Abstract
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 β4 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.
Footnotes
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This work was funded by SIBIA Neurosciences, Inc. and National Institutes of Health Grant DA 013452.
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DOI: 10.1124/jpet.103.051912.
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ABBREVIATIONS: CLD, chronic low dose; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; nAChR, novel neuronal nicotinic acetylcholine receptor; VDR, variable delayed response task; SIB-1508Y, (S)-(–)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine; SIB-1553A, (±)-4-{[2-(1-methyl-2-pyrrolidinyl)ethyl]thio}phenol hydrochloride.
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↵1 Current Address: Arena Pharmaceuticals, Inc., 6166 Nancy Ridge Dr., San Diego, CA 92121.
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↵2 Current Address: Nereus Pharmaceuticals, Inc., 10480 Wateridge Circle, San Diego, CA 92121.
- Received March 20, 2003.
- Accepted April 15, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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