Low bone turnover and low bone density in a cohort of adults with Down syndrome.

UNLABELLED: Increased incidence of osteoporosis in Down syndrome has been reported, but etiology is not established. We report low bone turnover markers and bone mineral density (BMD) in a cohort of people with Down syndrome without consistent clinical risk factors. Our results should guide future studies and treatments for this common problem. INTRODUCTION: To better understand the etiology for osteoporosis in Down syndrome (DS), we measured bone density by dual-energy X-ray absorptiometry (DXA) and circulating biochemical markers of bone formation and resorption in a cohort of 30 community-dwelling DS adults. METHODS: Seventeen males and 13 females followed in the University of Arkansas Down Syndrome Clinic were evaluated by DXA to estimate BMD and underwent phlebotomy to measure serum procollagen type-1 intact N-terminal propeptide (P1NP) to evaluate bone formation, and serum C-terminal peptide of type-I collagen (CTx) to evaluate bone resorption. RESULTS: Seven of 13 DS females and 12 of 17 DS males had low bone mass at one of measured sites (z≤-2.0). When data were grouped by age, males had apparent osteopenia earlier than females. The mean P1NP in the normal group was 19.2±5.2 ng/ml vs. 2.2±0.9 ng/ml in the DS group (P=0.002). Serum CTx levels in the normal group were 0.4±0.1 ng/ml vs. 0.3±0.1 ng/ml (P=0.369). CONCLUSIONS: Low BMD in adults with DS is correlated with a significant decrease in bone formation markers, compared to controls without DS, and is independent of gender. These data suggest that diminished osteoblastic bone formation and inadequate accrual of bone mass, with no significant differences in bone resorption, are responsible for the low bone mass in DS. These observations question the use of antiresorptive therapy in this population and focus attention on increasing bone mass by other interventions.

Pharmacophore/receptor models for GABA(A)/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) via a comprehensive ligand-mapping approach.

Pharmacophore/receptor models for three recombinant GABA(A)/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) have been established via an SAR ligand-mapping approach. This study was based on the affinities of 151 BzR ligands at five distinct (alpha1-3,5,6beta3gamma2) recombinant GABA(A)/BzR receptor subtypes from at least nine different structural families. Examination of the included volumes of the alpha1-, alpha5-, and alpha6-containing subtypes indicated that region L(2) for the alpha5-containing subtype appeared to be larger in size than the analogous region of the other receptor subtypes. Region L(Di), in contrast, appeared to be larger in the alpha1 subtype than in the other two subtypes. Moreover, region L(3) in the alpha6 subtype is either very small or nonexistent in this diazepam-insensitive subtype (see Figure 16 for details) as compared to the other subtypes. Use of the pharmacophore/receptor models for these subtypes has resulted in the design of novel BzR ligands (see 27) selective for the alpha5beta3gamma2 receptor subtype. alpha5-Selective ligand 27 when injected directly into the hippocampus did enhance memory in one paradigm (Bailey et al., unpublished observations); however, systemic administration of either 9 or 27 into animals did not provide an observable enhancement. This result is in complete agreement with the observation of Liu (1996). It has been shown (Liu, 1996; Wisden et al., 1992) that in the central nervous system of the rat (as well as monkeys and pigeons) there are several native subtypes of the GABA(A) receptor which exhibit different functions, regional distributions, and neuronal locations. Although 27 binds more potently at alpha5beta3gamma2 receptor subtypes and is clearly an inverse agonist (Liu et al., 1996; Liu, 1996), it is possible that this ligand acts as an agonist at one or more subtypes. Liu (1996) clearly showed that a number of imidazobenzodiazepines were negative modulators at one subtype and agonists at another. Therefore, selectivity for a particular subtype at this point is not sufficient to rule out some physiological effect at other GABA(A)/BzR subtypes. The inability of 27 to potentiate memory when given systemically is again in support of this hypothesis, especially since alpha1beta2gamma2 subtypes are distributed throughout the brain (Wisden et al., 1992). A drug delivered systemically is far more likely to interact with all subtypes than one delivered to a specific brain region. This observation (systemic vs intrahippocampal) provides further support for the design of more subtype-specific ligands at the BzR to accurately define their pharmacology, one key to the design of new drugs with fewer side effects.

Effects of drugs of abuse on acquisition of behavioral chains in squirrel monkeys.

