Resection of focally progressive gastrointestinal stromal tumours resistant to imatinib therapy.

AIMS: To analyse the outcome of patients with gastrointestinal stromal tumour (GIST) who receive imatinib therapy and undergo subsequent resection of focally progressive disease. METHODS: We reviewed the records of all cases of GIST discussed at the West of Scotland Sarcoma regional multi-disciplinary team meeting between January 2002 and December 2009 inclusive. We analysed all patients who had undergone surgery for progressive disease on imatinib therapy. Focally progressive disease was diagnosed on computated tomography (CT) and positron-emission tomography-CT and was defined by a GIST lesion initially responsive to imatinib therapy but then underwent growth with evidence of metabolic activity. All procedures were undertaken in a university teaching hospital by a single surgeon. RESULTS: Nine patients were identified who underwent ten resections of focally progressive GIST. Six had previously undergone resection of their primary tumour while three had presented with un-resectable disease. Nine operations were for resection of a solitary progression while one operation was for three foci of progression. Five patients underwent liver resection which was confined to the segments were there was focal progression of GIST; of these one patient had multiple liver metastases and portal hypertension with a mass at the porta hepatis. The absolute survival for patients after resection was 18.4±13.7 months (mean±standard deviation), with progression free survival of 14.1±13.5 months equating to 56% at 1-year. Four patients had been switched from imatinib to sunitinib, for further multi-focal progression. CONCLUSIONS: Surgical resection of focally progressive GIST may prolong survival and a second or third resection is a feasible option in selected patients.

Provisional Stenting for the Treatment of Bifurcation Lesions: In Vitro Insights.

Provisional stenting is considered the gold standard approach for most bifurcation lesions, but the benefit of routine side branch (SB) strut dilatation has not been fully elucidated. A benchtop model was used to determine the benefits of routine side branch (SB) dilatation techniques on strut apposition, acute thrombogenicity, and flow disruption. Three different provisional bifurcation techniques were compared: no SB dilatation "keep it open" method (KIO), sequential balloon dilatation (SBD), and kissing balloon inflation (KBI). Stents were deployed in a silicon bifurcation model and perfused with blood at a flow rate of 200 ml/min for 60 min. Optical coherence tomography (OCT) pullbacks were obtained before and after flow perfusion to conduct strut analysis and acute thrombus measurement respectively. Computational fluid dynamics (CFD) models were created using OCT pullbacks and simulated based on experimental conditions to analyze flow disruption. The strut analysis showed that KBI had the lowest percentage of floating (10.6 ± 2.3%) (p = 0.0004) and malapposed (41.2 ± 8.5%) struts (p = 0.59), followed by SBD and then KIO. This correlated to KBI having the lowest amount of thrombus formed at the SB, followed by SBD, with KIO being the most thrombogenic (KBI: 0.84 ± 0.22mm2, SBD: 1.17 ± 0.25mm2, KIO: 1.31 ± 0.36mm2, p = 0.18). CFD models also predicted a similar trend, with KBI having the lowest amount of area of high shear rate as well as flow recirculation. Based on this benchtop model, SB intervention strategies demonstrated a reduction in number of struts and resulting thrombogenicity at the bifurcation ostia. Graphical abstract.

An expedited stroke triage pathway: the key to shortening the door-to-needle time in delivery of thrombolysis.

OBJECTIVES: To assess time management of stroke thrombolysis triage and functional outcomes in patients receiving recombinant tissue plasminogen activator for hyperacute stroke, and identify bottlenecks in delivery of the treatment. DESIGN: Prospective study. SETTING: A university teaching hospital in Hong Kong. PATIENTS: Patients with suspected hyperacute stroke referred to the stroke thrombolysis team during October 2008 to September 2009. MAIN OUTCOME MEASURES: Time performance records including door-to-stroke team, door-to-needle, and onset-to-thrombolysis times. Functional outcomes by modified Rankin Scale score at 3 months, and thrombolysis-related complications including haemorrhagic transformations and mortality. RESULTS: During the 12-month period, 95 thrombolysis calls were received; recombinant tissue plasminogen activator was given intravenously to 17 (18%) of the patients and intra-arterially to 11 (12%). The mean (standard deviation) door-to-stroke team and the door-to-needle times for intravenous recombinant tissue plasminogen activator patients were 33 (25) and 80 (25) minutes, respectively; both were about 20 minutes longer than that recommended by the National Institute of Neurological Disorders and Stroke. The mean National Institute of Health Stroke Scale score for patients received intravenous recombinant tissue plasminogen activator was 16 (standard deviation, 7). The mean (standard deviation) onset-to-treatment time was 144 (42) minutes. Nine (53%) patients who received intravenous recombinant tissue plasminogen activator achieved favourable outcomes at 3 months, with a modified Rankin Scale score of 0 to 1. Symptomatic haemorrhage and mortality occurred in one (6%) patient. CONCLUSION: A dedicated stroke triage pathway is essential to ensure efficient and safe delivery of thrombolysis therapy. Improvements in door-to-stroke team time through integration with emergency medicine staff and neuroradiologists may improve thrombolysis eligibility.

