bluuebunny/crossref_metadata_2025 huggingface dataset:
Grain Growth Control and Solid‐State Crystal Growth by Li2O/PbO Addition and Dislocation Introduction in the PMN–35PT System
Authors: Kim Min‐Soo , Fisher John G. , Kang Suk‐Joong L. , Lee Ho‐Yong
Published: February 2006

Grain growth behavior and solid‐state single crystal growth (SSCG) in the Pb(Mg1/3Nb2/3)O3–35 mol% PbTiO3 (PMN–35PT) system have been investigated with varying Li2O/PbO ratios. The effect of dislocation density on crystal growth has also been studied. For SSCG, a BaTiO3 single‐crystal seed was embedded in a polycrystalline PMN–PT matrix. During annealing, a PMN–PT single crystal grew from the seed at the cost of the small matrix grains. Addition of Li2O dopant first enhanced and then reduced abnormal grain growth in the matrix. In the 2 mol% Li2O and 6 mol% PbO excess PMN–PT samples annealed at 1200°C, considerable single‐crystal growth occurred without formation of abnormally large grains in the matrix. Increasing the dislocation density in the BaTiO3 seed crystal resulted in enhanced growth of single crystals. These results were explained in terms of interface reaction‐controlled nucleation and growth, based on crystal growth theories.
Effect of Particle Size and Concentration on Microwave‐Absorbing Properties of CuxCo2−xY (x=0, 1) Hexaferrite Composites
Authors: Li Xiangcheng , Gong Rongzhou , Feng Zekun , Yan Junbing , Shen Xiang , He Huahui
Published: February 2006

Co2Y‐type hexaferrites (Ba2CuxCo2−xFe12O22, x=0,1) have been fabricated by the conventional ceramic process. The complex permittivity and permeability of Co2Y hexaferrite composites have been measured using a vector network analyzer in the frequency range of 2–18 GHz. The results show that Co2Y hexaferrite composites have a high permeability and a low permittivity. This can be adjusted by a CuO additive and particle sizes. The reflection loss (RL) values of Co2Y hexaferrite composites backed with a conducting plate indicate that the composites possess good microwave‐absorbing properties. The minimum RL value of the composites was below −30 dB. The microwave‐absorbing materials with 10 GHz (8 GHz) bandwidth for attenuation of 5 dB (10 dB) can be achieved.
The Truman Doctrine: Containing Communism and Modernity
Authors: MERRILL DENNIS
Published: February 2006

This article examines the enunciation in March 1947 of the Truman Doctrine. The doctrine pledged the United States to “assist free peoples who are resisting attempted subjugation by armed minorities or by outside pressures.” Although the statement was initially aimed at winning congressional support for U.S. aid to Greece and Turkey, where the administration feared Soviet penetration, it ultimately underpinned U.S. Cold War policy throughout Europe and around the world. Moreover, the doctrine addressed a broader cultural insecurity regarding modern life in a globalized world. The administration's concern over communism's domino effect, its media‐sensitive presentation of the doctrine, and its mobilization of U.S. economic and military power to modernize unstable regions marked the advent of a modern U.S. foreign policy. In its maintenance of military preponderance, its nation‐building activities, its organization of alliances, its advocacy of “regime change,” and its resort at times to limited war against armed insurgencies, the Truman Doctrine foreshadowed the contemporary Bush Doctrine against international terrorism.
The Reagan Doctrine: Principle, Pragmatism, and Policy
Authors: PACH CHESTER
Published: February 2006

Ronald Reagan never planned to announce what became known as the Reagan Doctrine. Two months after Reagan declared in his 1985 State of the Union address that the United States should not “break faith” with anti‐Communist resistance groups, a political commentator called that declaration the Reagan Doctrine. The Reagan administration's policies toward anti‐Communist resistance groups varied far more than the term “Reagan Doctrine” suggested. This article shows that differences in local conditions and U.S. security interests as well as sharp disputes between administration policy makers produced divergent policies toward “freedom fighters” in Afghanistan, Nicaragua, Mozambique, Angola, and Cambodia during Reagan's presidency.
The Contemporary Presidency: The Sixth Year Curse
Authors: SHOGAN COLLEEN J.
Published: February 2006

There is a prevailing pattern of ill‐fated events that routinely unfold during a president's sixth consecutive year in the White House. Republican strategist Kevin Phillips called the tendency of the president's party to lose seats in a midterm election the “sixth year itch.” The term is actually an understatement. Due to the fact that sixth years are typically filled with scandals, economic depressions, and weakened political coalitions, it is more accurate to refer to this phenomenon as a full‐fledged “curse.” A historical analysis of the past seven reelected presidents reveals the problems faced in sixth years of office. Although every president since Ulysses S. Grant has suffered from some version of the “sixth year curse,” its negative effects vary in intensity. The article concludes with an evaluation of George W. Bush's leadership and cautiously predicts how he will attempt to handle the difficulties and challenges of his administration's sixth year.
The crystal structure of a plant 2C‐methyl‐D‐erythritol 4‐phosphate cytidylyltransferase exhibits a distinct quaternary structure compared to bacterial homologues and a possible role in feedback regulation for cytidine monophosphate
Authors: Gabrielsen Mads , Kaiser Johannes , Rohdich Felix , Eisenreich Wolfgang , Laupitz Ralf , Bacher Adelbert , Bond Charles S. , Hunter William N.
Published: February 2006

