Vol. 301, Issue 1, 284-292, April 2002

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. Risbrough¹ , J. J. Buccafusco and F. Menzaghi²

Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Medical College of Georgia, Augusta, Georgia (A.V.T.); Alzheimer's Research Center and Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia (A.V.T., J.J.B.); Department of Veterans Affairs Medical Center, Augusta, Georgia (A.V.T., J.J.B.); and Merck Research Laboratories, La Jolla, California (V.B.R., F.M.)

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 4 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.