Introduction

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Inattention and the susceptibility to distracting stimuli (i.e., distractibility) are among the cognitive changes that may occur in normal aging (Hoyer et al., 1979) and are salient features of numerous neurodegenerative and psychiatric disorders, including Alzheimer's disease (Lawrence and Sahakian, 1995), schizophrenia (Addington et al., 1997), and attention deficit hyperactivity disorder (ADHD) (Zametkin and Ernst, 1999). First line therapeutic agents available for attention deficits (particularly those associated with ADHD) are psychostimulants such as methylphenidate, which have clearly demonstrated efficacy (Spencer et al., 1996). Approximately 25% of ADHD patients however, fail to respond to psychostimulants or exhibit serious side effects (Green, 1991; Elia et al., 1999), requiring the development of alternative agents for attentional disorders.

Nicotine, a nonselective ligand for nicotinic acetylcholine receptors (nAChRs) appears to improve attention and reduce distractibility in animals and humans (Rezvani and Levin, 2001). Improvements of attention in Alzheimer's disease and ADHD patients administered nicotine (Jones et al., 1992; Levin et al., 1996; White and Levin, 1999) appear particularly promising. Although the numerous side effects (such as cardiovascular, gastrointestinal dysfunction, and addiction) induced by nicotine prevent its use as a therapeutic agent, it is hypothesized that subtype-selective nAChR ligands, with potential improved efficacy and limited side effect profiles compared with nicotine, may offer potential therapeutic benefits to humans with cognitive impairments and attention deficits in particular. Accordingly, subtype-selective nAChR agonists with predominant activity for the nAChR 2 subtype, such as ABT-418, ABT-089, and SIB-1765F, have been shown to improve attention in animals (Prendergast et al., 1998; Grottick and Higgins, 2000).

The purpose of this study was to evaluate the attention-enhancing properties of the nAChR ligand (±)-4-{[2-(1-methyl-2-pyrrolidinyl)ethyl]thio}phenol hydrochloride] (SIB-1553A), which has demonstrated predominant agonist activity at the human ₄ subtype, with no activity at muscle nAChR subtypes (Menzaghi et al., 1999; Vernier et al., 1999). In vivo, SIB-1553A induces a dose-dependent increase in acetylcholine (ACh) release in the rat prefrontal cortex and hippocampus, both brain regions known to play an important role in cognitive functions. Ex vivo studies also demonstrated that SIB-1553A induces the release of other neurotransmitters besides ACh, including dopamine and norepinephrine from rat prefrontal cortex (Menzaghi et al., 1999). Furthermore, recent studies with SIB-1553A in rodents and nonhuman primates have indicated enhancements in working memory tasks (Bontempi et al., 2001), which led to the suggestion that this effect may be secondary to enhanced attention and warrants the evaluation of SIB-1553A in models of attention. SIB-1553A also represents a pharmacological tool with which to probe the function of nAChR subtypes, because it is presently one of the few 4 subunit-selective ligands described in the literature and its effects have not yet been reported in models of attention.

In the present studies, we assessed the effects of SIB-1553A on attention by using a choice serial reaction time task (SRTT) in rats and a delayed matching to sample task with distractor (DMTS-D) in young monkeys.

The DMTS-D is a method to assess distractibility in nonhuman primates performing a working memory task by using delayed matching to sample in which brief distracting (task relevant) stimuli are presented during some of the trials. This model has been shown to be sensitive to nAChR ligands as well as methylphenidate and is therefore considered a relevant model to evaluate the effect of SIB-1553A.

