Novel partial 5HT3 agonist pumosetrag reduces acid reflux events in uninvestigated GERD patients after a standard refluxogenic meal: a randomized, double-blind, placebo-controlled pharmacodynamic study.

BACKGROUND: Low basal lower esophageal sphincter (LES) pressure and transient LES relaxations are major causes of gastroesophageal reflux disease (GERD). Pumosetrag, a novel selective partial 5HT3 receptor agonist, showed a promising effect on reducing reflux events in health. We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, lower esophageal sphincter pressure (LESP), and specific symptoms in patients with GERD receiving a refluxogenic meal. METHODS: Patients with GERD, who developed heartburn and/or regurgitation after ingestion of a refluxogenic meal, were randomized to 1 of 3 dose levels of pumosetrag (0.2, 0.5, or 0.8 mg) or placebo. Before and after 7 days of treatment, patients underwent manometry, intraesophageal multichannel, intraluminal impedance and pH after a standard refluxogenic meal. KEY RESULTS: A total of 223 patients with GERD [125 (56%) women, mean (SD) age = 36 (12) years] were enrolled. No overall treatment effects were detected for the total number of reflux episodes (acidic and weakly acidic) (p > 0.5); however, significant treatment effects (p < 0.05) on the number of acid reflux episodes were observed with lower values on pumosetrag 0.2 mg (10.8 ± 1.1), 0.5 mg (9.5 ± 1.1), and 0.8 mg (9.9 ± 1.1) compared with placebo (13.3 ± 1.1). Significant treatment effects (p < 0.05) were also observed for the percentage of time pH was <4, with less time for pumosetrag at 0.5 mg (10%) and 0.8 mg (10%) compared with placebo (16%). CONCLUSIONS & INFERENCES: In GERD, the partial 5HT3 agonist pumosetrag significantly reduced the rate of acid reflux events but did not result in a significant change in LESP or symptomatic improvement over a 1-week treatment period.

Frequency of maternal licking and grooming correlates negatively with vulnerability to cocaine and alcohol use in rats.

Because licking and grooming behavior of dams with pups can influence some behaviors of pups when they are adults, we tested if licking and grooming scores in a maternal separation protocol correlated with cocaine or ethanol self-administration in the pups as adults. The protocol produced litters that were separated from dams for 0 (MS0), 15 (MS15) or 180 (MS180) min, and a nonhandled (NH) group as well. Self-administration of both drugs as shown in earlier studies was lowest in the MS15 group, highest in the NH group and intermediate in the other groups. Licking and grooming scores correlated negatively with drug intake and suggests that maternal care of pups can influence drug use in pups when they are adults.

Maternal separation alters drug intake patterns in adulthood in rats.

Maternal separation/handling (MS/H) is an animal model of early life stress that causes profound neurochemical and behavioral alterations in pups that persist into adulthood. Many recent studies have used the MS/H model to study changes in drug effects in adulthood that are linked to behavioral treatments and stressors in the perinatal period. The drug effects focused on in this review are the reinforcing properties of the abused drugs, cocaine and alcohol. A striking finding is that variations in maternal separation and handling cause changes in ethanol and cocaine self-administration. Further, these changes indicate that various manipulations in the perinatal period can have long lasting effects of interest to biochemical pharmacologists. This article will review recent studies on ethanol and cocaine self-administration using the MS/H model and the neurochemical alterations that may play a role in the effects of MS/H on ethanol and cocaine self-administration. Studying the MS/H model can provide important clues into the vulnerability to drug abuse and perhaps identify a crucial window of opportunity for therapeutic intervention.

Effects of early maternal separation on ethanol intake, GABA receptors and metabolizing enzymes in adult rats.

RATIONALE: Maternal separation (MS) in neonatal rats affects ethanol self-administration (SA) in adulthood; however, the conditions and mechanisms need to be clarified. OBJECTIVES: The goal of this study was to determine the effect of MS on ethanol SA in adulthood in different groups of rats, which control for time of separation, handling, and rearing conditions and, for mechanistic assessment, to examine GABA-A receptors in the central nucleus of the amygdala (CeA) and levels of liver metabolizing enzymes. METHODS: Newborn, male Long-Evans rats were randomly assigned to different groups and treated over postnatal days 2-14. The rats were picked up by their tails and put back down with no separation (MS0), separated from their mother for 15 min/day (MS15), separated from their mother for 180 min/day (MS180), handled once for a bedding change (NH), or were animal facility reared (AFR). In adulthood, these rats were allowed 5-day continuous access to ethanol, and GABA-A receptors and liver enzymes were measured. RESULTS: The MS15 group consumed and preferred significantly less ethanol (about one third) than the MS180 group; however, neither group was different from the MS0 or the AFR group. The NH group consumed and preferred significantly more ethanol than all other groups, at least twice that of the MS180s. GABA-A receptors were increased in the CeA in MS15s, which could help explain the effects. Alcohol dehydrogenase may have been altered in the AFRs. CONCLUSIONS: Various treatments in neonates affect ethanol intake and GABA-A receptors, and possibly ethanol metabolism, in adulthood. These changes were not simply related to time of separation but were also due to the degree of handling.

Naturally occurring differences in maternal care are associated with the expression of oxytocin and vasopressin (V1a) receptors: gender differences.