The acute effects of various drugs of abuse on the acquisition of chains of behavior were assessed in squirrel monkeys trained to respond on three keys for food. Each new session the monkeys acquired a different four-response chain by responding sequentially on three keys in the presence of four different stimuli. Incorrect responses inactivated the keys and darkened the chamber for 10 s (time-out). Dose-effect curves were obtained by administering the drugs intramuscularly before the session and recording their effects on the rate and accuracy of responding. Cocaine, d-amphetamine, and delta 9-tetrahydrocannabinol all decreased the accuracy and rate of responding within the dose range of 0.56-3 mg/kg. The highest dose of morphine tested (3 mg/kg) produced parallel decreases in the accuracy and rate of responding in some monkeys but had no effect at lower doses. These drugs decreased within-session accuracy though clearly acquisition did occur, but high doses of caffeine (30 and 56 mg/kg) prevented acquisition and recovery of performance and, furthermore, at 30 mg/kg these effects were observed in the absence of decreases in the rate of responding. The drugs of abuse tested all produced dose-related decreases in both the accuracy and rate of responding, and the decreases in accuracy were primarily observed only at doses that also decreased response rates. Therefore, based on these results from nonhuman primates each of these drugs has the potential to alter learning particularly when doses that disrupt other behaviors are administered.

The discriminative stimulus properties of barbiturate stereoisomers.

Pigeons were trained to discriminate an IM injection of racemic pentobarbital sodium (5.0 mg/kg) from saline under a second-order color-tracking schedule of mixed grain presentation. In a time-course study, maximal pentobarbital-appropriate responding occurred 15 min after administration of 5.0 mg/kg racemic pentobarbital sodium, the pretreatment time used for subsequent experiments. Racemic pentobarbital sodium, the R(+) and S(-) isomers of pentobarbital, racemic secobarbital sodium, and the R(+) and S(-) isomers of secobarbital all produced dose-dependent increases in pentobarbital-appropriate responding. Racemic secobarbital sodium, the secobarbital isomers, and the R(+) isomer of pentobarbital were equipotent to each other and slightly less potent than racemic pentobarbital and the S(-)-pentobarbital isomer in this regard. Except for R(+)-pentobarbital, all barbiturates caused dose-dependent decreases in response rate over the dose range tested.

Effects of drugs of abuse and scopolamine on memory in rats: delayed spatial alternation and matching to position.

Drugs of abuse produce amnestic effects in humans and laboratory animals in a variety of tasks. Generally, only a few compounds have been examined in any particular procedure. It was the goal of the present studies to examine drugs of abuse of different pharmacological classes in rats responding under two behavioral schedules historically employed as experimental models of memory: spatial alternation and matching to position. One group of rats responded under a single-response spatial-alternation baseline with a 10-s delay and another group responded under a matching-to-position baseline with delay values of 3, 10 and 30 s. Performance under the spatial-alternation baseline was characterized by low variability and >90% accuracy. Under the matching-to-position baseline, saline control percent accuracy was >95% at 3 s, >85% at 10 s and >70% at 30 s. Under spatial alternation cocaine, d-amphetamine, pentobarbital, diazepam, phencyclidine, scopolamine and methscopolamine produced significant (P<0.05) effects on accuracy, whereas only cocaine, d-amphetamine, pentobarbital and phencyclidine disrupted accuracy under the matching-to-position baseline. These results suggest that spatial alternation may be a more sensitive baseline for determining drug effects on working memory in the rat.

Effects of phencyclidine-like drugs on responding under multiple fixed ratio, fixed interval schedules.

The effects of phencyclidine and a series of related drugs were studied on rates and patterns of responding by rats under a multiple fixed-interval 300s, fixed-ratio 30-response schedule of food presentation. Dizocilipine produced large increases in the rate of FI responding and smaller increases in the rate of FR responding. TCP slightly increased the rate of FI responding and PCE slightly increased the rate of FR responding. Higher doses of all drugs decreased rates of responding under both schedule components with the potency order of dizocilpine > PCE > PCP > TCP > ketamine. This relative potency for decreasing rates of FI and FR responding correlated highly with the affinity of these drugs for PCP receptors, suggesting that the rate decreasing effects of these drugs are mediated through these receptors. An analysis of local rates of responding within the FI suggested that dizocilpine was different from the arylcyclohexylamines in that it was the only drug that increased rates of responding late in the FI component. Previous reports have shown that the ability of arylcyclohexylamines to increase punished responding and to act as discriminative stimuli are correlated highly with binding to PCP receptors. The present experiments suggest that decreases in rates of responding under multiple schedule control are also mediated by PCP receptors.