The SRTT is a visuospatial attentional task that has been used extensively to examine the role of the cholinergic system in attention. A light stimulus is presented randomly in one of five possible apertures and a nose-poke response in the lit aperture is reinforced by a food reward. Well trained animals reach a level of performance accuracy that usually precludes observation of attentional enhancement over baseline. Procedural manipulations such as decreasing stimulus duration, which reduces accuracy, have been shown to unmask attentional deficits in animals with lesions of the basal forebrain, suggesting a cholinergic component to performance in these conditions (Muir et al., 1994). SIB-1553A was therefore evaluated after reduction of the stimulus duration. In a second experiment, performance was disrupted by pharmacological manipulations by administration of the noncompetitive blocker of the glutamate N-methyl-D-aspartate (NMDA) receptor dizocilpine. Because glutamergic hypofunction occurs in many cognitive disorders, dizocilpine is commonly used as a pharmacological model of cognitive deficits in rats and monkeys (Buffalo et al., 1994; Dai and Carey, 1994). Interestingly, dizocilpine inhibits nAChRs, with receptors containing the 4 subunit showing greater sensitivity than those containing 2 subunits (Amador and Dani, 1991; Yamakura et al., 2000). It was therefore hypothesized that SIB-1553A would reverse the procedural and dizocilpine-induced attentional deficits in the SRTT in rats.

	Materials and Methods

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Subjects

Rats. Male Lister hooded rats (Harlan Sera-Lab, Crawley Down, Sussex, UK) (300 g at the start of the study) were housed two per cage and maintained in a humidity- (50-55%) and temperature- (22-24°C) controlled facility on a 12-h light/dark cycle (lights on at 6:30 AM). Food was restricted to that earned during the test [maximum of 100 × 45 mg Formula 1 pellets (P. J. Noyes Co. Inc., Lancaster, NH)] and 12 g of standard rodent chow (Harlan-Teklad 4% rat diet 7001), which was given a minimum of 1 h post-testing. This food restriction regimen maintained their body weight at an average of 350 g (i.e., 80% of normal body weight). Except for during testing, water was available ad libitum. All testing was conducted during the light cycle. Only rats that have reached consistent baseline performance (see below) before and between testing were used. All procedures were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee.

Monkeys. Five adult pigtail macaques (Macaca nemestrina, one female and four male), originally colony-reared at the Washington Regional Primate Center (Seattle, WA), served as subjects. The gender, weight, age, and testing parameters (delays) used for the behavioral tests appear in Table 1. The subjects were individually housed at the Animal Behavior Center of the Medical College of Georgia in stainless steel cages composed of multiple 50- × 28- × 26-in. units. Toys and foraging tubes were provided routinely and monkeys were allowed to observe television programs each afternoon after testing to promote psychological well-being. During a test week, monkeys were maintained on a feeding schedule that allowed approximately 15% of their normal daily food intake to be derived from banana-flavored reinforcement pellets awarded for correct responses during testing. Testing was conducted 5 days/week. Standard laboratory monkey chow, fresh fruits, and vegetables comprised the remainder of their daily food intake, which was given after completion of testing each day. Water was available ad libitum. All procedures used during this study were reviewed and approved by the Medical College of Georgia Institutional Animal Care and Use Committee and are consistent with Association for Assessment and Accreditation of Laboratory Animal Care guidelines.

Behavioral Procedures

Choice Serial Reaction Time Task Procedure in Rats. Apparatus. The SRTT was performed in automated nine-hole operant chambers (Paul Fray Ltd., Cambridge, UK) housed in sound-insulated and ventilated enclosures. In brief, each SRTT apparatus contained a food magazine on one wall, and on the opposite wall five square niches (i.e., nose-poke holes) (2.5-cm-wide square, 4 cm in depth) arranged on a curved panel and raised 2 cm above a grid the floor. All apertures in the chamber, including the food magazine, were controlled by a photocell monitoring the entrance. Each hole could be illuminated by a 2.8-W lamp located at the rear of the hole. Each animal had to poke its nose in one of the holes when it was illuminated then turn around and go to the food magazine to collect a food pellet as a reward. The rat collected the food pellets by pushing a Perspex panel that covered the food magazine.

Training and testing procedures. The training procedure was as reported by Muir et al. (1995). In brief, during each session, the rat was trained to push the food magazine to initiate a trial. Five seconds later, one of the five nose-poke apertures was lit for 0.5 s. The rat was then trained to quickly respond with a nose poke in the hole in which the stimuli was just presented (correct response). The stimuli were presented across the five possible nose-poke apertures in a pseudorandom order. Each correct response was rewarded with a food pellet, and each failure to respond (omissions, longer than 5-s poststimuli presentation) or incorrect response (response in aperture that was not lit by light stimulus) was punished with a 10-s time-out with no access to a food pellet.