The homodimeric 2C‐methyl‐d‐erythritol 4‐phosphate cytidylyltransferase contributes to the nonmevalonate pathway of isoprenoid biosynthesis. The crystal structure of the catalytic domain of the recombinant enzyme derived from the plant Arabidopsis thaliana has been solved by molecular replacement and refined to 2.0 Å resolution. The structure contains cytidine monophosphate bound in the active site, a ligand that has been acquired from the bacterial expression system, and this observation suggests a mechanism for feedback regulation of enzyme activity. Comparisons with bacterial enzyme structures, in particular the enzyme from Escherichia coli, indicate that whilst individual subunits overlay well, the arrangement of subunits in each functional dimer is different. That distinct quaternary structures are available, in conjunction with the observation that the protein structure contains localized areas of disorder, suggests that conformational flexibility may contribute to the function of this enzyme.
An ecological approach to study the physical and chemical effects of rye cover crop residues on Amaranthus retroflexus, Echinochloa crus‐galli and maize
Authors: Moonen A.C. , Bàrberi P.
Published: February 2006

Weeds can be suppressed in the field by cover crop residues, extracts of which have been demonstrated to exert chemical inhibition of crop and weed germination and early growth in bioassays. In this study, two complementary bioassays were developed with soil and mulch material originating from a long‐term maize–cover crop experiment to determine the relative physical and chemical effect of rye cover crop residues on weed and maize germination and early growth. This was compared with the effect exerted by residue material from the natural vegetation that developed in the crop stubble during the winter before maize sowing. Germination percentage and early growth of maize and two maize weeds, Amaranthus retroflexus and Echinochloa crus‐galli, were assessed in a seed incubator in tilled (green manured) and nontilled (surface mulched) soil, with and without N fertilisation, at various dates after cover crop destruction. Responses were compared to those of the same species in a standard soil without mulch or with an inert poplar mulch. A second bioassay was set up in a glasshouse to determine the effect of different quantities of fresh residue material and additional N fertilisation on emergence speed and percentage and on plant vigour during the first 22 days after cover crop destruction. These results were compared with no‐mulch controls and poplar mulch controls. Results of these trials were compared with weed density and biomass that developed in the maize crop sown after cover crop destruction. Soil and mulch chemical and biological properties were determined for material collected in the field at different times after cover crop destruction. Chemical properties of the mulch differed only occasionally between the treatments, but variation in cover crop biomass production led to significantly different soil chemical properties. Although soil total phenolic acid content did not always correlate to weed and maize germination and early growth inhibition, soil microbial activity did. In suboptimal conditions, as is often the case in the field, plant residue material exerted both a physical and a chemical effect on maize and weed emergence and early growth. Nitrogen fertilisation and application timing can give the maize crop a competitive advantage with respect to the weeds, but the final response and the practical consequences depended largely on the weed species involved.
CHROMATOGRAPHIC SEPARATION AT A PREPARATIVE SCALE OF EGG WHITE OVALBUMIN AND ITS APPLICATION IN THE ELABORATION OF YOGURT MOUSSE
Authors: PAREDES B. , GONZÁLEZ S. , RENDUELES M. , DÍAZ M.
Published: February 2006

Egg white contains high‐quality proteins. Some processes using eggs produce egg white as by‐product. These egg white proteins may be recovered for use as additive in food products. In the first part of this study, a new polymeric material was developed and used in the chromatographic separation of ovalbumin at preparative scale. Ovalbumin is the major component of egg white and thus, it has the greatest weight in terms of its functional effects. An application of the purified ovalbumin was subsequently studied in the elaboration of yogurt mousse. The results obtained showed that the poly(glycidil methacrylate‐co‐ethylene dimethacrylate) resin that was manufactured enabled the separation of ovalbumin with good efficiency. This study also showed that the formulation obtained from the yogurt mousse with ovalbumin had a greater yield in volume than the commercial product used as a benchmark, improving the majority of its organoleptic qualities without appreciably affecting its stability and organoleptic properties.
MENTORS AND CRIMINAL ACHIEVEMENT*
Authors: MORSELLI CARLO , TREMBLAY PIERRE , MCCARTHY BILL
Published: February 2006

Much of the research focusing on conventional occupations concludes that mentored individuals are more successful in their careers than those who are not mentored. Early research in criminology made a similar claim. Yet contemporary criminology has all but ignored mentors. We investigate this oversight, drawing on Sutherland's insights on tutelage and criminal maturation and incorporating ideas on human and social capital. We argue that mentors play a key role in their protégés' criminal achievements and examine this hypothesis with data from a recent survey of incarcerated adult male offenders in the Canadian province of Quebec. In this sample, a substantial proportion of respondents reported the presence of an influential individual in their lives who introduced them to a criminal milieu and whom they explicitly regarded as a mentor. After studying the attributes of offenders and their mentors, we develop a causal framework that positions criminal mentor presence within a pathway that leads to greater benefits and lower costs from crime.
THE IMPACT OF RACIALLY INCLUSIVE SCHOOLING ON ADULT INCARCERATION RATES AMONG U.S. COHORTS OF AFRICAN AMERICANS AND WHITES SINCE 1930*
Authors: LAFREE GARY , ARUM RICHARD
Published: February 2006