Physiological changes in the size of the septal swell body correlate with changes in inferior turbinate size.

OBJECTIVE: The nasal septal swell body is a normal anatomical structure located in the superior nasal septum anterior to the middle turbinate. However, the impact of the septal swell body in nasal breathing during normal function and disease remains unclear. This study aimed to establish that the septal swell body varies in size over time and correlates this with the natural variation of the inferior turbinates. METHOD: Consecutive patients who underwent at least two computed tomography scans were identified. The width and height of the septal swell body and the inferior turbinates was recorded. A correlation between the difference in septal swell body and turbinates between the two scans was performed using a Pearson's coefficient. RESULTS: A total of 34 patients (53 per cent female with a mean age of 58.3 ± 20.2 years) were included. The mean and mean difference in septal swell body width between scans for the same patient was 1.57 ± 1.00 mm. The mean difference in turbinate width between scans was 2.23 ± 2.52 mm. A statistically significant correlation was identified between the difference in septal swell body and total turbinate width (r = 0.35, p = 0.04). CONCLUSION: The septal swell body is a dynamic structure that varies in width over time in close correlation to the inferior turbinates. Further research is required to quantify its relevance as a surgical area of interest.

Insulin mediators from rat skeletal muscle have differential effects on insulin-sensitive pathways of intact adipocytes.

The effects of partially purified insulin-generated mediators from rat skeletal muscle were compared to those of insulin on intact adipocytes. Insulin and insulin mediator stimulated both pyruvate dehydrogenase and glycogen synthase activity of intact adipocytes. In contrast, insulin stimulated glucose oxidation and 3-O-methylglucose transport, whereas insulin-generated mediators had no effect. Insulin-generated mediators cannot account for all the pleiotropic effects of insulin, especially membrane-controlled processes.

Asenapine: a novel psychopharmacologic agent with a unique human receptor signature.

Asenapine is a novel psychopharmacologic agent under development for the treatment of schizophrenia and bipolar disorder. We determined and compared the human receptor binding affinities and functional characteristics of asenapine and several antipsychotic drugs. Compounds were tested under comparable assay conditions using cloned human receptors. In comparison with the antipsychotics, asenapine showed high affinity and a different rank order of binding affinities (pKi) for serotonin receptors (5-HT1A [8.6], 5-HT1B [8.4], 5-HT2A [10.2], 5-HT2B [9.8], 5-HT2C [10.5], 5-HT5 [8.8], 5-HT6 [9.6] and 5-HT7 [9.9]), adrenoceptors (alpha1 [8.9], alpha2A [8.9], alpha2B [9.5] and alpha2C [8.9]), dopamine receptors (D1 [8.9], D2 [8.9], D3 [9.4] and D4 [9.0]) and histamine receptors (H1 [9.0] and H2 [8.2]). It had much lower affinity (pKi

Antifungal susceptibilities, biofilms, phospholipase and proteinase activities in the Candida rugosa complex and Candida pararugosa isolated from tertiary teaching hospitals.