Standard DMTS Procedure in Monkeys. The monkey's home cage was equipped with testing panels for the DMTS procedure (Terry et al., 1993). Stimuli on the test panels were three 2.54-cm-diameter colored disks (red, yellow, or green) presented by light-emitting diodes located behind clear plastic push keys. A trial began with the illumination of one of the push keys (the sample key) by one of the colored disks. A key press extinguished the sample light and initiated one of four preprogrammed delay intervals, during which no disks were illuminated. After the delay interval, two choice lights located below the sample key were illuminated. One of the choice lights matched the hue of the sample light. These disks remained illuminated until a monkey pressed one of the two lit keys. Key presses of choice stimuli that matched the hue of the sample stimulus were rewarded with a 300-mg banana-flavored pellet. Nonmatching choices were neither rewarded nor punished. Matching configurations were fully counterbalanced for side, delay, and hue. A new trial was initiated 5 s after the second key press on a preceding trial. Monkeys completed 96 trials on each day of testing. The lack of a response by a monkey for 700 s resulted in the preprogrammed cessation of the session.

DMTS Procedure with Distractors (DMTS-D) in Monkeys. On 18 of the 96 trials completed during DMTS-D test sessions, a distractor stimulus consisting of a random array of flashing colored lights appeared on the test panels and lasted for 3 s (Prendergast et al., 1998). Distractor lights were generated by the same diodes, as were sample and choice stimuli. This duration of the distractor was chosen based on our observation that distractors of lesser duration were not effective in disrupting DMTS performance. The remaining trials were presented as standard DMTS trials distributed across all delay intervals.

Compounds. All drugs were diluted in 0.9% saline. Dizocilpine maleate was obtained from Sigma/RBI (Natick, MA). SIB-1553A was synthesized at SIBIA Neurosciences, Inc. (now Merck Research Laboratories) as per methods previously described (Vernier et al., 1999). Doses of dizocilpine are expressed as base, whereas doses of SIB-1553A are expressed as salt. Compounds were administered s.c. in rats after administration into the dorsal neck region in a volume of 1 ml/kg of body weight, and i.m. in monkeys after administration in the gastrocnemius muscle within a volume of 0.035 ml/kg of body weight.

Statistical Analysis. Data were analyzed by either one- and two-way analyses of variance with or without repeated measures or one-tailed Student's t test when appropriate. Post hoc analysis was made using the Newman-Keuls, Fisher's, or Dunnett's test as necessary for appropriate comparison. In the SRTT in rats, the effects of reducing stimulus duration on performance were assessed with a paired t test comparing the vehicle treatment day of testing (0.15-s stimulus duration) to their average baseline performance (0.5-s stimulus duration) measured for 1 week before testing. In monkeys, DMTS accuracy on short, medium, and long delay distractor and nondistractor trials during interference trials were compared with accuracy on trials completed during standard DMTS testing. Accuracy on distractor and nondistractor trials completed after administration of doses of SIB-1553A was compared with like trials completed after saline administration and to accuracy during standard DMTS testing. Median latencies (in s) for both sample and choice were analyzed by the nonparametric method of Kruskal-Wallis (analysis of variance on ranks). All analysis was performed using SigmaStat (Jandel Scientific, San Rafael, CA) with the criterion for significance being p < 0.05.