Despite the substantial body of research on the psychological and social effects of racial segregation in schools on African Americans, few studies have considered the possibility that more racially inclusive schools might reduce the risk of extremely negative adult life experiences such as incarceration. Yet such a connection is made plausible by research linking black racial isolation in schools to variables that are often associated with incarceration rates, including concentrated poverty, and low educational and occupational aspirations and attainment. In this paper, we apply methods first developed by labor economists to assess the impact of racial inclusiveness in schools on individual incarceration rates for 5‐year cohorts of African Americans and whites born since 1930. We find strong support for the conclusion that blacks educated in states where a higher proportion of their classmates were white experienced significantly lower incarceration rates as adults. Moreover, our analysis suggests that the effects of racial inclusiveness on black incarceration rates have grown stronger over time. These longitudinal effects are consistent with the argument that the educational climate of predominantly black schools has deteriorated in more recent decades.
BUSINESS CYCLES AND STREET CRIME
Authors: ARVANITES THOMAS M. , DEFINA ROBERT H.
Published: February 2006

This study examines the influence of business cycle fluctuations on street crime in the conceptual framework of Cantor and Land's(1985) seminal work distinguishing between opportunity and motivation effects. The analysis contributes to the literature three ways. First, we use cross‐section/time series data, which has several important advantages over simple time‐series or cross‐section data of previous studies. Second, it introduces a new and broader measure of business cycle conditions, one that more faithfully captures the logic of Cantor and Land's framework than previous measures do. Third, it focuses on the large decline in street crime of the 1990s, a central issue facing criminologists. Statistical models indicate that the strong economy of the 1990s reduced all four index property crimes and robbery by reducing criminal motivation. Business cycle growth produced no significant opportunity effect for any of the crimes studied.
PREDICTING WHO REOFFENDS: THE NEGLECTED ROLE OF NEIGHBORHOOD CONTEXT IN RECIDIVISM STUDIES*
Authors: KUBRIN CHARIS E. , STEWART ERIC A.
Published: February 2006

Prior studies of recidivism have focused almost exclusively on individual‐level characteristics of offenders and their offenses to explore the correlates of reoffending. Notably absent from these studies are measures reflecting the neighborhood contexts in which individuals live. The current research addresses this shortcoming. Using data on a sample of ex‐offenders in Multnomah County, Oregon (Portland and surrounding area) in conjunction with 2000 census data, we answer two questions. First, which individual‐level factors influence rates of recidivism? Second, to what extent does neighborhood socioeconomic status account for variation in the reoffending behavior of ex‐prisoners that is not explained by their individual‐level characteristics? We find that those who return to disadvantaged neighborhoods recidivate at a greater rate while those who return to resource rich or affluent communities recidivate at a lesser rate, controlling for individual‐level factors.
RETHINKING THE “NORM” OF OFFENDER GENERALITY: INVESTIGATING SPECIALIZATION IN THE SHORT‐TERM
Authors: SULLIVAN CHRISTOPHER J. , MCGLOIN JEAN MARIE , PRATT TRAVIS C. , PIQUERO ALEX R.
Published: February 2006

The life‐course approach to criminal career research has devoted a good deal of attention to the generality or specialization of offending behavior. Typically, extant research demonstrates versatility on the part of offenders, yet such findings could be attributable, at least in part, to time and measurement aggregation bias. This work uses a temporally disaggregated and individualized measure of diversity in offending to determine whether the previous findings of generality hold up to shifts in methodology. Using data from a sample of serious felons, results indicated that the magnitude of specialization is greater than in prior studies. Regression results indicated that certain demographic and local life‐circumstance variables are related to the extent of diversity. Theoretical and methodological implications are identified and discussed.
Applying the School Health Index to a Nationally Representative Sample of Schools
Authors: Brener Nancy D. , Pejavara Anu , Barrios Lisa C. , Crossett Linda , Lee Sarah M. , McKenna Mary , Michael Shannon , Wechsler Howell
Published: February 2006

Abstract: The School Health Index (SHI) is a self‐assessment and planning tool that helps individual schools identify the strengths and weaknesses of their health policies and programs. To determine the percentage of US schools meeting the recommendations in the SHI, the present study analyzed data from the School Health Policies and Programs Study (SHPPS) 2000. The SHPPS 2000 data were collected through computer‐assisted personal interviews with faculty and staff in a nationally representative sample of schools. The SHPPS 2000 questions were then matched to SHI items to calculate the percentage of schools meeting the recommendations in 4 areas: school health and safety policies and environment, health education, physical education and other physical activity programs, and nutrition services. Although schools nationwide are meeting a few SHI items in each of these areas, few schools are addressing the entire breadth of items. A more coordinated approach to school health would help schools reinforce health messages. (J Sch Health. 2006;76(2):57‐66)
Cocaine and the AP‐1 Transcription Factor Complex
Authors: HOPE BRUCE T.
Published: February 2006

