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Research ArticleBEHAVIORAL PHARMACOLOGY

Effects of (±)-4-{[2-(1-Methyl-2-pyrrolidinyl)ethyl]thio}phenol Hydrochloride (SIB-1553A), a Selective Ligand for Nicotinic Acetylcholine Receptors, in Tests of Visual Attention and Distractibility in Rats and Monkeys

A. V. Terry Jr., V. B. Risbrough, J. J. Buccafusco and F. Menzaghi
Journal of Pharmacology and Experimental Therapeutics April 2002, 301 (1) 284-292; DOI: https://doi.org/10.1124/jpet.301.1.284
A. V. Terry Jr.
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V. B. Risbrough
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J. J. Buccafusco
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F. Menzaghi
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Abstract

Nicotine, a nonselective ligand for nicotinic acetylcholine receptors (nAChRs), has been shown to improve attention and reduce distractibility in humans. Although the numerous side effects induced by nicotine prevent its use as a therapeutic agent, it is hypothesized that subtype-selective nAChR ligands may offer a potential therapeutic benefit to humans with attention deficits. In this study, we evaluated the attention-enhancing properties of (±)-4-{[2-(1-methyl-2-pyrrolidinyl)ethyl]thio}phenol hydrochloride (SIB-1553A), a ligand selective for neuronal nAChRs with predominant activity at the human β4 subtype. SIB-1553A was evaluated in a test of attention (i.e., five-choice serial reaction time task or SRTT) and distractibility (i.e., delayed matching to sample task with distractor or DMTS-D) in adult rats and monkeys, respectively. SIB-1553A did not improve SRTT performance in normal rats, but reversed deficits induced by the N-methyl-d-aspartate (NMDA) antagonist dizocilpine. In the DMTS-D, SIB-1553A improved accuracy across several doses at the short delay intervals, which were affected most by distracting stimuli in adult monkeys. Subsequent testing with optimal doses for each monkey was also associated with significant improvements in DMTS-D accuracy at short delays, indicating the reproducibility of the drug effect. In both species, SIB-1553A had no significant effects on latencies for sample or choice selection and was not associated with adverse effects at efficacious doses. Although it remains to be further demonstrated, SIB-1553A may act through combined nicotinic and non-nicotinic mechanisms. Collectively, the present data suggest that in specific conditions SIB-1553A may improve certain aspects of attentional function in young adult rats and nonhuman primates without adverse side effects.

Footnotes

  • ↵1 Present address: University of California, San Diego, CA 92093.

  • ↵2 Present address: Arena Pharmaceuticals Inc., San Diego, CA 92121.

  • A.V.T. and V.B.R. contributed equally to this publication.

  • Abbreviations:
    ADHD
    attention deficit hyperactivity disorder
    nAChR
    nicotinic acetylcholine receptor
    ACh
    acetylcholine
    SRTT
    serial reaction time task
    DMTS-D
    delayed matching to sample task with distractor
    NMDA
    N-methyl-d-aspartate
    ABT-418
    (S)-3-methyl-2-pyrrolidinyl isoxazole
    ABT-089
    2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride
    SIB-1765F
    (±)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine fumararte
    • Received October 25, 2001.
    • Accepted January 7, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 1
1 Apr 2002
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Effects of (±)-4-{[2-(1-Methyl-2-pyrrolidinyl)ethyl]thio}phenol Hydrochloride (SIB-1553A), a Selective Ligand for Nicotinic Acetylcholine Receptors, in Tests of Visual Attention and Distractibility in Rats and Monkeys
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Research ArticleBEHAVIORAL PHARMACOLOGY

Effects of (±)-4-{[2-(1-Methyl-2-pyrrolidinyl)ethyl]thio}phenol Hydrochloride (SIB-1553A), a Selective Ligand for Nicotinic Acetylcholine Receptors, in Tests of Visual Attention and Distractibility in Rats and Monkeys

A. V. Terry, V. B. Risbrough, J. J. Buccafusco and F. Menzaghi
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 284-292; DOI: https://doi.org/10.1124/jpet.301.1.284

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Research ArticleBEHAVIORAL PHARMACOLOGY

Effects of (±)-4-{[2-(1-Methyl-2-pyrrolidinyl)ethyl]thio}phenol Hydrochloride (SIB-1553A), a Selective Ligand for Nicotinic Acetylcholine Receptors, in Tests of Visual Attention and Distractibility in Rats and Monkeys

A. V. Terry, V. B. Risbrough, J. J. Buccafusco and F. Menzaghi
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 284-292; DOI: https://doi.org/10.1124/jpet.301.1.284
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