	Results

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Effect of SIB-1553A on SRTT Performance in Rats. As illustrated in Fig. 1, decreasing the stimulus duration significantly disrupted SRTT performance by decreasing percentage of correct responses, but having no significant effect on inappropriate responding [t₄ = 5.16, p = 0.003 and t₄ = 2.03, N.S.]. This effect was maintained over the course of the study. One-way analysis of variance with repeated measures revealed that SIB-1553A alone has no significant effect on accuracy or inappropriate responding [F(4,15) = 1.27, N.S. and F(4,15) = 0.27, N.S., respectively]. Furthermore, there were no effects of SIB-1553A administration on speed of correct responding (data not shown). There was a slight, but significant increase in latency to respond for food at the highest dose tested [F(4,15) = 8.97, p < 0.001; vehicle = 1.96 ± 0.087 s versus 4.0 mg/kg = 2.32 ± 0.12 s, p < 0.05; Dunnett's test]. No carryover effects of SIB-1553A administration were found on nondrug test days. Effects of day (i.e., order effects) were also not observed, with response accuracy and inappropriate responding remaining constant over the entire testing period (data not shown). In this study the 4-mg/kg dose of SIB-1553A was found to significantly increase latency for reward collection. Thus, a 3-mg/kg dose of SIB-1553A was arbitrarily chosen to ensure pharmacological efficacy (Bontempi et al., 2001) without task disruption in the subsequent dizocilpine study.

View larger version (18K): [in this window] [in a new window]   Fig. 1.   Effect of SIB-1553A on SRTT performance in rats exposed to short stimuli duration. A, percentage of correct responses (total correct responses/total trials attempted). B, total inappropriate responses. Black columns represent animals tested under 0.15-s stimulus duration conditions. White columns represent the same animals tested under 0.5-s stimulus duration conditions. Animals were administered with SIB-1553A and tested 15 min later. Data are presented as mean ± S.E.M., n = 5/group, within-subject Latin square design. *, p < 0.05 versus baseline performance at 0.5-s stimulus duration, paired t test.

Effect of SIB-1553A on Dizocilpine-Induced Deficits in SRTT Performance in Rats. As shown in Fig. 2, dizocilpine dose-dependently decreased percentage of correct responses and increased inappropriate responding compared with vehicle-treated group with the highest tested dose (0.05 mg/kg) being the most effective dose [F(3,19) = 5.60, p = 0.006; F(3,19) = 5.24, p = 0.008, respectively]. Dizocilpine markedly reduced performance accuracy without disrupting speed of responding (correct latency) or motivation (latency to collect food rewards) (data not shown). The 0.05-mg/kg dose of dizocilpine was therefore selected to test the effect of SIB-1553A on dizocilpine-induced disruption of SRTT performance in rats.

View larger version (18K): [in this window] [in a new window]   Fig. 2.   Effect of dizocilpine on SRTT performance in rats. A, percentage of correct responses (total correct responses/total trials attempted). B, total inappropriate responses. The rats were administered dizocilpine (s.c.) 15-min pretest. Black columns represent the groups treated with 0.0125 to 0.05 mg/kg base dizocilpine. White columns represent the saline-treated group. *, p < 0.05 versus saline group, Dunnett's post hoc test. Data are represented as mean ± S.E.M., n = 5 to 6/group.

View larger version (17K): [in this window] [in a new window]   Fig. 3.   Effect of SIB-1553A on dizocilpine-induced disruptions of SRTT performance in rats. A, percentage of correct responses (total correct responses/total trials attempted). B, total inappropriate responses. The rats were administered with dizocilpine (s.c.) followed by SIB-1553A 1 min later. The animals were tested 15 min after the administration of SIB-1553A. Black columns represent the groups treated with dizocilpine at a dose of 0.05 mg/kg combined with vehicle (0) or SIB-1553A (3 mg/kg). White columns represent vehicle/vehicle group. *, p < 0.05 versus vehicle/vehicle group; +, p < 0.05 versus vehicle/dizocilpine group; Student's t test. Data are represented as mean ± S.E.M., n = 7 to 8/group.