Pentobarbital, diazepam and phencyclidine disrupt delayed matching performance: interactions with picrotoxin in pigeons and squirrel monkeys.

The ability of picrotoxin to antagonize selectively the effects of pentobarbital was investigated in pigeons and squirrel monkeys responding under a titrating matching-to-sample schedule of reinforcement. Under the titrating matching-to-sample baseline, the length of the delay changed as a function of the animal's matching accuracy. Picrotoxin (0.03-1mg/kg) failed to alter significantly the matching accuracy of pigeons; however, rate of responding was markedly suppressed at a dose of 1mg/kg. In squirrel monkeys responding under a similar schedule, picrotoxin (0.001-0.3mg/kg) was without significant effect. Selected doses of picrotoxin in both pigeons (0.3 and 0.56mg/kg) and squirrel monkeys (0.1 and 0.3mg/kg) failed to shift the pentobarbital or diazepam dose-response curve for mean delay length to the right. However, in both species, picrotoxin shifted the dose-response curve for pentobarbital on rate of responding to the right. No such shift was observed for the effect of diazepam on rate of responding. In both species, the combination of picrotoxin and phencyclidine shifted the dose-response curves for phencyclidine on rate of responding, but not mean delay, downward and to the left, in an apparent additive manner. Thus, picrotoxin failed to produce a significant pharmacological antagonism of the effects of pentobarbital, diazepam or phencyclidine on matching accuracy. This failure to observe an antagonism of the effects of pentobarbital on matching accuracy, at doses of picrotoxin that antagonized the effects of pentobarbital on rate of responding, suggests that the effects of pentobarbital on matching accuracy and rate of responding are mediated by different receptor sites.

Disruption of temporal discrimination by drugs of abuse: I. Unmasking of a color bias.

Pigeons were trained to discriminate the length of a delay period (3s vs. 10s). Under control conditions, pigeons were able to discriminate between the two delay period lengths with a high degree of accuracy (>90%). When delays of 1, 3, 5, 7, 9 and 11s were randomly presented, the percentage of responses appropriate to the 10s delay increased as a function of increasing delay length. Dose-response curves determined for a series of drugs of abuse showed that pentobarbital, diazepam and phencyclidine displayed the greatest efficacy in disrupting the discrimination. The decrease in accuracy was a function of both a decrease in the ability of the pigeon to discriminate the passage of time, and the expression of a drug-induced red color bias. When the stimulus colors were changed, these drugs still decreased accuracy of the discrimination without any evidence of a color bias. Morphine disrupted the discrimination at doses which produced marked response suppression; there was no evidence of a drug-induced color bias. Delta(9)-THC failed to produce any significant effect on the discrimination. d-amphetamine and cocaine initially had no effect; however, upon subsequent determinations and when the stimulus colors were changed during the last part of the experiment, they did disrupt discrimination performance. These results show that drugs of abuse have differential effects on temporal discrimination, with some drugs affecting temporal discrimination at doses that do not suppress responding, some affecting the discrimination at doses that decrease response rates, and others that do not appear to affect temporal discrimination. Only sedative/hypnotic drugs disrupted temporal discrimination in part by producing a red-color bias.

Effects of clozapine, chlorpromazine and haloperidol on schedule-controlled behavior.

The effects of clozapine, chlorpromazine, and haloperidol were determined in mice and pigeons responding under a multiple fixed-ratio 30, fixed-interval 600 sec schedule of food presentation. In both species, low doses were without effect and moderate to high doses of all three antipsychotics decreased responding. In contrast to other behavioral tests used to predict antipsychotic activity, clozapine was equipotent or more potent than chlorpromazine in decreasing responding under the multiple fixed-ratio 30, fixed-interval 600 sec schedule. The order of potency observed in the mouse was: haloperidol greater than chlorpromazine greater than or equal to clozapine. The order of potency in the pigeon was: haloperidol greater than clozapine greater than chlorpromazine. In mice and pigeons, the rate of responding under the fixed-ratio component was decreased at lower than, or the same doses of clozapine as that required to decrease fixed-interval responding. However, in both species, chlorpromazine and haloperidol decreased fixed-interval responding at lower doses or the same dose as that required to decrease fixed-ratio responding.

Chronic administration of S-(-)-pentobarbital in pigeons and rats: tolerance development.