Variations in maternal care have been associated with long-term changes in neurochemistry and behaviour in adult rats. Rats receiving high levels of licking and grooming as pups are less fearful and more maternal than rats receiving low levels of maternal licking and grooming. Central pathways for oxytocin and vasopressin have been implicated in the neurobiology of anxiety and social behaviours. We assessed whether variations in maternal care were associated with differences in oxytocin receptors (OTR) or vasopressin (V1a) receptors in the brains of adult offspring. In the central nucleus of the amygdala and bed nucleus of the stria terminalis, OTR binding was increased in adult females, but not adult males, that had received high levels of maternal licking and grooming as pups. Conversely, amygdala V1a receptor binding was increased in males, but not females, that had received high levels of maternal licking and grooming. These findings suggest that variations in maternal care may influence the expression of oxytocin and vasopressin receptors in a gender-specific manner.

Use of Spectral Radiance to Estimate In-Season Biomass and Grain Yield in Nitrogen- and Water-Stressed Corn.

Current technologies for measuring plant water status are limited, while recently remote sensing techniques for estimating N status have increased with limited research on the interaction between the two stresses. Because plant water status methods are time-consuming and require numerous observations to characterize a field, managers could benefit from remote sensing techniques to assist in irrigation and N management decisions. A 2-yr experiment was initiated to determine specific wavelengths and/or combinations of wavelengths indicative of water stress and N deficiencies, and to evaluate these wavelengths for estimating in-season biomass and corn (Zea mays L.) grain yield. The experiment was a split-plot design with three replications. The treatment structure had five N rates (0, 45, 90, 134, and 269 kg N ha(-1)) and three water treatments [dryland, 0.5 evapotranspiration (ET), and full ET]. Canopy spectral radiance measurements (350-2500 nm) were taken at various growth stages (V6-V7, V13-V16, and V14-R1). Specific wavelengths for estimating crop biomass, N concentration, grain yield, and chlorophyll meter readings changed with growth stage and sampling date. Changes in total N and biomass in the presence of a water stress were estimated using near-infrared (NIR) reflectance and the water absorption bands. Reflectance in the green and NIR regions were used to estimate total N and biomass without water stress. Reflectance at 510, 705, and 1135 nm were found for estimating chlorophyll meter readings regardless of year or sampling date.

Variations in maternal behaviour are associated with differences in oxytocin receptor levels in the rat.

Female Long-Evans rats exhibit stable individual differences in maternal behaviours such as pup licking/grooming and arched-back nursing posture (LG-ABN). These variations in maternal behaviour are accompanied by differences in lactation-induced increases in oxytocin receptor levels in brain regions known to mediate the expression of maternal care in this species (i.e. the bed nucleus of the stria terminalis, the medial preoptic area and the lateral septum). Oxytocin receptor levels in the central nucleus of the amygdala were significantly higher in high compared to low LG-ABN females regardless of reproductive status. These findings suggest that individual differences in maternal behaviour may be directly related to variations in oxytocin receptor expression.

Maternal care, hippocampal synaptogenesis and cognitive development in rats.

We report that variations in maternal care in the rat promote hippocampal synaptogenesis and spatial learning and memory through systems known to mediate experience-dependent neural development. Thus, the offspring of mothers that show high levels of pup licking and grooming and arched-back nursing showed increased expression of NMDA receptor subunit and brain-derived neurotrophic factor (BDNF) mRNA, increased cholinergic innervation of the hippocampus and enhanced spatial learning and memory. A cross-fostering study provided evidence for a direct relationship between maternal behavior and hippocampal development, although not all neonates were equally sensitive to variations in maternal care.

The role of corticotropin-releasing factor--norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress.

Naturally occurring variations in maternal care in early postnatal life are associated with the development of individual differences in behavioral and hypothalamic-pituitary-adrenal responses to stress in the rat. These effects appear to be mediated by the influence of maternal licking and grooming on the development of central corticotropin-releasing factor (CRF) systems, which regulate the expression of behavioral, endocrine, and autonomic responses to stress through activation of forebrain noradrenergic systems. These findings provide a neurobiologic basis for the observed relationship between early life events and health in adulthood. In more recent studies, we explored the behavioral transmission of individual differences in stress reactivity, and thus, vulnerability to stress-induced illness, across generations.

Maternal care and the development of stress responses.

Studies dating from the 1950s have documented the impact of early life events on the development of behavioral and endocrine responses to stress. Recent findings suggest that these effects are mediated through changes in mother-offspring interactions and have identified central corticotropin-releasing factor systems as a critical target for the effects of variations in maternal care.

Stress-induced disturbances in Morris water-maze performance: interstrain variability.

Marked differences were observed across strains of mice (i.e., DBA/2J, C57BL/6J, BALB/cByJ and CD-1 mice) in acquisition, performance and reversal of a place learning response in a Morris water-maze. While DBA/2J, C57BL/6J and CD-1 mice typically learned the response readily, only 20% of BALB/cByJ mice acquired the response. Commensurate with the effects of hippocampal disturbances, the performance deficits in BALB/cByJ mice were not evident when the position of the platform in the water-maze was cued. Exposure to uncontrollable foot shock did not affect the acquisition or performance of this response in the former three strains, but provoked a modest disruption of reversal performance in DBA/2J mice and markedly impaired reversal performance in BALB/cByJ mice. It seemed, however, that the response strategies adopted in these strains could be distinguished from one another. In the reversal paradigm BALB/cByJ mice initially persisted in returning to the original training quadrant rather than to the new goal quadrant. Following 2 days of training the perseveration was no longer apparent and animals seemed to adopt a random search strategy. In contrast, DBA/2J mice, which exhibited a smaller stress-induced disturbance, did not display a perseverative response style. These data suggest that inescapable shock does not disturb response-outcome associations, but may result from the induction of a perseverative response style. However, it appears that the mechanisms responsible for an interference of performance may not be uniform across strains.(ABSTRACT TRUNCATED AT 250 WORDS)