ABSTRACT: Cocaine addiction in humans develops gradually with repeated administrations and persists long after cocaine has cleared the body. The mechanisms underlying this persistent form of neuroplasticity are not understood and can involve both structural and biochemical mechanisms. The long time course for cocaine addiction in humans and for development of cocaine self‐administration in animal models suggests the involvement of alterations in gene expression leading to altered signaling in the brain. In the striatum (Str) and nucleus accumbens (NAc) of rats, pretreatment with repeated cocaine administrations downregulates the induction of various immediate early genes (IEGs) by a subsequent acute challenge with cocaine. Some of these downregulated IEGs encode Fos‐related components of the activator protein‐1 (AP‐1) complex, which is likely to regulate a number of genes important for neuronal function. Interestingly, repeated cocaine administration induces novel delta FosB‐related proteins (called chronic Fos‐related antigens (Fras)) in the NAc and Str that replace the downregulated isoforms of Fos. Unlike the acutely induced, short‐lasting isoforms of Fos and FosB, the chronic Fras persist long after the last cocaine administration. The known form of delta FosB per se lacks the domain required to activate transcription. If the chronic Fras are similar in structure to delta FosB, then the induction of chronic Fras likely leads to a blockade of AP‐1‐dependent transcription resulting in altered gene expression. We are presently purifying the chronic Fras to obtain amino acid sequence in order to directly examine our hypothesis about the effects of repeated cocaine administration on AP‐1‐dependent transcription and gene expression in the brain.
The Serotonergic System Modulates the Cocaine‐Induced Expression of the Immediate Early Genes egr‐1 and c‐fos in Rat Brain
Authors: HUMBLOT N. , THIRIET N. , GOBAILLE S. , AUNIS D. , ZWILLER J.
Published: February 2006

ABSTRACT: Transcription regulatory factors are rapidly induced in brain by a wide variety of stimuli and may be important in coordinating changes in gene expression underlying neuronal plasticity. Using in situ hybridization, we found that acute cocaine administration (20 mg/kg, intraperitoneally (i.p.)) produced a robust induction of both c‐fos and egr‐1 immediate early genes. Egr‐1 messenger RNA induction was highest in the caudate putamen and in the shell of the nucleus accumbens. No significant induction was noticed after injection of fluoxetine, a selective inhibitor of serotonin uptake. Cocaine‐induced egr‐1 and c‐fos expression was substantially reduced in the brain areas from rats in which the serotonergic projections were lesioned by injection of the neurotoxin 5,7‐dihydroxytryptamine, and in rats that have been injected with tropisetron, an antagonist of the 5‐hydroxytryptamine (5‐HT3) receptor. Conversely, the 5‐HT3 receptor agonist 2‐methyl‐serotonin induced the expression of these early genes in structures including the caudate putamen and nucleus accumbens.
Cell Death Mediated by Amino Acid Transmitter Receptors in Human Alcoholic Brain Damage: Conflicts in the Evidencea
Authors: DODD P. R. , LEWOHL J. M.
Published: February 2006

ABSTRACT: Human alcoholics have reduced neuronal counts in certain brain regions, such as superior frontal cortex (SFC), where the form and quantity of synaptic γ‐aminobutyric acid type A (GABAA) receptor sites are atypical. We measured the expression of GABAA receptor isoform mRNA and protein, since GABAA receptor pharmacology is strongly influenced by its subunit composition. Cortex samples were obtained at autopsy; whole‐tissue extracts were assayed for mRNA by quantitative reverse transcriptase polymerase chain reaction (RT‐PCR), while synaptic membranes were studied for both GABAA receptor pharmacology and subunit protein levels by Western blots with isoform‐specific antibodies. Although α1 and α3 mRNA species were more strongly expressed in alcoholics irrespective of cirrhosis than in controls, α1 protein differed little between case groups, and α3 protein showed some complex variations. Differences in GABAA pharmacology conformed more closely with differences in protein levels than with altered mRNA expression.
Methamphetamine‐Induced Changes in Antioxidant Enzymes and Lipid Peroxidation in Copper/Zinc‐Superoxide Dismutase Transgenic Mice
Authors: JAYANTHI SUBRAMANIAM , LADENHEIM BRUCE , CADET JEAN LUD
Published: February 2006

ABSTRACT:The present study was conducted to investigate the effects of methamphetamine (METH)‐induced toxicity on brain cortical and striatal antioxidant defense systems. Because METH‐induced toxicity is attenuated in copper/zinc‐superoxide dismutase transgenic (Cu/Zn‐SOD‐Tg) mice, we sought to determine if METH had differential effect on antioxidant enzymes on these mice in comparison to non‐Tg mice. METH (4 × 10 mg/kg) induced a significant decrease in Cu/Zn‐SOD activity in the cortical region without altering striatal enzymatic activity in non‐Tg mice; whereas homozygous SOD‐Tg mice showed a significant increase in the striatum. In addition, METH caused decrease in catalase (CAT) activity in the striatum of non‐Tg mice and significant increase in the cortex of homozygous SOD‐Tg mice. METH also induced decreases in glutathione peroxidase (GSH‐Px) in both cortical and striatal regions of non‐Tg mice and in the striatum of heterozygous SOD‐Tg mice. Lipid peroxidation was increased in both cortices and striata of non‐Tg and heterozygous SOD‐Tg mice, whereas the homozygous SOD‐Tg mice were not affected. These results are discussed in terms of their substantiation of a role for oxygen‐based radicals in METH‐induced toxicity in rodents.
Methamphetamine‐Induced Rapid and Reversible Reduction in the Activities of Tryptophan Hydroxylase and Dopamine Transporters: Oxidative Consequences?a
Authors: HANSON GLEN R. , GIBB JAMES W. , METZGER RYAN R. , KOKOSHKA JERRY M. , FLECKENSTEIN ANNETTE E.
Published: February 2006