The development of tolerance to pentobarbital and cross-tolerance to other barbiturates has been documented in both laboratory animals and man. This study was undertaken to determine the extent of tolerance development to S-(-)-pentobarbital in rats and pigeons receiving 10 mg/kg/day S-(-)-pentobarbital, PO. In addition, the extent of cross-tolerance was determined to R-(+)-pentobarbital and both isomers of secobarbital. Rats were trained to respond under a variable-interval 60-sec (V160) schedule of food presentation while pigeons were trained to respond under a multiple fixed-ratio 30, fixed-interval 600-sec schedule of food presentation. After responding had stabilized, dose-response curves were determined for R-(+)-pentobarbital, S-(-)-pentobarbital, R-(+)-secobarbital, and S-(-)-secobarbital in both species. Upon the completion of the acute dose-response curves, both rats and pigeons were given 10 mg/kg/day S-(-)-pentobarbital, PO for 30 consecutive days prior to the redetermination of all four dose-response curves. Upon the completion of this second determination of each curve, the daily administration of the S-(-)-pentobarbital was discontinued, and the rats and pigeons remained drug free for 30 days. Following this 30-day drug free period, dose-response curves for the isomers of both pentobarbital and secobarbital were redetermined for a third time.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of control activity levels in the reported strain differences to the behavioral effects of drugs in mice.

The effect of d-amphetamine (3-100 mumoles/kg), scopolamine (0.3-100 mumoles/kg) and morphine (3-1000 mumoles/kg) were studied on the spontaneous motor activity (SMA) of four strains of mice: CF-1, DBA/2, C57BL/6 and CD-1. All three drugs increased the SMA of the CF-1, C57BL/6, and CD-1 strains at low to moderate doses and decreased SMA at higher doses. In the DBA/2 strain, d-amphetamine and scopolamine increased SMA at low doses and decreased SMA at high doses; only decreases in SMA were observed with morphine. When the drug effect was expressed relative to control levels of SMA, large apparent strain differences were shown to exist for all three drugs. In general, these strain differences were shown to exist for all three drugs. However, the majority of these strain differences could be attributed to the large differences which existed in the control level of SMA among the four strains. One important exception to this statement was shown to exist. The DBA strain responded differently (only decreases in SMA were observed) to morphine than did the other three strains. This decrease was not related to the control SMA level and could not be antagonized by naloxone (3 mumoles/kg, IP).

Behavioral effects of the isomers of pentobarbital and secobarbital in mice and rats.

To determine what stereoselective differences there may be in the behavioral effects of the isomers of pentobarbital and secobarbital, the effect of each isomer was determined on the spontaneous motor activity (SMA) and multiple fixed-ratio 30, fixed-interval 600-sec (mult FR30 FI600) responding of mice, and on the variable-interval 60-sec (VI60) responding of rats. The S-(-) isomers of pentobarbital and secobarbital decreased SMA at lower doses than those required for the R-(+) isomers. At moderate to high doses of R-(+)-pentobarbital (30-42.5 mg/kg) and low to moderate doses of S-(-)-secobarbital (5.6-17.5 mg/kg) SMA was increased. An increase in SMA following R-(+)-secobarbital was only observed at 30 mg/kg, and no increases were observed with S-(-)-pentobarbital. No potency differences were observed between the isomers of pentobarbital and secobarbital on the responding of mice under the mult FR30 FI600 schedule over a dose range of 1-30 mg/kg. Increases in FI600 responding were only observed following moderate doses of the S-(-) isomer of pentobarbital (5.6-17.5 mg/kg). In rats responding under the VI60 schedule of food presentation, no qualitative stereoselective differences were observed in the behavioral effects of the isomers of pentobarbital (1-13 mg/kg) and secobarbital (1-13 mg/kg), but small differences in potency were observed. Thus, differences in the effects of the isomers were usually restricted to differences in potency, but in some cases differences in efficacy were observed.

Cumulative dose-response curves in behavioral pharmacology.