PURPOSE: Non-albicansCandida species have emerged as fungal pathogens that cause invasive infections, with many of these species displaying resistance to commonly used antifungal agents. This study was confined to studying the characteristics of clinical isolates of the C. rugosa complex and C. pararugosa species. METHODOLOGY: Seven isolates of the C. rugosa complex and one isolate of C. pararugosa were obtained from two tertiary referral hospitals in Malaysia. Their antifungal susceptibilities, biofilm, proteinase, phospholipase, esterase and haemolysin activities were characterized. Biofilms were quantified using crystal violet (CV) and tetrazolium (XTT) reduction assays at 1.5, 6, 18, 24, 48 and 72 h.Results/Key findings. The E-test antifungal tests showed that both species have elevated MICs compared to C. albicans and C. tropicalis. The highest biomass was observed in one of the C. rugosa isolates (0.237), followed by C. pararugosa (0.206) at 18 h of incubation. However, the highest bioactivity was observed in the C. rugosa ATCC 10571 strain at 24 h (0.075), followed by C. pararugosa at 48 h (0.048) and the same C. rugosa strain at 24 h (0.046), with P<0.05. All isolates exhibited high proteinase activity (+++) whereas six isolates showed very strong esterase activity (++++). All the isolates were alpha haemolytic producers. None of the isolates exhibited phospholipase activity. CONCLUSION: Elevated MICs were shown for the C. rugosa complex and C. pararugosa for commonly used antifungal drugs. Further studies to identify virulence genes involved in the pathogenesis and genes that confer reduced drug susceptibility in these species are proposed.

Predictors of serious bacterial infection in children aged 3 to 36 months with fever without source.

INTRODUCTION: Children commonly present with fever without source yet there is no reliable and consistent method of identifying those at risk of serious bacterial infection. In this study, we sought to identify predictors of serious bacterial infection in children aged between three to 36 months with fever without source. METHODS: Inpatient records of all children aged three to 36 months admitted from the Emergency Department of Singapore's main paediatric hospital between October 2001 to February 2002 with International Classification of Diseases (ninth revision) diagnosis codes 038 (septicaemia), 079 (viral fever), or 780 (pyrexia of unknown origin), were retrieved and reviewed. Patients identified as having fever without source were enrolled. RESULTS: Of 86 enrolled children, 17 (19.8 percent) had serious bacterial infection. Duration of fever and white blood cell count were found to be significant predictors. Children with white blood cell count equal to or greater than 16,000/cubic mm had 6.9 times (95 percent confidence interval [CI] is 1.7 to 28.4) increased risk of serious bacterial infection, while children with fever of duration exceeding three days before presentation had 3.8 times (95 percent CI is 1.1 to 13.1) increased risk of serious bacterial infection. A combination of white blood cell count less than 16,000/cubic mm and duration of fever three days or less had a negative predictive value of 1.0 (95 percent CI is 0.88 to 1.0) and a sensitivity of 1.0 (95 percent CI is 0.82 to 1.0). CONCLUSION: The two identified predictors offer an estimate of the risk of serious bacterial infection in children aged three to 36 months with fever without source.

Central 5-HT4 receptors.

Activation of the 5-HT4 receptor mediates widespread effects in central and peripheral nervous systems. Recent developments, such as the identification of novel, selective agonists and antagonists, as well the cloning of the receptor, have provided insights into the physiological role of the receptor. In this article, Richard Eglen and colleagues assess the emerging evidence relating to the function of the 5-HT4 receptor in the brain. The cerebral distribution of the receptor, along with neurochemical and electrophysiological data, suggests a role in cognition. The role of the receptor in modulation of dopamine transmission and anxiolysis is also addressed.

Faecal prevalence of extended-spectrum Beta-lactamase (ESBL)-producing coliforms in a geriatric population and among haematology patients.

Antimicrobial resistance to the extended-spectrum cephalosporins is increasingly reported worldwide. In the local setting, nosocomial infections with multi-resistant Gram-negative bacilli are not uncommon and are a growing concern. However, there is limited data on the carriage rates of such organisms in the local setting. In May 2001, a prospective study was carried out to determine the enteric carriage rates of ceftazidime-resistant Gram negative bacilli (CAZ-R GNB) among residents of nursing homes and from in-patients of the geriatric and adult haematology wards of University Malaya Medical Centre. Ceftazidime-resistant Gram-negative bacilli (CAZ-R GNB) were detected in 25 samples (30%), out of which 6 were from nursing home residents, 5 from geriatric in-patients and 14 from the haematology unit. A total of 28 CAZ-R GNB were isolated and Escherichia coli (10) and Klebsiella pneumoniae (7) were the predominant organisms. Resistance to ceftazidime in E. coli and Klebsiella was mediated by extended-spectrum beta-lactamases (ESBLs). Although the majority of the CAZ-R GNB were from patients in the haematology ward, the six nursing home residents with CAZ-R GNB were enteric carriers of ESBL-producing coliforms. Prior exposure to antibiotics was associated with carriage of ESBL organisms and to a lesser extent, the presence of urinary catheters.

Hormonal regulation of phospholipid methyltransferase by 3',5'-cyclic adenosine monophosphate-dependent and independent mechanisms.