ABSTRACT:Treatment with high doses of methamphetamine (METH) results in dramatic changes in extrapyramidal monoaminergic systems. Elevated concentrations of extracellular dopamine (DA), caused by METH administration, are thought to contribute to these effects due to the oxidative potential of this reactive catecholamine. According to this hypothesis monoaminergic cellular elements, which are vulnerable to oxidative modification, may be especially sensitive to high‐dose METH treatments. We confirmed this possibility by observing that both tryptophan hydroxylase (the synthesizing enzyme for serotonin) and the DA transporter, proteins particularly susceptible to oxidative modification, were rapidly (within 30 min), but reversibly (returned to control levels by 36 hr) inactivated by a single administration of METH. These findings suggest that there also may be other cellular elements similarly altered by METH treatment due to oxidative mechanisms.
Effects of 7‐Nitroindazole, an NOS Inhibitor on Methamphetamine‐Induced Dopaminergic and Serotonergic Neurotoxicity in Micea
Authors: ALI SYED F. , ITZHAK YOSSEF
Published: February 2006

ABSTRACT:Methamphetamine (METH) is one of the major drugs of abuse that is postulated to cause neurotoxicity by depleting dopamine (DA) and its metabolites, high‐affinity DA uptake sites, and the activity of tyrosine hydroxylase. The present study was undertaken to investigate whether the relatively selective, neuronal nitric oxide synthase (NOS) inhibitor, 7‐nitroindazole (7‐NI), protects against METH‐induced neurotoxicity. Male Swiss Webster mice received the following injections intraperitoneally (i.p.) 3 times (every 3 hr): (i) vehicle/saline, (ii) 7‐NI (25 mg/kg)/saline, (iii) vehicle/METH (5 mg/kg), and (iv) 7‐NI (25 mg/kg)/METH (5 mg/kg). On the second day, groups (i) and (iii) received two vehicle injections and groups (ii) and (iv) received two 7‐NI injections (25 mg/kg each). The administration of vehicle/METH resulted in 68, 44 and 55% decreases in the concentration of DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), respectively, and a 48% decrease in the number of [3H]mazindol binding sites in the striatum compared to control values. The treatment with 7‐NI (group iv) provided a full protection against the depletion of DA and its metabolites, and the loss of dopamine transporter binding sites. Multiple injection of METH caused a significant decrease in the concentration of serotonin (5‐HT) and its metabolite 5‐hydroxyindole acetic acid (5‐HIAA). Treatment with 7‐NI partially blocked the depletion of 5‐HT and completely blocked the reduction in 5‐HIAA levels. The administration of 7‐NI/saline (group ii) affected neither the tissue concentration of DA, 5‐HT and their metabolites (DOPAC, HVA and 5‐HIAA) nor the binding parameters of [3H]‐mazindol compared to control (vehicle/saline) values. 7‐NI had no significant effect on the animals' body temperature, and it did not affect METH‐induced hyperthermia. These findings indicate a role for nitric oxide in METH‐induced neurotoxicity and also suggest that blockage of NOS may be beneficial for the management of Parkinson's disease.
In Vivo Correlates of Central Serotonin Function after High‐Dose Fenfluramine Administration
Authors: BAUMANN MICHAEL H. , AYESTAS MARIO A. , ROTHMAN RICHARD B.
Published: February 2006

ABSTRACT: High doses of fenfluramine (FEN) are known to deplete central serotonin (5‐HT) in animals, but functional impairments associated with such 5‐HT depletion have been difficult to identify. In the present work, we examined neuroendocrine responsiveness in rats exposed to repeated high‐dose FEN treatment. Male rats fitted with indwelling catheters received FEN (20 mg/kg, subcutaneously, twice a day) or saline for 4 days. At 1 and 2 weeks after treatment, rats were challenged with intravenous FEN (1.5 & 3 mg/kg) or saline. Repeated blood samples were drawn, and plasma was assayed for prolactin and corticosterone by radioimmunoassay. Acute FEN challenge caused dose‐dependent elevations of plasma prolactin and corticosterone in all rats. However, the FEN‐induced hormone responses were significantly blunted (p <0.01) in rats previously exposed to FEN. The repeated FEN dosing regimen dramatically reduced (>50%) postmortem 5‐HT levels in the mediobasal hypothalamus, basolateral amygdala, and hippocampus, while the lateral hypothalamus was unaffected. These data suggest that high‐dose FEN causes alterations in central 5‐HT systems involved with pituitary hormone secretion. The relevance of the present data to the clinical use of FEN is unclear. Because the neuroendocrine challenge paradigm is able to identify functional 5‐HT deficits in rats, we propose that similar experiments should be performed in humans. Neuroendocrine challenge tests represent a reliable method to test the existence of FEN‐induced neurotoxicity in human patients undergoing long‐term FEN treatment.
Acute Effects of Dexfenfluramine (d‐FEN) and Methylenedioxymethamphetamine (MDMA) before and after Short‐Course, High‐Dose Treatment
Authors: FREDERICK DAVID L. , ALI SYED F. , GILLAM MICHAEL P. , GOSSETT JEFF , SLIKKER WILLIAM , PAULE MERLE G.
Published: February 2006