Cumulative dose-response curves have been widely used in many areas of pharmacology. To date, the applicability of cumulative dose-response curves has not been assessed in behavioral pharmacology. To determine the feasibility of this procedure, mice were trained to respond under a multiple time-out 5 min, fixed-ratio 30 (mult TO 5, FR 30) schedule of reinforcement. The FR 30 component consisted of 15 presentations of an FR 30 schedule of reinforcement. At the start of each TO 5 component, an intraperitoneal (IP) injection was given, and the effect on the response rate during the following 15 presentations of the FR 30 schedule was assessed. d-Amphetamine (0.3--30 mu moles/kg), pentobarbital (3-300 mu moles/kg), morphine (1-100 mu moles/kg), ketamine (3-300 mu moles/kg), and phencyclidine (1-100 mu moles/kg) all produced dose-related decreases in FR responding. In each case the lowest dose tested was without effect, and the highest dose tested essentially eliminated responding. As a control, the normal 4th dose in the ascending series of each drug was given preceded by 3 saline injections. Whether this dose of each drug was preceded by 3 separate saline injections or by 3 lower ascending doses of the same drug, the observed effect was identical. Five consecutive saline injections during the experimental session were without effect. The application of this procedure should greatly decrease the time required to examine the behavioral effects of a wide range of doses.

Behavioral effects of cocaine and its interaction with d-amphetamine and morphine in rats.

Drugs of abuse are commonly co-abused, and frequently these combinations produce effects which cannot be predicted by studying the effects of the individual drugs. To investigate the behavioral interactions which occur following combinations of cocaine plus amphetamine or cocaine plus morphine, rats were trained to respond under a differential reinforcement of low rates (DRL) schedule (10-14 sec). Cocaine (0.1-10 mg/kg) and d-amphetamine (0.1-3 mg/kg) decreased the percentage of reinforced responses (efficiency) at doses which had no effect on overall rate of responding. Following moderate doses of either drug, the interresponse time (IRT) distribution showed an increase in the percentage of shorter (less than 10 sec) IRT's. Morphine (0.1-10 mg/kg) also decreased efficiency, but the decrease which occurred was only observed at doses which also decreased overall response rates. As might be expected, the IRT distribution for morphine showed a dose-related increase in the percentage of long IRT's (greater than 14 sec). When doses of morphine which had no significant effect when administered alone (1 or 3 mg/kg) were combined with cocaine, the cocaine dose-response curve for efficiency was shifted down and to the left and response rates were increased. Analysis of the IRT distribution showed that the combination of an ineffective dose of cocaine, 1 mg/kg, plus 3 mg/kg morphine produced a shift in the IRT distribution to the left (an increase in the percentage of short IRT's). When cocaine was combined with 0.3 mg/kg d-amphetamine, a dose which had no effect when given alone, no significant interactions were observed on efficiency or overall rate of responding.(ABSTRACT TRUNCATED AT 250 WORDS)

The acute effects of caffeine, cocaine and d-amphetamine on the repeated acquisition responding of pigeons.

The acute effects of caffeine, cocaine and d-amphetamine on the repeated acquisition of a four-response chain were investigated in pigeons. Subjects responded on three response keys under different predetermined sequences. Food was presented upon the completion of the four-response sequence under a fixed-ratio schedule. Incorrect responses resulted in a five-second timeout. No consistent increases in within session percent correct were observed following caffeine or d-amphetamine administration. However, cocaine (1.0 mg/kg) did produce consistent increases in within session percent correct. At higher doses of cocaine, d-amphetamine and caffeine the effects observed were similar in that there was a decrease in response rate and percent correct. The drugs did differ in the dose (potency) which decreased response rate and percent correct. Following all three drugs if percent correct was decreased there was a concurrent decrease in response rate.

Bias of morphine generalization to cyclazocine by drug history.

Pigeons trained to discriminate morphine from saline under a color tracking procedure received cumulative doses of cyclazocine after various regimens of daily morphine or saline administration. Cyclazocine generalization curves were obtained after zero, one, two, or six completely drug-free days. In four or five animals, cyclazocine produced more response generalization to morphine after six drug free days than after no drug free days. In two animals the cyclazocine dose-effect generalization curves were generally shifted to the left with increased time from last drug exposure. Morphine response generalization to cyclazocine was also related to the degree of stimulus control evident in the non-drug (saline) condition during early portions of the subjects' experimental histories. The less stimulus control evident in the non-drug (saline) condition (i.e., the more morphine-appropriate responses made after saline injections and the greater variability of such responding), the more likely it was to obtain morphine-appropriate responding after cyclazocine administration.

Morphine discrimination in the pigeon using a color tracking procedure.