DMTS-D Baseline in Monkeys. Baseline performance of standard DMTS and DMTS-D with interference sessions (distractor and nondistractor trials) was acquired from data obtained during sessions initiated 10 min after saline injections on individual days throughout the study (i.e., nine standard saline-DMTS sessions and eight DMTS-D sessions). Averaged baseline performance across the study for each method is illustrated and compared in Fig. 4. Performance (accuracy) of each task was significantly different as were the effects of the imposed delay intervals: task effect, F(2,8) = 13.5, p = 0.003; delay effect, F(2,8) = 70.6, p < 0.001; and task × delay interaction, F(4,16) = 6.18, p = 0.003. Post hoc analysis (Fisher's test) indicated that under standard DMTS testing conditions (i.e., days in which no distractors were used) accuracy was reduced significantly with each increase in the duration of delay interval (i.e., accuracy at short > medium > long delays, p < 0.05). On days in which distractors were included (DMTS-D), in the case of nondistractor trials, accuracy at short delays was higher than at medium and long delays (i.e., short > medium and long), and in the case of the distractor associated trials, accuracy at short and medium delays was higher than at long delays (i.e., short and medium > long). Post hoc analyses further revealed that there was a significant difference between the accuracy of each method (i.e., DMTS was different from DMTS-D) at short delay intervals (p < 0.05). Exposure to a distractor of 3-s duration immediately after depression of the sample key significantly impaired DMTS performance on short delays, producing a mean reduction in accuracy of 21.8% correct compared with standard DMTS trials. Performance efficiency was also somewhat impaired on the nondistractor trials (i.e., mean reduction in accuracy of 9.3% correct).

View larger version (33K): [in this window] [in a new window]   Fig. 4.   Baseline performance of monkeys on standard DMTS and DMTS with interference sessions (distractor and nondistractor trials). The data were averaged across the study. Saline was administered i.m. 10 min before testing. , p < 0.05 versus standard DMTS trial accuracy. +, p < 0.05 versus DMTS with interference sessions, nondistractor trials, n = 5.

SIB-1553A Dose-Effect Study in Monkeys. The effects of SIB-1553A across 10 different doses (one to two replicates per dose) on short delay trials appear in Figs. 5 and 6. The compound significantly improved performance accuracy of distractor-associated trials [dose effect, F(11,41) = 2.46, p = 0.018 (Fig. 5)]. Post hoc analyses revealed that improvements in accuracy occurred after the test subjects received four of the 10 different doses. No dose of SIB-1553A significantly affected performance associated with nondistractor trials [dose effect: F(11,41) = 1.41, p = 0.204 at short delays (Fig. 6)]. In addition, significant effects of SIB-1553A were not observed at the other delay intervals (data not shown).

View larger version (32K): [in this window] [in a new window]   Fig. 5.   Dose-dependent effects of SIB-1553A on short delay distractor trial performance during interference sessions. SIB-1553A was administered i.m. 10 min before testing. , p < 0.05 versus saline-distractor performance. Data represented as mean percentage correct ± S.E.M. BL, saline baseline for standard DMTS performance; SAL, saline baseline performance associated with 3-s distractor trials, n = 5.

View larger version (41K): [in this window] [in a new window]   Fig. 6.   Dose-dependent effects of SIB-1553A on short delay nondistractor trial performance during interference sessions. SIB-1553A was administered i.m. 10 min before testing. Data are represented as mean percentage correct ± S.E.M. BL, saline baseline for standard DMTS performance; SAL, saline baseline performance associated with nondistractor trials, n = 5.

SIB-1553A Repeated Optimal Dose Study in Monkeys. After analysis of the dose-effect data, the optimal (best) dose was selected for each monkey and repeated on a separate occasion (at least 2 weeks after dose-effect studies) and randomized with additional saline interference and standard DMTS-saline sessions. The best dose was determined by examining the scores for short-delay performance for each test subject (see the legend of Fig. 7 for the doses selected). Best dose re-administration was associated with highly significant improvements in accuracy for trials associated with short delays [treatment effect: F(2,6) = 30.89, p < 0.001 (Fig. 7)]. Post hoc analyses revealed that the drug produced significant reversal of the performance decrement induced by distractor trials associated with short delay intervals, but it did not significantly affect the accuracy of the nondistractor-associated trials of DMTS-D method.

View larger version (39K): [in this window] [in a new window]   Fig. 7.   Best dose effect of SIB-1553A on accuracy for the short delay interval of the DMTS task. The selected best doses were 2.5 µg/kg for monkeys 13 and 787, 5.0 µg/kg for 146, and 1.25 µg/kg for 270. The columns represent DMTS accuracy (96 trials/session) in percentage points per session. Data are represented as mean percentage correct ± S.E.M. , p < 0.05 versus saline controls in which interference sessions were included, n = 4.