ABSTRACT: The acute behavioral effects of methylenedioxymethamphetamine (MDMA) and dexfenfluramine (d‐FEN) were assessed in six rhesus monkeys using performance in the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB); three additional animals served as controls for neurochemical endpoints. The OTB consists of five food‐reinforced tasks designed to model aspects of learning, short‐term memory and attention, time estimation, motivation, and color and position discrimination. Shortly after the acute effects of each drug were determined, three of the monkeys received a short‐course, high‐dose exposure (2×/day × 4 days, intramuscular (i.m.) injections) of MDMA (10 mg/kg), while three monkeys were exposed to an identical regimen of d‐FEN (5 mg/kg). Approximately one month later, the acute effects of each drug were again determined. In monkeys exposed to high‐dose d‐FEN, the sensitivities of the OTB tasks to acute disruption by either MDMA or d‐FEN were essentially unchanged. Conversely, monkeys treated with high‐dose MDMA were less sensitive to the acute behavioral effects of both drugs, although such an effect was seen more frequently for d‐FEN and was OTB task specific. Thus a residual behavioral tolerance to the acute behavioral effects of MDMA and d‐FEN was noted after high‐dose MDMA exposure, but not after high‐dose d‐FEN exposure. These findings are surprising, as similar neurochemical effects (i.e., significant decreases of ca. 50% in serotonin in frontal cortex and hippocampus) were observed in all monkeys approximately six months after short‐course, high‐dose MDMA or d‐FEN treatment.
Methamphetamine Treatment Affects Blood and Liver S‐Adenosylmethionine (SAM) in Mice: Correlation with Dopamine Depletion in the Striatuma
Authors: COONEY CRAIG A. , WISE CAROLYN K. , POIRIER LIONEL A. , ALI SYED F.
Published: February 2006

ABSTRACT: Methamphetamine (METH) is a major drug of abuse which causes neurotoxicity by depleting dopamine, its metabolites, high‐affinity dopamine uptake sites and tyrosine hydroxylase activity in the striatum. Dopamine depletion and reduced dopamine transit are associated with depression. S‐Adenosylmethionine (SAM) is the chief methyl donor used in dopamine and other neurotransmitter metabolism in mammals. Low SAM is associated with depression and other psychological and neurological disorders in humans. SAM is used to treat depression and some other neurological and psychiatric disorders. The present study was designed to determine if single or multiple doses of METH induce alterations in blood or liver SAM in mice and if these correlate with dopamine levels in the striatum. Adult male C57 mice were injected intraperitoneally with either single (1 × 40 mg/kg) or multiple (4 × 10 mg/kg) doses of METH. Animals were sacrificed at various intervals. A single injection of METH resulted in slightly higher blood SAM levels at 4 hr. Multiple doses of METH resulted in decreased hepatic and blood SAM levels at 72 hr. Blood SAM returned to control levels by 1 wk. Published work shows that dopamine levels increase hours after a single injection of METH, whereas dopamine decreases days after multiple injections of METH. These present data clearly demonstrate that METH dosing leads to significant alterations in liver and blood SAM and that these changes in SAM levels correlate with changes in striatal dopamine levels.
Calcium Channel Antagonist Isradipine Attenuates Cocaine‐Induced Motor Activity in Rats: Correlation with Brain Monoamine Levelsa
Authors: MILLS K. , ANSAH T. A. , ALI S. F. , SHOCKLEY D. C.
Published: February 2006

ABSTRACT: Cocaine is a widely abused psychomotor stimulant which acts in the central nervous system (CNS) by blocking the reuptake site. It has been estimated that between 30–60million people have abused cocaine in the United States. Unfortunately, an effective therapy for cocaine abuse is not available. The calcium channel antagonists (CCAs) are commonly used in the therapy of various cardiovascular diseases and are under investigation due to their potential in modulating calcium‐dependent neurotransmitter release. The purpose of this study was to evaluate the acute effect of isradipine on cocaine‐induced locomotor and stereotypic activity and correlate the changes in dopamine, serotonin and their metabolites‐dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5‐hydroxyindoleacetic acid (5‐HIAA)‐levels in the rat brain. Animals were pretreated intraperitoneally (i.p.) with vehicle or CCAs. After 30 minutes they were administered cocaine (20 mg/kg, i.p.). During this period, motor and stereotypic activity was monitored. In a separate experiment, animals were dosed as described above and were sacrificed by decapitation after the 30‐minute treatment period. The nucleus accumbens and caudate nucleus were dissected and analyzed for monoamines using a high‐performance liquid chromatography‐electrochemical detector (HPLC‐ECD). Isradipine (5mg/kg, i.p.) inhibited cocaine‐induced locomotor and stereotypic activity by 49% and 36%, respectively, as compared to controls. In the nucleus accumbens cocaine (20 mg/kg, i.p.) increased extracellular dopamine and serotonin levels by 28% and 73%, respectively, as compared to controls. Isradipine (5 mg/kg, i.p.) pretreatment decreased cocaine‐induced extracellular dopamine levels in the nucleus accumbens by 8% while decreasing serotonin levels by 9%. Cocaine (20 mg/kg, i.p.) produced increased levels of both extracellular dopamine and serotonin (9% and 4%, respectively) in the caudate nucleus. Isradipine (5 mg/kg, i.p.) pretreatment decreased cocaine (20 mg/kg i.p.)‐induced extracellular dopamine and serotonin levels in the caudate nucleus by 18% and 8%, respectively. These experiments suggest that a central mechanism may be involved in attenuation of cocaine‐induced motor behaviors by isradipine.
Influence of Concurrent Heroin and Cocaine Abuse on the Adrenergic and Serotonergic Systems in Mana
Authors: MERCADO T.R. A. , RIBEIRO C.A. FONTES , MORGADINHO T. , ABREU M.A. V.
Published: February 2006