Treatment of isolated rat adipocytes with epinephrine or isoproterenol caused a time- and concentration-dependent increase in phospholipid methyltransferase (PLMT) activity that was blocked by propranolol and unaffected by phentolamine. Forskolin mimicked the stimulatory effect on PLMT, and insulin inhibited this effect. In both the absence and presence of insulin, there was a linear relationship between PLMT activity and lipolysis. PLMT activity was also increased in response to oxytocin, which does not activate adenylate cyclase in adipocytes and does not stimulate lipolysis. The effects of oxytocin were inhibited by insulin and were additive with those of isoproterenol on PLMT. These data support the hypothesis that in adipocytes, PLMT is activated by a cAMP-dependent protein kinase and a cAMP-independent mechanism, both of which can be regulated independently, and both of which are sensitive to inhibition by insulin.

Stimulation of pyruvate dehydrogenase activity in intact rat adipocytes by insulin mediator from rat skeletal muscle.

This study compared the effects of insulin and insulin mediator from skeletal muscle of control and insulin-treated rats on intact adipocyte pyruvate dehydrogenase. Increasing insulin concentrations stimulated pyruvate dehydrogenase activity in a biphasic manner with a maximal stimulation at 100 microU/ml which was 2-fold and sustained for up to 1 h. The mediators from control or insulin-treated rats also stimulated pyruvate dehydrogenase of intact adipocytes with the effect increasing in a linear manner up to a 1:10 final dilution. The latter mediator had twice the stimulatory activity as the former. Peak stimulation of pyruvate dehydrogenase by the mediators was attained within 10 min of incubation. The enzyme activity rapidly declined thereafter, with the stimulation by mediator from control rats decreasing at a faster rate than that due to mediator from insulin-treated rats. The stimulatory effect of the mediators on adipocyte pyruvate dehydrogenase was found to be additive to that of insulin. This study demonstrates: 1) that insulin mediator can act on mitochondrial pyruvate dehydrogenase of intact, functional adipocytes as it does on isolated intact or broken mitochondria; 2) that the mediator is degraded by the adipocyte; and 3) that the amount of mediator generated by insulin probably limits the stimulation of pyruvate dehydrogenase by insulin. These findings further substantiate the physiological relevance of this putative insulin second messenger.

Rat fibroblast cells overexpressing kinase-inactive human insulin receptors are insulin responsive: influence of growth conditions.

The effects of insulin to stimulate metabolic and mitogenic responses were examined in Rat 1 fibroblast cells that overexpressed either normal (HIRc) or kinase-deficient human insulin receptors. When studied at the optimal growth stage for each cell line, insulin-stimulated responses measured in cells containing kinase-defective receptors with a Lys1018-Ala1018 substitution in the ATP-binding site of the kinase domain (A/K1018). Maximal insulin responsiveness for all these effects, measured as fold-increase over basal, was comparable in parental and HIRc cells (1.8- to 2.4-fold increases). Relative insulin responsiveness for all effects was greatest in A/K 1018 cells. One clone (AK-I) expressing a similar number of kinase-inactive receptors as in the HIRc cells displayed maximal responsiveness of 3.6- to 5.5-fold increases. A second A/K cell line containing 1/10 the number of kinase-inactive receptors displayed responsiveness intermediate between AK-I and parental or HIRc cells (1.5- to 4.8-fold increases). Both clones of kinase-deficient A/K1018 cells displayed impaired insulin sensitivity compared with HIRc cells. These findings suggest that expression of insulin receptor kinase activity is a determinant of insulin sensitivity but not necessarily of the final biological responsiveness of cells to insulin.

Deep cerebral infarcts extending to the subinsular region.