Sample/Choice Latencies in Monkeys. Two measures of response latency were also recorded during DMTS testing conducted after drug administration: choice latency, the time interval between presentation of the two choice stimuli and depression of one of the choice keys; and sample latency, the time interval between initiation of a new trial (illumination of the stimulus light behind the sample key) and depression of the sample key by the monkeys. Latency data were analyzed for both correctly and incorrectly completed trials after administration of each dose of SIB-1553A. Median sample and choice latencies on trials completed correctly or incorrectly under baseline conditions (during both standard DMTS testing and during sessions in which distractors were present) are provided in Table 2. Although there appeared to be a slight trend toward longer latencies associated with sessions in which distractors were present, no statistically significant differences were found. Furthermore, none of the latencies were significantly altered after administration of any dose of SIB-1553A (data not shown).

	Discussion

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The aim of the present study was to explore the effect of SIB-1553A in tests of visual attention and distractibility in rats and monkeys, respectively. The data indicate that SIB-1553A reduces distractibility in young monkeys but has no effect on choice reaction time performance in young rats. On the other hand, SIB-1553A administration was found to attenuate dizocilpine-induced impairment of attentional performance in rats.

The lack of effect of SIB-1553A on SRTT performance in normal rats is in agreement with previous reports on the activity of other nicotinic ligands or cholinergic agents on SRTT performance under similar testing parameters. For example, no effects of acute administration of nicotine or physostigmine, a cholinesterase inhibitor, were found on attentional performance in the SRTT during baseline or low-stimulus duration conditions (Muir et al., 1994, 1995; Stolerman et al., 2000). Shortened stimulus durations, however, have been used successfully to probe both deficits in SRTT performance induced by excitotoxic lesions of the cholinergic basal forebrain and the subsequent reversal of those deficits by procholinergic compounds, suggesting a cholinergic component to the attenuation of performance deficits induced by the decrease of stimulus presentation (Muir et al., 1994, 1995). The assumption was that a drug such as SIB-1553A that induces the release of cortical ACh in rats will reverse the deficits induced by the decrease of stimulus duration in the SRTT. However, the level of ACh in cortical areas does not appear to correlate with modulation of the stimulus duration in normal intact rats (Passetti et al., 2000). It has been recently reported that basal levels of ACh are already substantially increased in performing rats (Passetti et al., 2000; Himmelheber et al., 2001) and the modulation of stimulus duration, although creating the expected changes in performance accuracy, does not produce further changes in the ACh efflux. Because the release of ACh induced by SIB-1553A was reported in nonperforming rats and was not explored in rats performing the SRTT, it is speculated that rats performing the SRTT task have already high levels of ACh, which cannot be further increased by a cholinergic drug. Thus, the effects of SIB-1553A on ACh release may be minimal when cortical efflux levels are already high. This may explain why SIB-1553A did not improve performance in this task, even though it has been shown to enhance cortical ACh release. ACh release in this particular condition may not be relevant. Recently, nAChR agonists have been reported to enhance SRTT performance in rats in conditions where the stimulus presentation was made temporally unpredictable (Stolerman et al., 2000). Further studies are needed to examine the efficacy of SIB-1553A under other conditions. Taken together, these data suggest that cortical ACh release data alone may be limited as an explanation for the observed functional effects on attention and task performance. This may also be applied to the dizocilpine study.

In agreement with a report by Grottick and Higgins (2000), administration of the noncompetitive NMDA antagonist dizocilpine disrupted SRTT performance in rats as measured by decreases in accuracy and increases in inappropriate responding (premature and perseverative responses). In the present study, SIB-1553A was shown to significantly attenuate the dizocilpine-induced deficits in accuracy without affecting inappropriate responding. These data suggest that SIB-1553A effects are specific to the attentional disruptions induced by dizocilpine, and not to the disruption of response sequence or behavioral inhibition. It is therefore unlikely that SIB-1553A acts through direct competition at the NMDA receptor (Aizenman et al., 1991) because SIB-1553A only attenuated the effects of dizocilpine on accuracy, and had no effect on dizocilpine-induced increases in inappropriate responding.