ABSTRACT: Drugs of abuse interfere with the adrenergic activity at the periphery and the study of their effects In Vivo at this level may contribute to understand the central mechanisms of action. Free and sulfoconjugated catecholamines and serotonin (5‐hydroxytryptamine, 5‐HT) were measured by high‐performance liquid chromatography with electrochemical detection (HPLC‐ECD); plasma dopamine (DA)‐b‐hydroxylase (DBH) activity was determined by a HPLC technique. When compared with healthy subjects (n = 49), the results in drug addicts (n = 48) revealed: a) Significant increases in plasma DA (free and sulfoconjugated), epinephrine (Epi)‐ and norepinephrine (NE)‐sulfate levels; b) no significant differences in the levels of plasma free NE or Epi, serum and platelet 5‐HT. Concerning DBH activity, there was a tendency for an increase. In conclusion, since catecholamines are rapidly inactivated during blood circulation, the measurement of their sulfates may better reflect catecholamine turnover. The differences found may be interpreted as a reflection of the activation of adrenergic neurotransmission, principally as a consequence of catecholamine uptake blockade by cocaine. Finally, in our conditions the abuse of cocaine plus heroin does not significantly interfere with 5‐HT uptake by platelets.
Mechanisms of Antiaddictive Actions of Ibogainea
Authors: GLICK STANLEY D. , MAISONNEUVE ISABELLE M.
Published: February 2006

ABSTRACT: Ibogaine, an alkaloid extracted from Tabemanthe iboga, is being studied as a potential long‐acting treatment for oploid and stimulant abuse as well as for alcoholism and smoking. Studies in this laboratory have used animal models to characterize ibogaine's interactions with drugs of abuse, and to investigate the mechanisms responsible. Ibogaine, as well as its metabolite, noribogaine, can decrease both morphine and cocaine self‐administration for several days in some rats; shorter‐lasting effects appear to occur on ethanol and nicotine intake. Acutely, both ibogaine and noribogaine decrease extracellular levels of dopamine in the nucleus accumbens of the rat brain. Ibogaine pretreatment (19 hours beforehand) blocks morphine‐induced dopamine release and morphine‐induced locomotor hyperactivity while, in contrast, it enhances similar effects of stimulants (cocaine and amphetamine). Ibogaine pretreatment also blocks nicotine‐induced dopamine release. Both ibogaine and noribogaine bind to kappa opioid and N‐methyl‐d‐aspartate (NMDA) receptors and to serotonin uptake sites; ibogaine also binds to sigma‐2 and nicotinic receptors. The relative contributions of these actions are being assessed. Our ongoing studies in rats suggest that kappa agonist and NMDA antagonist actions contribute to ibogaine's effects on opioid and stimulant self‐administration, while the serotonergic actions may be more important for ibogaine‐induced decreases in alcohol intake. A nicotinic antagonist action may mediate ibogaine‐induced reduction of nicotine preferences in rats. A sigma‐2 action of ibogaine appears to mediate its neurotoxicity. Some effects of ibogaine (e.g., on morphine and cocaine self‐administration, morphine‐induced hyperactivity, cocaine‐induced increases in nucleus accumbens dopamine) are mimicked by a kappa agonist (U50,488) and/or a NMDA antagonist (MK‐801). Moreover, a combination of a kappa antagonist and a NMDA agonist will partially reverse several of ibogaine's effects. Ibogaine's long‐term effects may be mediated by slow release from fat tissue (where ibogaine is sequestered) and conversion to noribogaine. Different receptors, or combinations of receptors, may mediate interactions of ibogaine with different drugs of abuse.
Medication Development of Ibogaine as a Pharmacotherapy for Drug Dependencea
Authors: MASH DEBORAH C. , KOVERA CRAIG A. , BUCK BILLY E. , NORENBERG MICHAEL D. , SHAPSHAK PAUL , HEARN W. LEE , SANCHEZ‐RAMOS JUAN
Published: February 2006

ABSTRACT: The potential for deriving new psychotherapeutic medications from natural sources has led to renewed interest in rain forest plants as a source of lead compounds for the development of antiaddiction medications. Ibogaine is an indole alkaloid found in the roots of Tabernanthe iboga (Apocynaceae family), a rain forest shrub that is native to equatorial Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and in higher doses as a sacrament in religious rituals. Members of American and European addict self‐help groups have claimed that ibogaine promotes long‐term drug abstinence from addictive substances, including psychostimulants and cocaine. Anecdotal reports attest that a single dose of ibogaine eliminates withdrawal symptoms and reduces drug cravings for extended periods of time. The purported antiaddictive properties of ibogaine require rigorous validation in humans. We have initiated a rising tolerance study using single administration to assess the safety of ibogaine for the treatment of cocaine dependency. The primary objectives of the study are to determine safety, pharmacokinetics and dose effects, and to identify relevant parameters of efficacy in cocaine‐dependent patients. Pharmacokinetic and pharmacodynamic characteristics of ibogaine in humans are assessed by analyzing the concentration‐time data of ibogaine and its desmethyl metabolite (noribogaine) from the Phase I trial, and by conducting in vitro experiments to elucidate the specific disposition processes involved in the metabolism of both parent drug and metabolite. The development of clinical safety studies of ibogaine in humans will help to determine whether there is a rationale for conducting efficacy trials in the future.
Prenatal Cocaine Exposure Affects Postnatal Dopaminergic Systems in Various Regions of the Rat Braina
Authors: CHOI SUN‐JO , MAZZIO ELIZABETH , KOLTA MALAK G. , SOLIMAN KARAM F.A.
Published: February 2006