Pigeons were trained to discriminate 5.0 mg/kg morphine from saline. After morphine, subjects tracked the location of red response keys and after saline, the location of green keys. When stimulus generalization to other drugs was investigated dl-methadone produced morphine-like responding and this response generalization was primarily due to the l-isomer. Pretreatment with 1.0 mg/kg naloxone shifted the morphine generalization curve 10-fold to the right but only shifted the rate suppression curve 3-fold to the right. dl-Cyclazocine generated dose-related increases in responding on the red key location and in 3 of 5 birds, responses after 1.0 mg/kg were indistinguishable from those after morphine training doses. Meperidine did not produce responding on the red keys, nor did diazepam, cocaine, d-amphetamine, phencyclidine or pentobarbital. The discriminative stimulus effects of morphine are thus stereo-selective and pharmacologically specific. Generalization of responding to dl-cyclazocine but not to phencyclidine suggests that the morphine-like discriminative dl-cyclazocine cue was not due to interaction at sigma opiate receptors.

Titrating matching-to-sample performance: effects of drugs of abuse and intertrial interval.

Previous reports have shown that increasing the length of the intertrial interval (ITI) in a matching-to-sample schedule of reinforcement results in increased matching accuracy. This has traditionally been interpreted in the context of proactive inhibition, the disruption of memory for a stimulus as a consequence of events that occurred prior to the presentation of the stimulus. In an effort to more fully characterize a titrating matching-to-sample baseline, the effect of ITI ranging from 0-30 s was determined in pigeons trained to respond under the titrating matching-to-sample procedure. In addition, the effect of ITI length on the dose-response curve for pentobarbital, phencyclidine, D-amphetamine, and cocaine were determined. Surprisingly, performance under the titrating matching-to-sample was not altered as a function of ITI length, nor did the effects of the four drugs of abuse change as a function of ITI length. These results suggest that performance under the titrating matching-to-sample is under a different control than matching-to-sample using fixed delays.

The effects of cocaine in combination with other drugs of abuse on schedule-controlled behavior in the pigeon.

The present experiment sought to provide information regarding the consequences of combining cocaine with other drugs of abuse. The effects of cocaine alone and in combination with d-amphetamine, caffeine, morphine or delta-9-tetrahydrocannabinol were determined in five male white Carneaux pigeons responding under a multiple fixed-ratio 30, fixed-interval 600 schedule (mult FR FI). Drug interactions were studied by redetermining the cocaine dose-response curve in the presence of various fixed doses of the other drugs. Under the mult FR FI schedule, when cocaine (1 to 10 mg/kg) was combined with inactive doses of d-amphetamine (0.1, 0.3, 1.0, and 1.8 mg/kg), caffeine (10, 30, and 100 mg/kg), morphine (0.3, and 1.0 mg/kg), and delta-9-tetrahydrocannabinol (0.1 mg/kg), the FR and FI response rate dose-response curves were not shifted relative to the cocaine-alone curves. When cocaine was combined with an active dose of a drug which decreased response rate when given alone (0.3 mg/kg delta-9-tetrahydrocannabinol and 3 mg/kg morphine), the position of the response rate dose-response curves shifted compared to the cocaine-alone curves. The most frequent and consistent outcome of these interactions can be described as less than or approximately equal to an effect-additive interaction. Thus, these data indicate that the potential consequences of coabusing cocaine with the drugs tested in the present experiment can most often be predicted from the effects of each drug when taken alone.

Linopirdine does not improve matching performance in the titrating matching-to-sample paradigm.

Linopirdine (DUP 996), a proposed cognitive enhancing agent, was studied in four squirrel monkeys (Saimiri sciureus) and six White Carneau pigeons responding under a titrating matching-to-sample paradigm (TMTS). Briefly, under this titration schedule, each trial began with the presentation of a sample stimulus on the center key of a three-key pigeon or squirrel monkey chamber. Completion of a fixed-ratio on the center key resulted in the termination of the stimulus presentation and the initiation of a delay period. The length of the delay changed as a function of the subject's performance. During the first five trials of each session, the delay was fixed at 3 s in length. On the sixth and all subsequent trials, the length of the delay increased, did not change, or decreased such that accuracy was maintained at approximately 80%. Following the delay, two of the three response keys were transilluminated with different colored lights. A single response on the key transilluminated with the same stimulus as the sample stimulus resulted in the presentation of food. A response on the key transilluminated with the stimulus that did not match the sample stimulus resulted in a timeout. Linopridine was administered in the pigeon (0.001-5.6 mg/kg) and squirrel monkey (0.01-1.0 mg/kg) 15 min before testing. Matching performance was not affected as measured by changes in mean delay values or percent accuracy even at doses that decreased rate of responding. These results suggest that the enhancement in cognitive function previously reported after administration of linopiridine may be limited to specific situations.