On the other hand, it has been shown that dizocilpine inhibits nicotinic receptors, with receptors containing a 4 subunit showing greater sensitivity than those containing a 2 subunit (Amador and Dani, 1991; Yamakura et al., 2000). This suggests the possibility that dizocilpine-induced deficits in attention may be in part due to direct activity at 4-containing nAChRs, whereas the effects on behavioral inhibition are not. This effect could have therefore been reversed by SIB-1553A. These data warrant the investigation of the effect of SIB-1553A on the modulation of glutamatergic synaptic transmission.

Although SIB-1553A did not improve attentional performance of normal rats in the SRTT, it significantly reduced the distractibility of adult monkeys performing the DMTS-D, improving accuracy across several doses at the delay that was most affected by interference sessions (i.e., short delays). Optimal dose re-administration was also associated with significant improvements, indicating reproducibility of the drug effect. This discrepancy across species could be due to the different behaviors and attentional components being probed in each task. It is also surprising that the efficacious doses of SIB-1553A in monkeys were low compared with the doses used in rodents. This may be due to differences in pharmacokinetic profile and this should be further investigated. It is also interesting to note that SIB-1553A did not significantly affect standard DMTS (i.e., nondistractor trials) trials in the present study in young monkeys as was observed previously in aged monkeys (Bontempi et al., 2001). Young and aged monkeys represent two different types of behavioral subjects with proven differences in cognitive performance (Prendergast et al., 1997) and response to cholinergic manipulations (Bartus and Uehara, 1979; Buccafusco and Jackson, 1991). It is thus certainly conceivable to observe an effect of a particular drug in aged, compromised monkeys without seeing an effect in young animals that may reach a ceiling level of performance in the same cognitive test. Furthermore, it is not clear at present how standard DMTS trials compare between studies when distractor trials are included in one investigation and not the other.

Overall, SIB-1553A appears to share some properties with other nicotinic agonists such as nicotine and particularly the nicotinic agonists ABT-418 and ABT-089 (Prendergast et al., 1998), which also improved DMTS-D performance at doses lower than those that improved working memory. This may imply that nicotinic ligands have preferential effects on certain attentional components rather than memory per se. It is also important to note that the ABT compounds that are effective in this task are reported to demonstrate predominant activity at 2 subunits (as well as 4 and 2) (Prendergast et al., 1998), a different nAChR subtype profile than SIB-1553A. Therefore, the role of 4 in attentional processes can be hypothesized, but this does not exclude the possibility of additional, and/or alternative effects by other nAChR subtypes on attentional processes.

In addition to activity at nAChR receptors, SIB-1553A shows weak agonist activity at histaminergic H₃, serotonergic 5-hydroxytryptamine_1A, and sigma sites, and antagonist activity at 5-hydroxytryptamine₂ receptors. Antagonism of H₃ receptors has been shown to improve attention processes (Passani and Blandina, 1998), and therefore the affinity of SIB-1553A for H₃ receptors may not contribute to the effects presently reported or may have undermined the effect observed. On the other hand, the activity at certain serotoninergic receptors and at sigma sites may contribute to the cognitive enhancement properties of SIB-1553A, and therefore a non-nicotinic component cannot be excluded. Finally, both dopaminergic and noradrenergic activity in the prefrontal cortex have been described as consequential in attention and distractibility in nonhuman primates (Goldman-Rakic and Brown, 1981; Arnsten and Goldman-Rakic, 1984). Accordingly, the beneficial effects of SIB-1553A may have been attributed at least in part to enhanced noradrenergic and dopaminergic activity in frontal cortex (Arnsten and Contant, 1992; Levin and Simon, 1998) but there is not enough information at this stage to link these effects to the 4 nAChR subtype.

In conclusion, the selective nAChR ligand SIB-1553A improved performance in a rat model of disrupted visual attention and improved accuracy in a nonhuman primate model of distractibility in specific conditions only. Thus, SIB-1553A or related compounds may offer a potential benefit for disorders associated with the susceptibility to distraction or specific forms of attentional deficits. The possibility that the 4-preferring properties of SIB-1553A may account for some of the beneficial effects on attention observed in the present study deserves further examination.