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Biomedical subjects

Terry E Robinson

Publications and source records attributed to Terry E Robinson.

At least 37 records · Page 2Linked to original sources
PubMed2005

Dornase alfa reduces air trapping in children with mild cystic fibrosis lung disease: a quantitative analysis.

PURPOSES: To evaluate quantitative air trapping measurements in children with mild cystic fibrosis (CF) lung disease during a 1-year, double-blind, placebo-controlled, recombinant human deoxyribonuclease (rhDNase) [dornase alfa] intervention trial and compare results from quantitative air trapping with those from spirometry or visually scored high-resolution CT (HRCT) scans of the chest. MATERIALS AND METHODS: Twenty-five children with CF randomized to either daily rhDNase or placebo aerosol were evaluated at baseline, and at 3 months and 12 months by spirometer-triggered HRCT and spirometry. Outcome variables were percentage of predicted FVC, FEV1, and forced expiratory flow, midexpiratory phase (FEF(25-75%)); total and subcomponent visual HRCT scores; and quantitative air trapping measurements derived from chest HRCT images. RESULTS: At baseline, there were no statistical differences between groups in any of the variables used as an outcome. After 3 months of treatment, both groups had improvements in percentage of predicted FEV1 and FEF(25-75%), and total HRCT visual scores. In contrast, the rhDNase group had a 13% decrease in quantitative air trapping from baseline (severe air trapping [A3]), compared to an increase of 48% in the placebo group (p = 0.023). After 12 months, both groups had declines in percentage of predicted FVC and FEV1, but the rhDNase group retained improvements in percentage of predicted FEF(25-75%) and quantitative air trapping. The mucus plugging and total HRCT visual scores were also improved in the rhDNase group after 12 months of treatment, with and without significant differences between groups (p = 0.026 and p = 0.676). Quantitative air trapping (A3) remained improved in the rhDNase group (- 15.4%) and worsened in the placebo group (+61.3%) with nearly significant differences noted between groups (p = 0.053) after 12 months of treatment. CONCLUSIONS: Quantitative air trapping is a more consistent sensitive outcome measure than either spirometry or total HRCT scores, and can discriminate differences in treatment effects in children with minimal CF lung disease.

Air↗
PubMed2004

Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional lability.

The molecular mechanisms that control the range and stability of emotions are unknown, yet this knowledge is critical for understanding mood disorders, especially bipolar illness. Here, we show that the glucocorticoid receptor (GR) modulates these features of emotional responsiveness. We generated transgenic mice overexpressing GR specifically in forebrain. These mice display a significant increase in anxiety-like and depressant-like behaviors relative to wild type. Yet, they are also supersensitive to antidepressants and show enhanced sensitization to cocaine. Thus, mice overexpressing GR in forebrain have a consistently wider than normal range of reactivity in both positive and negative emotionality tests. This phenotype is associated, in specific brain regions, with increased expression of genes relevant to emotionality: corticotropin-releasing hormone, serotonin, norepinephrine and dopamine transporters, and 5-hydroxytryptamine(1A) receptor. Thus, GR overexpression in forebrain causes higher "emotional lability" secondary to a unique pattern of molecular regulation. This finding suggests that natural variations in GR gene expression can contribute to the fine-tuning of emotional stability or lability and may play a role in bipolar disorder.

Affective Symptoms↗
PubMed2004

Opposite effects of amphetamine self-administration experience on dendritic spines in the medial and orbital prefrontal cortex.

We studied the long-term effects of amphetamine self-administration experience (or sucrose reward training) on dendritic morphology (spine density) in nucleus accumbens (Nacc), medial (MPC) and orbital prefrontal cortex (OFC), and hippocampus (CA1 and dentate). Independent groups of rats were trained under a continuous schedule of reinforcement to nose-poke for infusions of amphetamine (0.125 mg/kg/inf) or to receive sucrose pellets during 2 h daily test sessions for 14-20 days. One month after the last training session, the brains were collected and processed for Golgi-Cox staining. We found that: (i) amphetamine self-administration experience selectively increased spine density on medium spiny neurons in the Nacc and on pyramidal neurons in the MPC; (ii) in contrast, amphetamine self-administration decreased spine density in the OFC, whereas sucrose-reward training increased spine density; and (iii) both amphetamine self-administration and sucrose-reward experience increased spines in the CA1, but had no effect in the dentate gyrus. Thus, amphetamine self-administration experience produces long-lasting and regionally-selective morphological alterations in rat forebrain--alterations that may underlie some of the persistent psychomotor, cognitive and motivational consequences of chronic drug exposure.

Adaptation, Physiological↗
PubMed2004

The rate of cocaine administration alters gene regulation and behavioral plasticity: implications for addiction.

The rapid delivery of drugs of abuse to the brain is thought to promote addiction, but why this occurs is unknown. In the present study, we characterized the influence of rate of intravenous cocaine infusion (5-100 sec) on three effects thought to contribute to its addiction liability: its ability to block dopamine (DA) uptake, to activate immediate early gene expression, and to produce psychomotor sensitization. Rapid infusions potentiated the ability of cocaine to block DA reuptake, to induce c-fos and arc mRNA expression, especially in mesocorticolimbic regions, and to produce psychomotor sensitization. Thus, the rate at which cocaine is delivered influences both its neurobiological impact and its ability to induce a form of drug experience-dependent plasticity implicated in addiction. We propose that rapidly delivered cocaine may be more addictive, in part, because this more readily induces forms of neurobehavioral plasticity that lead to the compulsive pursuit of drugs.

Animals↗
PubMed2004

Quantitative air-trapping analysis in children with mild cystic fibrosis lung disease.

The purpose of this study was to compare quantitative computed tomography air trapping (AT) and pulmonary function measurements between subjects with mild cystic fibrosis lung disease (MCF; forced expiratory volume in 1 sec (FEV1) > 70% predicted) and normal age-matched controls. Quantitative AT measurements at different levels of expiration were evaluated. Ten subjects from the MCF group and 10 normal subjects underwent inspiratory and expiratory spirometer-triggered chest high-resolution computed tomography (HRCT) and pulmonary function tests. Six matched CT images were obtained at full inflation and at a lung volume near residual volume (nRV). Quantitative measurements of AT were determined by evaluating expiratory CT lung density and by the percent of segmented lung which demonstrated AT on expiratory scans. Percent AT was evaluated for all lung slices combined (global AT), and also by regional assessment. Additional comparisons of lung density and percent air trapping were made in 10 CF subjects with three matched axial HRCT images at lung volumes corresponding to full inflation, near functional residual capacity (nFRC), and nRV. All measurements of expiratory lung density in CF subjects were significantly lower and % AT significantly higher than normal controls. Significant correlations for all subjects were observed between % global AT and RV/TLC as well as forced expiratory flow between 25-75% of forced vital capacity (FEF(25-75)) % predicted. Pulmonary density measurements and % AT better discriminated differences between groups than PFTs. Measurements made on expiratory scans near FRC showed significantly higher values for AT than those made near RV.

Adolescent↗
PubMed2004

Structural plasticity associated with exposure to drugs of abuse.

Persistent changes in behavior and psychological function that occur as a function of experience, such those associated with learning and memory, are thought to be due to the reorganization of synaptic connections (structural plasticity) in relevant brain circuits. Some of the most compelling examples of experience-dependent changes in behavior and psychological function, changes that can last a lifetime, are those that accrue with the development of addictions. However, until recently, there has been almost no research on whether potentially addictive drugs produce forms of structural plasticity similar to those associated with other forms of experience-dependent plasticity. In this paper we summarize evidence that, indeed, exposure to amphetamine, cocaine, nicotine or morphine produces persistent changes in the structure of dendrites and dendritic spines on cells in brain regions involved in incentive motivation and reward (such as the nucleus accumbens), and judgment and the inhibitory control of behavior (such as the prefrontal cortex). It is suggested that structural plasticity associated with exposure to drugs of abuse reflects a reorganization of patterns of synaptic connectivity in these neural systems, a reorganization that alters their operation, thus contributing to some of the persistent sequela associated with drug use--including addiction.

Animals↗
PubMed2004

Plasticity and functions of the orbital frontal cortex.

We compare the effects of psychoactive drugs such as morphine and amphetamine on the synaptic organization of neurons in the orbital frontal (OFC) and medial frontal (mPFC) regions in the rat. Both regions are altered chronically by exposure to intermittent doses of either drug but the effects are area-dependent. For example, whereas morphine produces increased spine density in OFC but decreased spine density in mPFC. The differential response of the OFC and mPFC to drugs is paralleled by an areal-dependent effect of gonadal hormones on these regions as well: males have greater dendritic arborization in the mPFC whereas females have a greater arborization in the OFC. We also compared the effects of neonatal injury to the OFC and mPFC on cognitive, motor, and social behaviors as well as on the anatomical organization of the remaining brain. Again, there were differential effects of the treatments to the OFC and mPFC. Neonatal OFC lesions allowed virtually complete functional recovery of cognitive and motor behaviors, which was correlated with mild abnormalities in cerebral development compared to the more severe deficits and morphological sequelae following mPFC lesions at the same ages. One exception was the effect of OFC on social behavior, which was severe regardless of whether the injury was in infancy or adulthood. It is proposed that both drug-induced and developmental abnormalities in the integrity of OFC neurons may lead to deficits in social behavior or other behavioral pathologies, possibly including depression.

Animals↗
PubMed2004

Biological basis of sex differences in the propensity to self-administer cocaine.

Women are at greater risk for cocaine addiction than are men, and female rats similarly show a greater propensity to self-administer cocaine than do male rats. This could be due to the intrinsic sex differences in brain organization, to the activational effects of circulating gonadal hormones, or both. For example, estradiol enhances dopamine release in the striatum and nucleus accumbens, and facilitates the behavioral sensitization induced by repeated cocaine exposure. We report here that independent of circulating gonadal hormones, female rats acquire cocaine self-administration behavior more rapidly, and they self-administer more cocaine at a faster rate than do male rats. This indicates that there is an intrinsic difference between male and female subjects in the neural systems mediating drug-seeking behavior due to sexual differentiation of the brain. Furthermore, we find that the administration of estradiol to gonadectomized female subjects greatly facilitates the acquisition of cocaine self-administration. These data demonstrate that both intrinsic sex differences in brain organization and the actions of circulating estradiol contribute to increased vulnerability for cocaine use in female subjects.

Analysis of Variance↗
PubMed2004

Morphine-induced c-fos mRNA expression in striatofugal circuits: modulation by dose, environmental context, and drug history.

Opiates and psychostimulants produce many shared behavioral and neurobiological adaptations, such as behavioral sensitization and the induction of immediate early genes in the caudate-putamen (CPu). Previous studies indicate that factors such as dose, the environmental context surrounding drug administration and drug history can influence both morphine- and psychostimulant-induced behavioral sensitization. In addition, these factors can modulate the ability of psychostimulants to engage striatofugal circuits in the CPu. The present study, therefore, sought to examine whether these factors have similar influences over the ability of morphine to engage cortico-striatofugal circuits. We report that, when given in the home cage, morphine produced a small, but significant increase in the number of c-fos+ striatonigral cells and c-fos+ cells in cingulate cortex, but had no effect on the number of c-fos+ striatopallidal cells. When given in a novel test environment, however, morphine dramatically increased the number of c-fos+ striatonigral cells in a dose-dependent fashion, and this effect was maintained following repeated treatment. Unexpectedly, morphine treatment in a novel environment produced a dose-dependent reduction in the number of c-fos+ striatopallidal cells and c-fos+ cells in cingulate cortex, relative to exposure to novelty alone-effects that were reversed by repeated morphine treatment. We suggest that alterations in c-fos expression patterns in striatofugal circuits following morphine administration may be involved in drug-experience-dependent plasticity.

Analgesics, Opioid↗
PubMed2004

High-resolution CT scanning: potential outcome measure.

PURPOSE OF REVIEW: High-resolution CT (HRCT) imaging of the chest can provide both structural and functional lung analysis useful to evaluate initial and progressive cystic fibrosis (CF) lung disease. Chest HRCT scoring systems have been used to evaluate the extent and severity of CF specific airway and lung parenchymal disease. The purpose of this review is to summarize recent developments in HRCT and volumetric chest CT imaging, CF chest CT scoring systems, and review how HRCT/volumetric CT can provide useful outcome measures for future CF clinical research. RECENT FINDINGS: Early manifestation of CF lung disease determined by chest CT/HRCT imaging in CF infants and children with mild disease include regional air trapping and bronchial wall thickness. The distribution of findings in more progressed CF lung disease are heterogeneous, and there appears to be a large amount of nonhomogeneity of progressive lung pathology. Recent CF studies have used new clinical CT parameters such as quantitative air trapping, quantitative airway measurements, and a composite CT/pulmonary function test (PFT) score, which appear to be promising new outcome measures that are more sensitive than global pulmonary function measurements or total chest CT scores in discriminating early or mild CF lung disease and treatment effects during clinical interventions. SUMMARY: Chest HRCT and volumetric CT imaging can detect regional CF lung changes before changes in global pulmonary function measurements. Chest HRCT scoring has been used in descriptive studies defining CF lung disease severity, in longitudinal studies to define progression of disease, and in clinical intervention studies to evaluate treatment effects. In the last 2 years, CF CT research has evolved from solely using chest HRCT scoring systems to utilization of composite CT/PFT scores, quantitative airway and air trapping measurements, and the utilization of volumetric CT imaging to evaluate three-dimensional data sets in patients with CF lung disease.

Cystic Fibrosis↗
PubMed2004

The induction of behavioural sensitization is associated with cocaine-induced structural plasticity in the core (but not shell) of the nucleus accumbens.

Repeated exposure to cocaine increases the density of dendritic spines on medium spiny neurons in the nucleus accumbens (Acb) and pyramidal cells in the medial prefrontal cortex (mPFC). To determine if this is associated with the development of psychomotor sensitization, rats were given daily i.p. injections of 15 mg/kg of cocaine (or saline) for 8 days, either in their home cage (which failed to induce significant psychomotor sensitization) or in a distinct and relatively novel test cage (which induced robust psychomotor sensitization). Their brains were obtained 2 weeks after the last injection and processed for Golgi-Cox staining. In the Acb core (AcbC) cocaine treatment increased spine density only in the group that developed psychomotor sensitization (i.e. in the Novel but not Home group), and there was a significant positive correlation between the degree of psychomotor sensitization and spine density. In the Acb shell (AcbS) cocaine increased spine density to the same extent in both groups; i.e. independent of psychomotor sensitization. In the mPFC cocaine increased spine density in both groups, but to a significantly greater extent in the Novel group. Furthermore, when rats were treated at Home with a higher dose of cocaine (30 mg/kg), cocaine now induced psychomotor sensitization in this context, and also increased spine density in the AcbC. Thus, the context in which cocaine is experienced influences its ability to reorganize patterns of synaptic connectivity in the Acb and mPFC, and the induction of psychomotor sensitization is associated with structural plasticity in the AcbC and mPFC, but not the AcbS.

Animals↗
PubMed2004

Amphetamine-evoked gene expression in striatopallidal neurons: regulation by corticostriatal afferents and the ERK/MAPK signaling cascade.

The environmental context in which psychostimulant drugs are experienced influences their ability to induce immediate early genes (IEGs) in the striatum. When given in the home cage amphetamine induces IEGs predominately in striatonigral neurons, but when given in a novel test environment amphetamine also induces IEGs in striatopallidal neurons. The source of the striatopetal projections that regulate the ability of amphetamine to differentially engage these two striatofugal circuits has never been described. We report that transection of corticostriatal afferents selectively blocks, whereas enhancement of cortical activity with an ampakine selectively augments, the number of amphetamine-evoked c-fos-positive striatopallidal (but not striatonigral) neurons. In addition, blockade of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling cascade preferentially inhibits the number of amphetamine-evoked c-fos-positive striatopallidal neurons. These results suggest that glutamate released from corticostriatal afferents modulates the ability of amphetamine to engage striatopallidal neurons through an ERK/MAPK signaling-dependent mechanism. We speculate that this may be one mechanism by which environmental context facilitates some forms of drug experience-dependent plasticity, such as psychomotor sensitization.

Afferent Pathways↗
PubMed2003

Amphetamine or cocaine limits the ability of later experience to promote structural plasticity in the neocortex and nucleus accumbens.

Drugs of abuse and many other kinds of experiences share the ability to alter the morphology of neuronal dendrites and spines, the primary site of excitatory synapses in the brain. We hypothesized, therefore, that exposure to psychostimulant drugs might influence later experience-dependent structural plasticity. We tested this hypothesis by treating rats repeatedly with amphetamine or cocaine and then housing them in either a complex environment or standard laboratory cages for 3-3.5 mo. The brains were processed for Golgi-Cox staining, and the number of dendritic branches and the density of dendritic spines on medium spiny neurons in the nucleus accumbens and pyramidal cells in the parietal cortex were quantified. On most measures, prior treatment with amphetamine or cocaine interfered with the ability of experience in a complex environment to increase dendritic arborization and spine density. We conclude that in some brain regions, repeated exposure to psychomotor-stimulant drugs limits the ability of later experience to produce this form of synaptic plasticity, which may contribute to the persistent behavioral and cognitive deficits associated with drug abuse.

Amphetamine↗
PubMed2003

Environmental complexity has different effects on the structure of neurons in the prefrontal cortex versus the parietal cortex or nucleus accumbens.