BACKGROUND AND PURPOSE: We sought to determine the clinical and radiological features and pathogenesis of deep cerebral infarcts extending to the subinsular region (DCIs). METHODS: - We defined DCIs as subcortical infarcts extending between the lateral ventricle and the subinsular region with a paraventricular extent >1.5 cm and a subinsular extent of at least one third of the anteroposterior extent of the insula. We identified patients by review of imaging records and noted the clinical information, risk factors, and investigations. We compared risk factors and clinical features between DCIs and "internal border zone" infarcts restricted to the paraventricular region. RESULTS: - Eight patients were studied. The typical clinical features of DCIs were hemiparesis, aphasia, dysarthria, and dysphagia. Aphasia was seen in 3 of 5 patients with left-sided infarcts. Six of 8 patients (75%) had hypoperfusion as a possible pathogenetic factor (carotid occlusion in 4, surgical clipping of MCA in 1, low ejection fraction in 1), and 3 patients (38%) had cardioembolism as a possible pathogenetic factor (atrial fibrillation in 2, low ejection fraction in 1). One patient (12%) had no cause for stroke. Clinical features were similar to those for paraventricular infarcts. Carotid occlusion was more frequent (P=0.04), and there was a trend toward a higher frequency of hypertension (P<0.1) and smoking with DCIs than with paraventricular infarcts. DCIs were located in a deep vascular border zone. CONCLUSIONS: - The clinical features and pathogenesis of DCIs overlap with those of internal border zone paraventricular infarcts. Hypoperfusion may give rise to DCIs since large-artery occlusion is their main risk factor. The larger size of DCIs compared with paraventricular infarcts may relate to a poorer collateral blood supply.

Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor.

BACKGROUND: Reboxetine is a potent antidepressant, with efficacy comparable to that of imipramine, desipramine, and fluoxetine, and has improved side-effect profile. The basis of its efficacy and improved tolerability is sought through studies of reboxetine in a number of pharmacological models of depression. METHODS: Pharmacological selectivity for uptake systems was defined by uptake and binding assays for the three monoamine uptake sites. Specificity was determined in 39 different receptor and 6 enzyme assays. In vivo selectivity was defined by measurement of neuronal firing rates in the locus coeruleus, dorsal raphe, and substantia nigra. Reserpine-induced blepharospasm and hypothermia, clonidine-induced hypothermia, defined reboxetine's in vivo pharmacology. Reboxetine's antidepressant potential was evaluated behaviorally by the tail-suspension test, forced swimming, and the DRL72 operant responding test. RESULTS: Reboxetine is a potent, selective, and specific norepinephrine reuptake inhibitor (selective NRI) as determined by both in vitro and in vivo measurements. Unlike desipramine or imipramine, reboxetine has weak affinity (Ki > 1,000 nmol/L)for muscarinic, histaminergic H1, adrenergic alpha1, and dopaminergic D2 receptors. In vivo action of reboxetine is entirely consistent with the pharmacological action of an antidepressant with preferential action at the norepinephrine reuptake site. Reboxetine showed an antidepressant profile in all tests of antidepressant activity used. Significant decreases in immobility were observed in the tail suspension test and behavioral despair test. Increased efficiency in responding was observed in the DRL72 test. CONCLUSIONS: Reboxetine is a potent, selective, and specific noradrenergic reuptake inhibitor. It has a superior pharmacological selectivity to existing tricyclic antidepressants and selective serotonin reuptake inhibitors when tested in a large number of in vitro and in vivo systems. Given the pharmacological profile, reboxetine is expected to be a selective and potent tool for psychopharmacological research. The use of reboxetine in the clinic will also help clarify the role norepinephrine plays in depression.

Effect of adenosine on insulin activation of rat adipocyte pyruvate dehydrogenase.

Adenosine and its analogue N6-phenylisopropyladenosine stimulated pyruvate dehydrogenase activity of isolated rat adipocytes. Maximal stimulation was obtained with concentrations between 50 and 100 mu M, with the effect decreasing at higher concentrations. The effects of insulin on this enzyme was modified by adenosine. The concentration of insulin (10 mu units/ml) that produced almost half-maximal stimulation, had little or no effect, when adenosine deaminase was present. Adenosine also enhanced the effect of suboptimal but not optimal concentrations of insulin. Thus, the mechanism of adenosine action on adipocyte pyruvate dehydrogenase could in some way be similar or related to that of insulin.

Adenosine and oxytocin reverse antagonism of cyclic AMP elevating agents to insulin activation of adipocyte pyruvate dehydrogenase.

ACTH, isoprenaline, forskolin, and dibutyryl cyclic AMP prevented insulin from stimulating adipocyte pyruvate dehydrogenase in the presence of adenosine deaminase. Antagonism was reversed by N6-phenylisopropyladenosine as well as oxytocin. The stimulatory effects of insulin, adenosine and oxytocin on adipocyte pyruvate dehydrogenase appear to be through (a) mechanism(s) which is (are) similar or related.

The effects of novel, selective 5-hydroxytryptamine (5-HT)4 receptor ligands in rat spatial navigation.

