed as poorly as long-delay trials. At lower doses (e.g., 0.025 mg/kg), SIB-1553A significantly improved performance on short-delay trials but only at 24 h after drug administration. At higher doses (e.g., 0.50 mg/kg), SIB-1553A significantly improved performance on both short- and long-delay trials at both 20 min and 24 h after drug administration. When tested 24 h after drug administration, monkeys performed long-delay trials with greater accuracy than they did under normal (pre-MPTP) conditions. These results suggest that at lower doses, SIB-1553A may be more effective in improving attentional deficits associated with CLD MPTP exposure, whereas at higher doses, SIB-1553A may effectively improve both attentional and memory performance.
Schneider
J S
JS
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, 521 JAH, Philadelphia, PA 19107, USA. jay.schneider@jefferson.edu
Tinker
J P
JP
Menzaghi
F
F
Lloyd
G K
GK
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001288:Attention / Q000187:drug effects* / Q000502:physiology; D015259:Dopamine Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D023421:Models, Animal; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013028:Space Perception / Q000187:drug effects
C119207:4-((2-(1-methyl-2-pyrrolidinyl)ethyl)thio)phenol hydrochloride; D015259:Dopamine Agents; D018722:Nicotinic Agonists; D010636:Phenols; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine