bluuebunny/crossref_metadata_2025 huggingface dataset:
Interrelationships between Hormones, Behavior, and Affect during Adolescence: Complex Relationships Exist between Reproductive Hormones, Stress‐Related Hormones, and the Activity of Neural Systems That Regulate Behavioral Affect. Comments on Part III
Authors: CAMERON JUDY L.
Published: July 2004

Abstract: Adolescence is a period in life marked by change, encompassing physiological changes associated with pubertal development, changes in social status and the social stresses that an individual faces, and changes in behavioral affect regulation. The interactions between activity in the reproductive axis, the neural systems that regulate stress, hormones produced in response to stress, and neural systems governing behavioral affect regulation are complex and multifaceted. Although our understanding of these interactions remains rudimentary, we do know that stress can suppress activity of the reproductive axis, that reproductive hormones can modulate the activity of neural systems that govern the body's responses to stress, that both reproductive function and stress responsiveness can be altered in depressed individuals, and that the function of some of the key neural systems regulating behavioral affect (i.e., serotonergic, noradrenergic, dopaminergic systems) are modulated by both gonadal steroid hormones and adrenal steroid hormones. This summary reviews the central interactions discussed in this session on the interrelationships between hormones, behavior, and affect during adolescence and identifies key topics that require further investigation in order to understand the role that pubertal changes in reproductive function, interacting with increased exposure to life stresses, play in modulating behavioral affect regulation during the adolescent period.
Adolescent Development of Forebrain Stimulant Responsiveness: Insights from Animal Studies
Authors: LESLIE FRANCES M. , LOUGHLIN SANDRA E. , WANG RUIHUA , PEREZ LILYANNA , LOTFIPOUR SHAHRDAD , BELLUZZIA JAMES D.
Published: July 2004

Abstract: Although initiation of drug abuse occurs primarily during adolescence, little is known about the central effects of nicotine and other abused drugs during this developmental period. Here evidence, derived from studies in rodents, is presented that suggests that tobacco use initiation during early adolescence results from a higher reward value of nicotine. The developmental profiles of the rewarding effects of other abused drugs, such as cocaine, differ from that of nicotine. Using in situ hybridization to quantify mRNA levels of the immediate early gene, cfos, the neuronal activating effects of nicotine in limbic and sensory cortices at different developmental stages are evaluated. Significant age changes in basal levels of cfos mRNA expression in cortical regions are observed, with a peak of responding of limbic cortices during early adolescence. A changing pattern of nicotine‐induced neuronal activation is seen across the developmental spectrum, with unique differences in both limbic and sensory cortex responding during adolescence. An attentional set‐shifting task was also used to evaluate whether the observed differences during adolescence reflect early functional immaturity of prefrontal cortices that regulate motivated behavior and psychostimulant responding. The finding of significantly better responding during adolescence suggests apparent functional maturity of prefrontal circuits and greater cognitive flexibility at younger ages. These findings in rodent models suggest that adolescence is a period of altered sensitivity to environmental stimuli, including abused drugs. Further efforts are required to overcome technical challenges in order to evaluate drug effects systematically in this age group.
Nicotine Withdrawal in Adolescent and Adult Rats
Authors: O'DELL LAURA E. , BRUIJNZEEL ADRIE W. , GHOZLAND SANDY , MARKOU ATHINA , KOOB GEORGE F.
Published: July 2004

Abstract: Previous research with animal models has demonstrated that adolescent rats display heightened sensitivity to the reinforcing and stimulant effects of nicotine relative to adult rats. Little work has focused on the response of adolescent rats to measures of nicotine withdrawal. To test the hypothesis that adolescent rats may be differentially sensitive to withdrawal relative to their adult counterparts, the present study was designed to compare precipitated withdrawal in adolescent and adult rats following chronic nicotine administration. Adult and adolescent rats were prepared with subcutaneous osmotic minipumps that delivered either saline or nicotine (9 mg/kg per day, salt; N =12 per group). All rats were challenged with the nicotinic receptor antagonist mecamylamine (1.5 mg/kg) on day 7 of chronic nicotine treatment. Twenty minutes after the injection, overt somatic signs of withdrawal (i.e., eye blinks, writhes, body shakes, teeth chatter, gasps, and ptosis) were recorded for 10 min. Adult rats were observed on postnatal day 73‐77, and adolescent rats were tested on postnatal day 36‐40. The results revealed a robust increase in mecamylamine‐induced withdrawal signs in adult rats receiving chronic nicotine relative to adult rats receiving saline. In contrast, mecamylamine did not precipitate withdrawal signs in adolescent rats receiving chronic nicotine. These results indicate that there is decreased sensitivity to the somatic aspects of nicotine withdrawal in adolescent rats that may maximize the reinforcing effects of nicotine during adolescence by minimizing the aversive effects of abstinence.
Adolescence and the Trajectory of Alcohol Use: Introduction to Part VI
Authors: SPEAR LINDA PATIA
Published: July 2004

Abstract: Research in the area of adolescent alcohol use is progressing rapidly, as exemplified by the chapters in this section. Basic animal research in rodents has revealed adolescents to be more sensitive than adults to ethanol‐induced disruptions in brain plasticity, although adolescents conversely are relatively insensitive to ethanol cues that serve to moderate intake. Risks for excessive alcohol consumption due to genetic background have been shown in primate research to be exacerbated by adverse early life experiences. Studies in clinical populations have revealed neurocognitive deficits evident years following adolescent alcohol abuse, along with evidence that some neural changes may predate adolescent alcohol abuse, whereas others appear to be a consequence of this abuse. Further research is needed to detail determinants and consequences of adolescent alcohol abuse and to identify potential protective factors to diminish the propensity for excessive use of alcohol during this critical developmental period.
The Use of Adolescent Nonhuman Primates to Model Human Alcohol Intake: Neurobiological, Genetic, and Psychological Variables
Authors: BARR CHRISTINA S. , SCHWANDT MELANIE L. , NEWMAN TIMOTHY K. , HIGLEY J DEE
Published: July 2004

Abstract: Traits characteristic of type I and type II alcoholism are thought to relate to dysregulated central nervous system serotonin functioning. In this review, we discuss variables associated with high adolescent alcohol consumption and other risk‐taking behaviors in a nonhuman primate model. Adolescent primates with low CSF concentrations of the serotonin metabolite 5‐HIAA are more impulsive and exhibit increased levels of alcohol consumption. Both genetic and environmental factors contribute to alcohol‐seeking behavior in adolescent macaques. Sequence variation within serotonin system genes, for example, a repeat polymorphism in the transcriptional control region of the monoamine oxidase gene (MAOA‐LPR), increases the propensity for adolescent males to consume alcohol. Environmental factors, such as early life stress in the form of peer‐rearing or early age of exposure to alcohol, are also associated with increased alcohol consumption. Peer‐reared females, especially those exposed to alcohol during early adolescence, exhibit increased rates of alcohol consumption compared to those exposed to alcohol later in development. When genetic variables are also considered, there is an interaction between the low activity serotonin transporter gene promoter s allele (rh5‐HTTLPR) and rearing condition on alcohol preference in females but not males, suggesting that the interactions between genes and the environment may be sexually dichotomous. By learning more about the interactions between genes, early experience, and alcohol intake in the adolescent nonhuman primate, we may be able to identify factors that contribute to the susceptibility, pathogenesis, and progression of impulse control disorders, such as alcoholism.
Adolescence and the Trajectory of Alcohol Use: Basic to Clinical Studies
Authors: BROWN SANDRA A. , TAPERT SUSAN F.
Published: July 2004

Abstract: Emerging findings from developmentally focused research indicates subtle but important neurocognitive disadvantages among adolescents with alcohol‐use disorders (AUD) as compared to teens without AUD. Even after 3 weeks of abstinence AUD youth display a 10% decrement in delayed memory functions. Neuropsychological testing of youth followed at 4 and 8 years demonstrates that heavy drinking during adolescence is associated with diminished retrieval of verbal and nonverbal material, and poorer performance on tests requiring attention skills. Alcohol withdrawal over the teen years appears to uniquely contribute to deterioration in functioning in visuospatial tasks. Brain imaging studies suggest reduced hippocampal volumes, white matter microstructure irregularities, brain response abnormalities while performing challenging cognitive tasks, and enhanced brain response when viewing alcohol cues (i.e., alcohol advertisements) among adolescents with AUD. Family characteristics such as history of alcoholism and socioeconomic status as well as personal features, including adolescent psychopathology, gender, and age of onset must be carefully considered when investigating the influence of teenage drinking on neurocognition. Further research is needed to understand how age at onset of drinking and duration of abstinence at the time of assessment affect cognitive findings. Longitudinal studies are needed to clarify neuromaturational changes associated with early alcohol exposure and patterns of resiliency. Although the magnitude of alcohol‐related effects observed in adolescents' neurocognition is relatively modest, the implications are major given the prevalence of alcohol involvement, and the important educational, occupational, and social transitions that occur during adolescence.
Trajectories of Alcohol Use and Electrophysiological and Morphological Indices of Brain Development: Distinguishing Causes from Consequences
Authors: HILL SHIRLEY Y.
Published: July 2004

Abstract: Alcoholism is a major public health problem. Patterns of drinking during adolescence can influence the likelihood of this outcome. Both environmental variation and familial/genetic susceptibility play important roles in this process. While there is some evidence to suggest that metabolic factors play a role in whether some individuals are protected from developing alcohol problems, there is substantial reason to look for cognitive factors that are associated with increased susceptibility. Developmental trajectories for information processing that can be reflected in P300 amplitude changes over time, as well as trajectories describing acquisition of postural control when compared in offspring from families with multiple cases of alcoholism or those with none or few, suggest that brain development provides a clue to why some individuals are more susceptible to becoming alcoholic. Finally, differences seen in amygdala volume between high‐ and low‐risk adolescents suggest that functional differences seen in electrophysiological responding or neuropsychological test performance may have anatomical correlates.
Regulation of Sleep and Arousal: Introduction to Part VII
Authors: BENCA RUTH M.
Published: July 2004

Abstract: This paper introduces the theme of the relationship between sleep deprivation and behavior.
Pubertal Development of Sex Differences in Circadian Function: An Animal Model
Authors: LEE THERESA M. , HUMMER DANIEL L. , JECHURA TAMMY J. , MAHONEY MEGAN M.
Published: July 2004

Abstract: The development of adult circadian function, particularly sexual dimorphism of function, has been well studied only in rapidly developed rodents. In such species development is complete by weaning. Data from adolescent humans suggest that significant development occurs during the pubertal period. We hypothesized that a more slowly developing rodent might better mimic the changes in circadian function around puberty in humans and allow us to determine the underlying neural changes. Entrained and free‐running circadian rhythms were analyzed and correlated with pubertal development in male and female Octodon degus (degu) that remained gonadally intact or were gonadectomized at weaning. Brains were collected during development to measure androgen and estrogen receptors in the suprachiasmatic nuclei (SCN) Adult circadian period does not develop until 10‐12 months of age in degus, long after the onset of gonadal maturation (3‐5 months). The timing of circadian period maturation correlates with the appearance of steroid receptors in the SCN. Changes in free‐running rhythms only occurred in gonadally intact degus. Adult phase angles of activity onset develop between 2 and 3 months of age (comparing results of two experiments), soon after the onset of pubertal changes. Conclusion: The development of sexually dimorphic adult circadian period occurs after gonadal puberty is complete and requires the presence of gonadal steroids. The delay in development until after gonadal puberty is likely due to the delayed appearance of steroid receptors in the SCN. Phase is not sexually dimorphic and changes in the absence of steroid hormones.
Regulation of Adolescent Sleep: Implications for Behavior
Authors: CARSKADON MARY A. , ACEBO CHRISTINE , JENNI OSKAR G.
Published: July 2004

Abstract: Adolescent development is accompanied by profound changes in the timing and amounts of sleep and wakefulness. Many aspects of these changes result from altered psychosocial and life‐style circumstances that accompany adolescence. The maturation of biological processes regulating sleep/wake systems, however, may be strongly related to the sleep timing and amount during adolescence—either as “compelling” or “permissive” factors. The two‐process model of sleep regulation posits a fundamental sleep‐wake homeostatic process (process S) working in concert with the circadian biological timing system (process C) as the primary intrinsic regulatory factors. How do these systems change during adolescence? We present data from adolescent participants examining EEG markers of sleep homeostasis to evaluate whether process S shows maturational changes permissive of altered sleep patterns across puberty. Our data indicate that certain aspects of the homeostatic system are unchanged from late childhood to young adulthood, while other features change in a manner that is permissive of later bedtimes in older adolescents. We also show alterations of the circadian timing system indicating a possible circadian substrate for later adolescent sleep timing. The circadian parameters we have assessed include phase, period, melatonin secretory pattern, light sensitivity, and phase relationships, all of which show evidence of changes during pubertal development with potential to alter sleep patterns substantially. However the changes are mediated—whether through process S, process C, or by a combination—many adolescents have too little sleep at the wrong circadian phase. This pattern is associated with increased risks for excessive sleepiness, difficulty with mood regulation, impaired academic performance, learning difficulties, school tardiness and absenteeism, and accidents and injuries.
Regulation of Sleep and Arousal: Comments on Part VII
Authors: DAHL RONALD E.
Published: July 2004

Abstract: This paper links the papers in this session and describes briefly how together they represent an ideal example of the kind of trans‐disciplinary approach to understanding aspects of adolescent maturation that can have major clinical and social policy implications. The issues of adolescent sleep needs, circadian changes linked to pubertal maturation, the effects of sleep deprivation on adolescent health and behavior, and social controversies such as delaying the start times of high schools to address the problems of adolescent sleep deprivation all point to the need for additional empirical studies. This will require studies of normal human development as well as animal models to investigate the mechanisms underpinning these developmental changes in sleep and circadian regulation.
The Emergence of Collaborative Brain Function: fMRI Studies of the Development of Response Inhibition
Authors: LUNA BEATRIZ , SWEENEY JOHN A.
Published: July 2004

Abstract: Adolescence marks the beginning of adult‐level cognitive control of behavior supported by the brain maturation processes of synaptic pruning and myelination. Cognitive development studies on adolescence indicate that this period is characterized by improvements in the performance of existing abilities including speed and capacity of information processing and the ability to have consistent cognitive control of behavior. Although adolescents can behave at adult levels in some ways, brain imaging studies indicate that the functional organization of brain systems that support higher‐cognitive processes are not fully mature. Synaptic pruning allows for more efficient local computations, enhancing the ability of discrete brain regions to support high‐level cognitive control of behavior including working memory. Myelination increases the speed of neuronal transmission supporting the collaboration of a widely distributed circuitry, integrating regions that support top‐down cognitive control of behavior. Functional brain imaging methods allow for the characterization of the relationship between cognitive development and brain maturation as we can map progressions in the establishment of distributed brain circuitry and its relation to enhanced cognitive control of behavior. We present a review on the maturation (as distinct from “development” in emphasizing the transition to maturity and stabilization) of response inhibition, brain structure, and brain function through adolescence. We also propose a model for brain‐behavior maturation that allows for the qualitative changes in cognitive processes that occur during adolescence.
ERP Correlates of Action Monitoring in Adolescence
Authors: LADOUCEUR CECILE D. , DAHL RONALD E. , CARTER CAMERON S.
Published: July 2004

Abstract: This study examines the development of action monitoring in adolescence by measuring the N200, the ERN (error‐related negativity) and the PE (error positivity), which are event‐related potentials (ERPs) that appear to be generated in the anterior cingulate cortex (ACC) and reflect action‐monitoring processes. We predicted that amplitude would be significantly greater in late compared to early adolescence. Participants consisted of 11 adolescents that were divided into early (age 9‐14) and late (age 14‐17) adolescence groups. ERPs were recorded during an 840‐trial arrow‐flanker task and using 128‐channel dense array EEG. Results indicated that there were no differences in PE amplitude but that N200 and ERN amplitudes were greater in the late adolescence group. According to the conflict monitoring hypothesis, this suggests that the ability to detect error‐related conflict, which is involved in the modulation of cognitive control, appears to be fully developed later in adolescence and may be linked to the maturation of the ACC.
Individual Differences in Executive Attention Predict Self‐Regulation and Adolescent Psychosocial Behaviors
Authors: ELLIS LESA K. , ROTHBART MARY K. , POSNER MICHAEL I.
Published: July 2004

Abstract: This study examined temperament, executive attention, parental monitoring and relationships, and involvement in pro‐ and antisocial behaviors in an ethnically diverse sample of adolescents. We sought to relate parent‐ and self‐reported effortful control to performance on measures of executive attention and to better understand the relative contributions of individual‐difference variables and environmental variables in predicting behaviors in adolescence. The results indicated a relationship between poor executive attention and mother‐reported effortful control. Inclusion of individual‐difference variables significantly increased prediction of problem‐behavior scores, suggesting the importance of including such variables in studies of adolescent deviance.
Sex Differences in the Effects of Pubertal Development on Responses to a Corticotropin‐Releasing Hormone Challenge: The Pittsburgh Psychobiologic Studies
Authors: STROUD LAURA R. , PAPANDONATOS GEORGE D. , WILLIAMSON DOUGLAS E. , DAHL RONALD E.
Published: July 2004

Abstract: We propose that sex differences in HPA regulation may emerge during puberty and help to explain sex differences in depression. In this study, we examined sex differences in cortisol responses to CRH challenge across pubertal stages in carefully screened control subjects from the Pittsburgh Psychobiologic Studies. Participants were 7‐16 years of age, physically healthy, and had no personal or family history of psychiatric disorder. Physician‐rated Tanner staging was conducted, followed by CRH challenge sessions including 30‐40 minutes pre‐infusion baseline, 1 μg/kg CRH infusion, 90‐180 minutes of post‐infusion measures, and 9‐10 plasma cortisol samples. Girls showed increasing total cortisol responses to CRH across Tanner stages, explained by slower recovery from peak cortisol levels, while boys showed similar total responses across Tanner stages. Results show subtle sex differences in the influence of puberty on HPA regulation at the pituitary level, which may represent one factor underlying the emergence of girls' greater rates of depression during this time.
Cognitive and Emotional Components of Frontal Lobe Functioning in Childhood and Adolescence
Authors: ROSSO ISABELLE M. , YOUNG ASHLEY D. , FEMIA LISA A. , YURGELUN‐TODD DEBORAH A.
Published: July 2004

Abstract: Frontal lobe functions include a range of cognitive, emotional, and social abilities that enable goal‐directed behavior. Although a number of studies have plotted the development of frontal lobe functions in childhood, few have extended into the adolescent years. There is also little information on which cognitive and emotional components of frontal functioning may be correlated. The aims of this study were to identify and compare age effects on different components of frontal functioning in childhood and adolescence and to examine whether abstract reasoning skills were associated with levels of emotional intelligence and social sensitivity. Twenty children (ages 9‐18) were recruited from the local community for a study of normal adolescent brain development. All subjects were free of psychiatric or developmental disorders, as determined by a structured interview. Subjects completed a comprehensive neuropsychological test battery, as well as self‐report measures of social sensitivity (anxiety) and emotional intelligence. Significant age effects were found for measures of abstract reasoning, response inhibition, and attentional set shifting. Levels of social anxiety increased moderately with age, although not significantly at this sample size. Abstract reasoning skills correlated positively with levels of social anxiety but not emotional intelligence. The pattern of results suggests differential developmental trajectories across various cognitive and emotional domains of frontal lobe functioning in childhood and adolescence. Increased abstract reasoning ability may be associated with increased vulnerability to social anxiety during this period.
The Human HPLC Column: “Minds‐On” Neuroscience for the Next Generation
Authors: FRANTZ KYLE J.
Published: July 2004

Abstract: Science education researchers have suggested that neuroscientists can play an important role in science education programs for adolescents by creating “minds‐on” teaching and learning modules for scientists and teachers to use in classrooms. Effective educational partnerships between teachers and visiting scientists not only ignite student interest but also provide opportunities for scientist and teacher professional development. The aim of the present teaching module was threefold: (1) to introduce adolescents to the acute neurochemical effects of psychomotor stimulant drugs and their analysis using high performance liquid chromatography (HPLC), (2) to spur maturation of analytical reasoning skills among adolescents, and (3) to spark enthusiasm for science education.
Significance of Adolescent Neurodevelopment for the Neural Circuitry of Bipolar Disorder
Authors: BLUMBERG HILARY P. , KAUFMAN JOAN , MARTIN ANDRÉS , CHARNEY DENNIS S. , KRYSTAL JOHN H. , PETERSON BRADLEY S.
Published: July 2004

Abstract:The deficits of executive control of emotions and impulses of adult BD implicate involvement of a ventral prefrontal cortex (VPFC) neural system that subserves these functions that include the VPFC, as well as its subcortical connection sites of amygdala, striatum, and thalamus. Differences in the timing of major developmental changes in the structures within this neural system suggest that abnormalities in particular components of this neural system may emerge during critical developmental epochs during the course of the illness. Our recent neuroimaging data suggest that abnormalities in the subcortical components of VPFC neural systems may be evident by early adolescence in BD, whereas VPFC deficits progress over the course of adolescence and may be difficult to detect prior to late adolescence or early adulthood. This potential neurodevelopmental model for BD could have important implications for the recognition of early signs of the disorder and for age‐specific treatment strategies.
Age and Experience Affect the Recruitment of New Neurons to the Song System of Zebra Finches during the Sensitive Period for Song Learning: Ditto for Vocal Learning in Humans?
Authors: WILBRECHT LINDA , NOTTEBOHM FERNANDO
Published: July 2004

Abstract:Vocal learning in songbirds and humans is a complex learned skill with sensory, motor, and social aspects. It culminates in the imitation of sounds produced by other, usually older individuals. Song learning and language learning may differ in their cognitive content, but both require coordination of auditory feedback and fine motor control, which may be supported by similar brain structures. Vocal learning in birds as in humans requires the use of forebrain networks; in songbirds these networks are thought to be related, in part, to the frontal association cortex‐basal ganglia loops that mature in humans at adolescence.
An fMRI Study of Response Inhibition in Youths with a Family History of Alcoholism
Authors: SCHWEINSBURG ALECIA D. , PAULUS MARTIN P. , BARLETT VALERIE C. , KILLEEN LAUREN A. , CALDWELL LISA C. , PULIDO CARMEN , BROWN SANDRA A. , TAPERT SUSAN F.
Published: July 2004

Abstract: Disinhibition among alcoholics may precede or result from alcohol use disorders (AUDs). It remains unclear how disinhibition might contribute to AUD risk among youths with a family history of alcoholism (FHP). We used functional magnetic resonance imaging (fMRI) to explore inhibition‐related neural risk factors for AUD. Participants were 12‐ to 14‐year‐old nondrinkers, including 12 FHP youths and 14 youths with no family history of alcoholism (FHN). Youths performed a go/no‐go task during fMRI acquisition. At a conservative threshold, FHN youths showed less inhibitory response than FHP youths in the left middle frontal gyrus, despite similar task performance between groups. Using a more liberal threshold, FHP youths also demonstrated less response in additional frontal regions. These preliminary findings suggest that FHP youths show less inhibitory frontal response than FHN youths. Altered neural activation among FHP youths may underlie subsequent disinhibition and could be related to the AUD risk.
A Comparative Developmental Study of Impulsivity in Rats and Humans: The Role of Reward Sensitivity
Authors: VAIDYA JATIN G. , GRIPPO ANGELA J. , JOHNSON ALAN KIM , WATSON DAVID
Published: July 2004

Abstract: The present study was conducted to test the hypothesis that differences in reward sensitivity between adolescents and adults account for differences in impulsivity. In a comparative study, we examined preferences for various concentrations of sucrose solutions as an operational measure of reward sensitivity in adolescent and adult rats and humans. Humans also completed self‐report measures of impulsivity and reward sensitivity. There was some indication that adolescents preferred sweeter solutions compared to adults. Also, adolescents scored substantially higher on impulsivity. However, adolescents and adults did not differ in self‐ratings of reward sensitivity and personality scores were not consistently related to sucrose preferences. The data highlight some of the benefits and issues that arise with developing comparative measures in humans and animals. Future comparative research using alternative behavioral paradigms is necessary to determine if and how changes in reward sensitivity influence developmental shifts in impulsivity.
Developmental Differences in Nicotine Place Conditioning
Authors: TORRELLA TRACY A. , BADANICH KIMBERLY A. , PHILPOT REX M. , KIRSTEIN CHERYL L. , WECKER LYNN
Published: July 2004

Abstract: To understand the motivations and implications of the prevalence of smoking, studies have compared the behavioral effects of nicotine, the psychoactive drug in tobacco, in adolescent and adult animals. The present study used a biased three‐chambered conditioned‐place preference procedure without prior habituation to examine the potential rewarding and anxiolytic effects of nicotine across adolescence and adulthood to assess the presence of age‐dependent differences in response to nicotine.
Age‐Related Differences in Elevated Plus Maze Behavior between Adolescent and Adult Rats
Authors: DOREMUS TAMARA L. , VARLINSKAYA ELENA I. , SPEAR LINDA PATIA
Published: July 2004

Abstract: Adolescence is a time of considerable transformations, often associated with increases in risk taking and novelty‐seeking behaviors. Little is known of a possible age‐dependent expression of anxiety‐related behaviors in novel or potentially dangerous situations. The present study explored age differences in anxiogenic and anxiolytic stimuli between adolescent and adult Sprague‐Dawley rats using the elevated plus maze (EPM). Data were compared across several experiments using factor analysis of multiple EPM measures. Under some circumstances, adolescents revealed a relatively low behavioral anxiety profile compared to adults, whereas in other situations results revealed the opposite pattern. Characteristics of the pretest circumstances altered considerably the nature of the conclusions reached regarding age‐related changes in anxiogenic and anxiolytic stimuli. In general, anxiety measures in adolescents were less affected by variations in pretest conditions compared to the same variables in adults, suggesting possible adolescent immaturity of brain mechanisms involved in the regulation of anxiety.
Long‐Term Neurobehavioral Effects of Alcohol or Nicotine Exposure in Adolescent Animal Models
Authors: SLAWECKI CRAIG J. , THORSELL ANNIKA , EHLERS CINDY L.
Published: July 2004

Abstract: Adolescent alcohol and nicotine abuse is common, but its neurodevelopmental consequences remain unclear. This laboratory utilized adolescent rodent models to assess the hypothesis that adolescents are highly susceptible to the effects of alcohol and nicotine. Rats were exposed to ethanol for 10‐14 days using an intermittent vapor inhalation paradigm. Rats were continuously exposed to nicotine for 5 days using Nicoderm CQ™ transdermal patches. Alcohol or nicotine exposure altered neurobehavioral function when assessed after 3‐7 weeks of abstinence. Alcohol‐induced changes include increased electroencephalographic (EEG) frequency, decreased amplitude of the cortical N1 and hippocampal P3 event‐related potential (ERP) components, enhanced anxiety‐like behavior, and enhanced depressive‐like behavior. Nicotine‐induced changes include decreased slow‐wave cortical EEG power, increased cortical N1 ERP amplitude, decreased motor activity, and increased anxiety‐like behavior. These findings support the hypothesis that adolescents are uniquely susceptible to the effects of chronic alcohol and nicotine exposure.
Changes in Sensitivity to Ethanol‐Induced Social Facilitation and Social Inhibition from Early to Late Adolescence
Authors: VARLINSKAYA ELENA I. , SPEAR LINDA P.
Published: July 2004

Abstract: Adolescent rats are more sensitive than adults to ethanol‐induced social facilitation, but are less sensitive to the suppression of social interactions seen at higher ethanol doses. Given recent findings that point to age differences in ethanol responsiveness, even within the adolescent period, the present study assessed acute effects of low to moderate doses of ethanol on social behavior of early, mid‐ or late adolescent rats. Age‐related changes in responsiveness to the effects of ethanol on social behavior were apparent even within the adolescent period, with early adolescents being more sensitive to ethanol‐induced social facilitation and less sensitive to ethanol‐induced social inhibition than mid‐ and late adolescents. Given that ethanol‐induced social facilitation as well as a lower sensitivity to the adverse effects of ethanol may contribute to heavy drinking, this pattern of early adolescent responsiveness to ethanol's social consequences may put them at higher risk for extensive alcohol use.
The Effects of Methylphenidate on Novel Object Exploration in Weanling and Periadolescent Rats
Authors: HEYSER CHARLES J. , PELLETIER MARSHA , FERRIS JENNIFER S.
Published: July 2004

Abstract: Methylphenidate (Ritalin®) is used in the treatment of attention‐deficit hyperactivity disorder. Surprisingly, little research has been conducted on the effects of methylphenidate during early development. Therefore, the present study was conducted to examine the effects of methylphenidate on object exploration in developing rats. Male and female weanling (21‐day‐old) and periadolescent (34‐day‐old) Sprague‐Dawley rats were tested after acute or chronic treatment with methylphenidate. In weanling rats, chronic methylphenidate (5.0 mg/kg) increased locomotor activity and disrupted novel object exploration. In periadolescent rats, methylphenidate disrupted explor‐ation of the novel object, but had no effect on locomotor activity at any dose tested. Periadolescent rats appear to be less sensitive to methylphenidate‐induced changes in activity compared to weanling animals, whereas methylphenidate disrupted novel object exploration in both ages. Our results suggest that methylphenidate may alter recognition memory and/or reactivity to or preference for novelty.
Circulating Nucleic Acids and Proteomics of Plasma/Serum: Clinical Utility
Authors: TABACK BRET , HOON DAVE S. B.
Published: July 2004

Abstract: Circulating tumor‐specific nucleic acids have been identified in plasma, serum, and other body fluids from cancer patients with tumors originating in almost any organ site. Polymerase chain reaction provides a highly sensitive and specific technique for the detection of these genetic changes in a limited amount of tissue/fluid. The presence of elevated levels of free DNA/RNA in many medical conditions, malignancy, and infectious processes is being investigated for screening, diagnosis, prognosis, surveillance for occult disease progression, identifying potential therapeutic targets, and monitoring treatment response. Additionally, elevated fetal DNA/RNA in maternal blood is being used to determine gender identity, assess chromosomal abnormalities, and monitor pregnancy‐associated complications. Questions remain on the etiology, characteristics, stability, and potential pathologic consequences of cell‐free DNA/RNA in the circulation. Nevertheless, nucleic acid‐based assays that monitor plasma, serum, and body fluids provide a noninvasive, facile, and practical method for assessing patients. Proteomic profiling may prove complementary to a total functionality approach in providing a comprehensive evaluation of the patient's disease.
Quantification of Circulating DNA in the Plasma and Serum of Cancer Patients
Authors: TABACK BRET , O'DAY STEVEN J. , HOON DAVE S.B.
Published: July 2004

Abstract: A variety of tumor‐genetic alterations have been identified circulating free‐form in the plasma and serum of cancer patients that may have diagnostic and prognostic implications. Currently, no consensus exists as to whether plasma or serum is preferable for circulating nucleic acid analysis, and the impact of collection and processing on yield is unknown. We prospectively assessed DNA content in paired plasma and serum obtained from 10 patients with AJCC stage IV advanced metastatic melanoma. Blood (30 mL) was collected from each patient as follows: 10 mL each was processed immediately for serum and plasma and an additional 10 mL was incubated overnight at 37°C and processed for serum. In addition, blood was collected from 25 normal healthy donor volunteers to determine the concentration of free DNA circulating in paired plasma and serum. DNA was isolated from 800 μl of plasma or serum and quantified. Median‐free DNA concentrations were fourfold greater in serum than in the corresponding plasma sample. Serum isolated from blood allowed to clot overnight yielded four times more DNA than serum processed immediately. Among normal healthy volunteers, only serum contained detectable free DNA. These findings provide conclusive evidence that elevated levels of circulating DNA could be identified consistently in patients with cancer than in normal healthy donors. Furthermore, the method of blood processing may significantly affect the levels of circulating nucleic acids and impact the investigator's results. Significant consideration must be given to the methods by which circulating nucleic acids are obtained for clinical analysis.
Circulating Methylated DNA
Authors: HERMAN JAMES G.
Published: July 2004

Abstract: Early detection of cancer would facilitate better management of patients, because survival is greatly affected by stage of presentation. Circulating nucleic acids represent a biomarker that might be used in the early detection of cancer. In addition, such biomarkers could potentially be used to follow the progression of patients with cancer. DNA methylation of the promoter region CpG islands of genes represents one such nucleic acid‐based marker, and possesses some advantages over other approaches. These include the stability of DNA as a molecule, the ability to detect such changes using simple polymerase chain reaction‐based approaches, and the potential for methylated DNA to be preferentially present in nucleosomes in plasma or serum. These factors are presented and their impact on the detection of methylated DNA circulating in the bloodstream is demonstrated.
Detection of Promoter Hypermethylation of Tumor Suppressor Genes in Urine from Kidney Cancer Patients
Authors: CAIRNS PAUL
Published: July 2004

Abstract: Kidney cancer is curable by surgical resection and therapy, if detected at an early stage. Using sensitive methylation‐specific polymerase chain reaction, we screened matched tumor DNA and preoperative urine DNA from 50 kidney cancer patients, for hypermethylation of a panel of six normally unmethylated tumor suppressor genes: VHL, p16/CDKN2a, p14ARF, APC, RASSF1A, and Timp‐3. When compared to the tumor DNA, an identical pattern of gene hypermethylation was found in the matched urine DNA from 44 of 50 patients (88% sensitivity) including 27 of 30 cases of stage I disease. By contrast, hypermethylation was not observed in normal and benign disease controls (100% specificity). We conclude that promoter hypermethylation is a common and early event in kidney tumorigenesis and can be detected in the urine DNA from patients with organ‐confined renal cancer of all histologic types.
Prognostic DNA Methylation Marker in Serum of Cancer Patients
Authors: MÜLLER HANNES M. , FIEGL HEIDI , WIDSCHWENDTER ANDREAS , WIDSCHWENDTER MARTIN
Published: July 2004

Abstract: Changes in the status of DNA methylation are among the most common molecular alterations in human neoplasia. Recent demonstrations of tumor‐derived methylated DNA in the blood stream of cancer patients allow the use of these epigenetic markers for risk assessment in cancer patients. We were interested in evaluating the prognostic value of several methylated genes in the serum of cancer patients. Using MethyLight, a high‐throughput DNA methylation assay, we analyzed 215 serum samples from patients with cervical (n= 93) or breast cancer (n= 122) for DNA methylation changes. In cervical cancer, hypermethylation of three genes (MYOD1, CDH1, and CDH13) in pretreatment sera was statistically significantly associated with a poorer disease outcome. Additionally, for the first time we used a so‐called gene evaluation set to identify the most important DNA methylation changes in the serum of breast cancer patients from a long list of candidate genes. In the gene evaluation set, we detected five genes (ESR1, APC, HSD17B4, HIC1, and RASSF1A) using our criteria for further analysis. Finally, two of the evaluated genes (APC and RASSF1A) proved to be independent prognostic parameters in breast cancer patients. In summary, we detected several prognostic DNA methylation markers in the serum of cervical and breast cancer patients. This finding indicates great potential for the use of these epigenetic markers in clinical, routine risk assessment in patients with various malignancies.
Detection of Mitochondrial DNA Alterations in Plasma of Malignant Melanoma Patients
Authors: TAKEUCHI HIROYA , FUJIMOTO AKIHIDE , HOON DAVE S.B.
Published: July 2004

Abstract: Genetic changes in mitochondrial DNA (mtDNA) have been detected in a variety of pathologic conditions including cancer. We hypothesized that malignant melanoma has genetic alterations in the displacement loop (D‐loop) region and that these mtDNA alterations can be detected in blood as a circulating DNA melanoma marker. D‐loop region from 20 melanoma cell lines, 12 metastatic melanoma specimens, and corresponding lymphocytes and plasma samples were sequenced using the CEQ 8000 XL Genetic Analysis System (Beckman Coulter). Nine of 20 (45%) melanoma cell lines and 5 of 12 (42%) melanoma specimens contained somatic mutations in the D‐loop region of mtDNA. DNA alterations in the polycytosine tract (C‐tract) of D‐loop were detected in 6 of 20 (30%) cell lines and 2 of 12 (17%) specimens. Two of five paired plasma samples (40%) contained the same mutations as did melanoma specimens. In a comparison of lymphocytes and plasma of melanoma patients, 9 of 44 paired plasma samples (20%) contained at least one mutation compared to corresponding lymphocytes. Somatic mutations in the D‐loop region of tumor and paired plasma did not correlate with the clinicopathological characteristics. However, circulating mtDNA alterations were more frequent in advanced disease. Studies indicate that circulating mtDNA mutations in the plasma of melanoma patients can be detected.
Mutant DNA in Plasma of Lung Cancer Patients: Potential for Monitoring Response to Therapy
Authors: KIMURA TATSUO , HOLLAND WILL S. , KAWAGUCHI TOMOYA , WILLIAMSON STEPHEN K. , CHANSKY KARI , CROWLEY JOHN J. , DOROSHOW JAMES H. , LENZ HEINZ‐JOSEF , GANDARA DAVID R. , GUMERLOCK PAUL H.
Published: July 2004

Abstract: The hypothesis tested was that mutant tumor DNA shed into plasma would show predictive value for monitoring response to therapy in non‐small cell lung carcinoma patients. Pretreatment plasma specimens from 25 patients on a phase I trial were evaluated, 12 with paired posttreatment specimens, and 138 patients on the Southwest Oncology Group S0003 trial, 38 with paired posttreatment specimens, for the presence of K‐RAS mutations. Thirteen tumor specimens from the phase I trial patients and seven tumor specimens from S0003 patients were also available for comparative analysis of K‐RAS mutations in tumor tissue and plasma. All patients were treated similarly with paclitaxel, and carboplatin chemotherapy. DNA was extracted and mutational analyses performed using an RFLP‐PCR assay. K‐RAS mutations were found in plasma DNA in 5/25 of the phase I patients (20%). Median survival was 10 months in all patients, 11.4 months in the wild‐type K‐RAS group, and 3.3 months in the mutant K‐RAS group (P= 0.056). Point mutations in plasma DNA were identical to mutations found in the tumors, confirming the tumor as the source. In two patients with K‐RAS mutations pretreatment, posttreatment plasmas were evaluated: a patient with clinical progressive disease retained the mutant DNA, while in a patient with a complete response (CR), the K‐RAS mutation was no longer detectable. In an ongoing analysis of S0003 patients, to date, K‐RAS mutations have been found in the plasma of 14 patients (10.1%). In 42 matched pre‐ and posttreatment specimens from both phase I and S0003 trials, four patients had K‐RAS mutations pretreatment that were not detectable posttreatment. Of these, two had a clinical CR or partial response, and the other two had stable disease. It was concluded that detection of tumor DNA in plasma is feasible using molecular techniques and that this approach shows promise for monitoring patient response to therapy.
TP53 Gene in Blood Plasma DNA of Tumor Patients
Authors: SCHLECHTE HORST H. , STELZER CORNELIA , WEICKMANN SABINE , FLEISCHHACKER MICHAEL , SCHULZE GUNTRAM
Published: July 2004

Abstract: Tumor‐specific TP53 mutations are detectable in the blood plasma of tumor patients. Mutations of the TP53 tumor suppressor gene are risk factors for tumor progression. The objective of this work is to compare the presence of TP53 mutations in plasma‐DNA before and after tumor treatment with the status of this gene in the tumor tissue sample. DNA was extracted from plasma samples of 25 patients with gastrointestinal tumors, and from paraffin‐embedded tumor tissues from the same patients. Temperature gradient gel electrophoresis (TGGE) was performed for mutation screening of exons 5–8 of GC‐clamped polymerase chain reaction products. Mutation‐positive and wildtype gel bands from TGGE were cut and reamplified for fluorescence‐labeled sequence analysis. The results of several mutation analyses were correlated with analysis of p53 autoantibodies in the same plasma. Mutation frequency (one or several mutations per sample) was 7.1% in blood plasma of tumor‐free patients, 87.0% in tumor tissues, 78.6% in plasma before tumor treatment, and 36.8% after treatment. Fifteen of 22 mutations in tumor tissues of 13 patients also were detected in the same exons of plasma before treatment (68.2%). Mutations in plasma after treatment (2–684 days) were the same in 6 of 30 cases of tissue mutations only. Six of seven patients with mutations after treatment in their plasma had metastases. One patient was p53 autoantibody negative, but has a terminator mutation of codon 196 in tissue and in posttreatment plasma as well. Genetic analysis of plasma in tumor patients should be further developed, as it might be of prognostic value.