Activation of central 5-hydroxytryptamine (5-HT4) receptors may enhance cognitive performance. In the present study, the effects of two novel, potent and selective 5-HT4 receptor agonists, RS 67333 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-burtl-4-piperidinyl)- 1-propanone) and RS 67506 (1-(4-amino- 5-chloro-2-methoxyphenyl)-3-[1-[2-[(methylsulfonyl)amino]ethyl]-4- piperidinyl]-1-propanone), were studied in a rat model of spatial learning and memory; the Morris water maze. RS 67333 (0.1, 10 and 1000 micrograms/kg, intraperitoneally (i.p.)), a highly potent, selective and hydrophobic 5-HT4 receptor agonist, reversed the decrements in cognitive performance induced by atropine (30 mg/kg, i.p.). By contrast, no effect was seen to RS 67506 (0.1, 10 and 1000 micrograms/kg, i.p.), a hydrophilic 5-HT4 receptor agonist, of equivalent potency and selectivity to RS 67333. This differential effect may reflect the enhanced ability of RS 67333 to enter the CNS, with respect to RS 67506. The ameliorative actions of RS 67333 on cognitive dysfunction were abolished by prior treatment with a selective 5-HT4 receptor antagonist, RS 67532 [1-(4-amino-5-chloro-2-(3, 5-dimethoxy benzyloxyphenyl)-5-(1-piperidinyl)-1-pentanone; 1 mg/kg, i.p.]. When given alone, or in naive rats, RS 67532 (0.1, 10 and 1000 micrograms/kg, i.p.), was without effect. None of the compounds tested affected the swim speed at any of the doses used. In separate locomotor studies, RS 67532 reduced activity at 1 and 10 mg/kg, i.p., although no effect was seen with RS 67333 or RS 67506 (0.01-10 mg/kg, i.p.). These data suggest that RS 67333 reversed the cognitive deficit induced by atropine and support a role of 5-HT4 receptors in rat spatial learning and memory.

Quantitative autoradiography of 5-HT4 receptors in brains of three species using two structurally distinct radioligands, [3H]GR113808 and [3H]BIMU-1.

Recent radioligand binding studies have demonstrated the presence of 5-HT4 receptors throughout the nigrostriatal and mesolimbic systems of mammalian brain. In many regions, the binding has not yet been correlated with functional responses. The present study was carried out to fully characterize the regional distribution of 5-HT4 receptors in brain sections from three species using two structurally distinct radioligands, [3H]GR113808, and [3H]BIMU-1. The highest density of 5-HT4 receptors labeled with [3H]GR113808 was found in the olfactory tubercle, substantia nigra, ventral pallium and striatum of rat and guinea pig, and similar regions of pig-tail macaque monkey. A similar distribution of 5-HT4 receptors was observed in guinea pig brain using [3H]BIMU-1. With either ligand, the binding was saturable and of high affinity (Kd = 0.08-0.53 nM for [3H]GR113808; 1.4-3.0 nM for [3H]BIMU-1). These results extend previous distribution studies, confirm the heterogenous distribution of 5-HT4 receptors throughout the nigrostriatal and mesolimbic systems of three species, and demonstrate a similar distribution using two structurally distinct 5-HT4 radioligands.

Stereoselective effects of (R)- and (S)-zacopride on cognitive performance in a spatial navigation task in rats.

In the present studies we investigated the actions of (R)- and (S)-zacopride, potent 5-HT3 receptor antagonists with 5-HT4 receptor agonists properties, on performance in a spatial learning and memory task in rats, the Morris water maze. A significant cognitive/performance deficit, as indicated by the increased escape latency across several trials, was produced by systemic administration of the muscarinic receptor antagonist atropine (30 mg/kg, IP). (R)-zacopride (0.001-1 microgram/kg, but not 10 or 100 micrograms/kg) significantly reduced escape latency in atropine-treated animals. (S)-Zacopride was inactive over the entire dose range examined (0.001-100 micrograms/kg, i.p.). Moreover, pretreatment with (S)-zacopride (1 or 100 micrograms/kg) did not alter the procognitive effects of (R)-zacopride (1 microgram/kg). These data demonstrate that the cognition enhancing properties of zacopride in this model of cholinergic hypofunction are exclusive to its (R)-enantiomer and imply that this action is unrelated to 5-HT, receptor antagonism or 5-HT4 receptor agonism. The possibility that the procognitive effects of (R)-zacopride may be related to actions at the novel "(R)-zacopride site" is discussed.