Complex housing has been used widely as a model of experience-dependent change. Animals housed in complex environments typically show synaptogenesis throughout the sensory and motor cortex as well as the striatum and hippocampus, and thus it is generally assumed that such changes are likely to be found throughout the cerebrum. The purpose of the present study was to determine whether persistent alterations of dendritic morphology would be found in two regions that had previously not been examined, namely, the medial prefrontal region (Cg3) and nucleus accumbens (NAcc). The results show that housing female rats in complex environments for 3.5 months increased dendritic arborization on medium spiny neurons in the NAcc and on pyramidal cells in the somatosensory cortex (Par 1), but not in Cg3. Environmental complexity increased spine density in all three areas, however. The failure to find increased dendritic length or branching in Cg3 was unexpected. Thus, the data suggest that complex housing may not engage prefrontal neurons in the same manner as neurons in sensory or motor areas. It appears that complex housing may not produce generalized changes in cerebral morphology. The data further suggest that it is prudent to measure both dendritic length and spine density in studies of experience-dependent effects on synaptic plasticity.

Animals↗
PubMed2003

Composite spirometric-computed tomography outcome measure in early cystic fibrosis lung disease.

With the advent of therapies aimed at young patients with cystic fibrosis, who have mildly reduced pulmonary function, the need for improved outcome measures that discriminate treatment effects has become important. Pulmonary function measurements or chest high-resolution computed tomography (HRCT) scores have been separately used to assess interventions. We evaluated these modalities separately and together during a treatment study to develop a more sensitive outcome measure. In a 1-year trial, 25 children randomized either to daily Pulmozyme or to normal saline aerosol were evaluated at randomization and at 3 and 12 months. Outcome variables were pulmonary function test (PFT) results, a global HRCT score, and a composite score incorporating PFTs and HRCT scoring. Regression analyses with generalized estimating equations permitted estimation of the difference in treatment effect between groups over time for each outcome. The largest difference in treatment effects observed at 12 months, measured by the percentage change from baseline, were with the composite total and maximal CT/PFT scores (35.4 and 30.4%), compared with mean forced expiratory flow during the middle half of the FVC (FEF25-75%) (13.0%) and total and maximal global HRCT scores (6.2%, 7.2%). The composite total and maximal CT/PFT scores were the most sensitive outcome measures for discriminating a treatment effect in children with cystic fibrosis with normal or mildly reduced pulmonary function during a 1-year trial of Pulmozyme.

Adolescent↗
PubMed2003

The location of persistent amphetamine-induced changes in the density of dendritic spines on medium spiny neurons in the nucleus accumbens and caudate-putamen.

Repeated intermittent treatment with amphetamine increases the density of dendritic spines on medium spiny neurons (MSNs) in the nucleus accumbens (NAcc). The purpose of this study was two-fold: (1) to determine whether amphetamine has similar effects on MSNs in the caudate-putamen (CPu) and (2) to determine if this effect is localized to distal dendrites, the site of convergence of dopamine (DA) and glutamate synapses in the striatum. An amphetamine treatment regimen that produced behavioral sensitization increased the density of dendritic spines on MSNs in both the NAcc and dorsolateral CPu. This effect was long lasting, because it was evident 3.5 months after the discontinuation of drug treatment. The increase in spine density was confined to distal dendrites of MSNs, and was not apparent on dendrites close to the cell body. It is concluded that amphetamine may preferentially reorganize synapses at the site of DA-glutamate interaction in the striatum, which may alter DA-glutamate signaling and thereby contribute to some of the persistent behavioral and psychological consequences of repeated exposure to psychostimulant drugs.

Amphetamine↗
PubMed2003

Effects of maternal separation on behavioural sensitization produced by repeated cocaine administration in adulthood.

We examined whether early maternal separation influenced the susceptibility to behavioural sensitization produced by repeated intravenous (i.v.) injections of cocaine in adult female rats. For the first 21 days of life litters were separated from their mother for either 15 min (MS-15) or 180 min/day (MS-180). Control animals were subjected only to regular cage changes (animal facility reared; AFR). In adulthood, these three groups did not differ in their locomotor response to placement in a novel environment or to an acute i.v. injection of cocaine. After six additional daily injections of either saline or cocaine and following a 7-day drug-free interval, sensitization was assessed by giving all rats a challenge i.v. injection of cocaine. Rats exposed to either period of maternal separation (MS-15 or MS-180) showed significantly less robust sensitization than AFR rats. Therefore, early maternal separation decreased susceptibility to behavioural sensitization produced by cocaine in adulthood and the specific duration of maternal separation had no effect on this outcome.

Animals↗