ABSTRACT: Pregnant female Sprague‐Dawley rats were injected once daily with either 40 mg/kg cocaine hydrochloride or 0.9% saline from gestation day (GD)12 to GD 21. On postnatal day (PND)30, male offspring were sacrificed and fresh tissue from the striatum (ST) and nucleus accumbens (NA) was dissected for assessment of dopamine (DA) receptor affinity, DA uptake and DA release. 10−6 M cocaine inhibited [3H]‐DA uptake in ST tissue, whereas 10−4 and 10−5 M cocaine inhibited [3H]‐DA uptake in the NA tissue of postnatally exposed cocaine offspring verses saline‐treated controls (p <0.05). DA release stimulated by 10−6 M amphetamine was significantly reduced in both the ST (p <0.001) and NA (p <0.01) of postnatal offspring exposed to cocaine in utero compared with saline controls. In utero cocaine exposure did not influence offspring ST or NA dopamine 1 (D1) dissociation constant (Kd) or receptor density (Bmax). However, the treatment group experienced a significant increase of binding affinity for the ST D2 receptor with no change in D2 Bmax. The treatment group also experienced no change in D2 receptor binding affinity or number of binding sites in the NA. These results show that in utero exposure to cocaine results in altered postnatal dopaminergic function.
Developmental Exposure to Methamphetamine: A Neonatal Model in the Rata
Authors: GOMES‐DA‐SILVA J. , SILVA M. C. , TAVARES M. A.
Published: February 2006

ABSTRACT: Taking into account that methamphetamine (MA) is a popular recreational drug among young adult women, i.e., in gestational age, the present model aims to assess the effects of its exposure during development. In this experimental model, MA effects are assessed in the rat during the first month of life, regarding both general growth parameters, and gross morphological effects in the retina as part of the evaluation of sensory systems. Experimental animals were obtained from 60‐day‐old nulliparous females. Litters were culled to 8 pups (4 males and 4 females, whenever possible), individually marked and weighed every two days. Experimental groups received 10 mg (+)methamphetamine hydrochloride kg body weight/day, subcutaneously, twice daily, from postnatal day (PND) 1 to the day before sacrifice; control groups received isovolumetric doses of saline, in the same protocol. Pups were weaned on PND 21. Groups were sacrificed on PND 5, 7 and 30. Animals exposed to MA presented increased percentage of retinal hemorrhages (18, 7 and 11% on PND 5, 7 and 30, respectively) compared to control groups (2% on PND 7, 0% on PND 5 and 30). On PND 30, the mean body weight of males exposed to MA was 75% of the mean weight of male controls, whereas for females, mean body weights were 70% of those of female controls. These findings support the view that developmental parameters in the rat are deleteriously affected by early exposure to MA.
The Ca2+‐ATPase of the Sarcoplasmic Reticulum in Skeletal and Cardiac Muscle: An Overview from the Very Beginning to More Recent Prospects
Authors: HASSELBACH WILHELM
Published: February 2006

ABSTRACT: The discovery of the ATP‐driven calcium pump in the sarcoplasmic reticulum membranes reaches back to the postwar (World War II) years and would not be possible without the generous support by the American scientific community. It was this community that in pre‐ and postwar years gave shelter to many European scientists, which in return stimulated scientific development in the United States. These pre‐ and postwar relations helped to establish the calcium pump as a physiologically relevant mechanism in all kinds of cells. The pump and its counterpart, the calcium release channel, proved to be controlled by various intrinsic mechanisms. Rising hydrogen concentrations as occuring in ischemic muscles switch off pump activity and counteract allosterically caffeine‐induced calcium release (CICR). Rising phosphate or the presence of other calcium‐precipitating anions, on the other hand, prevents pump inhibition by intraluminal calcium precipitation, which, simultaneously, can increase the quantity of releasable calcium. The inactivation of CICR by removing medium chloride must be considered as a hint of additional mechanisms by which calcium‐dependent activity regulation can be modified.
Sites of Regulatory Interaction between Calcium ATPases and Phospholambana
Authors: MacLENNAN DAVID H. , KIMURA YOSHIHIRO , TOYOFUKU TOSHIHIKO
Published: February 2006

ABSTRACT: Phospholamban (PLN) is a 52‐amino acid, integral membrane protein that interacts with and reversibly inhibits the activity of the cardiac sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). We have used site‐directed mutagenesis to analyze the sites of interaction between PLN and SERCA2a. First, we used chimera formation between SERCA2a and SERCA3 (which is weakly inhibited by PLN) to determine the interacting residues in cytoplasmic sequences of SERCA2 and PLN. Then, we expressed SERCA2a with the transmembrane sequence of PLN and demonstrated that the sites of inhibitory interaction are located in transmembrane sequences of the two proteins. We proposed that a four‐base circuit involving noninhibitory cytoplasmic and inhibitory transmembrane sites in PLN and SERCA2a best describes the interaction. Recently, we have used alanine‐scanning mutagenesis to show an asymmetric distribution of function in the transmembrane domain of PLN‐one helical face interacts with PLN molecules in a pentamer, and the other interacts with SERCA2a. Gain of function by mutation of PLN‐interacting residues indicates that the inhibitory species of PLN is a monomer. Thus regulatory steps include PLN dissociation, PLN/SERCA2a inhibitory association, and PLN/SERCA2a dissociation induced by phosphorylation of PLN (in the noninhibitory cytoplasmic domain) or by binding of Ca2+ by SERCA2a (in the inhibitory transmembrane domain).