bluuebunny/crossref_metadata_2025 huggingface dataset:
Recombinant Human Interleukin-3 Induces Extramedullary Hematopoiesis at Subcutaneous Injection Sites in Cynomolgus Monkeys
Authors: Khan Kanwar Nasir M. , Kats Alex A. , Fouant Monique M. , Snook Sandra S. , Mckearn John P. , Alden Carl L. , Smith Peter F.
Published: April 2009

Parenteral administration of recombinant hematopoietic growth factors has been sporadically associated with cutaneous complications, including injection site reactions in humans and nonhuman primates. In this study, subcutaneous injection sites were evaluated from 12 cynomolgus monkeys administered a recombinant human interleukin-3 (rhIL-3) at dose levels of 0, 70, or 700 μg/kg daily for 18 days. Monkeys administered rhIL-3 developed small (0.5-1-cm-diameter), firm nodules at the subcutaneous injection sites. Histologically, these nodules from 4 of 8 rhIL-3-treated monkeys contained trilineage extramedullary hematopoiesis (EMH) represented by precursors of myeloid, erythroid, and megakaryocytic series cells. The lineage of hematopoietic cells was confirmed by histochemical and immunohistochemical methods. Hematopoietic cells of myeloid and megakaryocytic lineages were more common than erythroid cells. Of myeloid cells, immature eosinophils were more common, which usually formed small sheets or clusters in the panniculus and deep dermis. This report describes, for the first time, the occurrence of cutaneous EMH at the injection sites of recombinant hematopoietic growth factors, which should be differentiated from inflammation. We believe the cutaneous EMH was the exaggerated pharmacologic effect of rhIL-3.
Characterization of Coronary Arterial Lesions in the Dog Following Administration of SK&F 95654, a Phosphodiesterase III Inhibitor
Authors: Joseph E.C. , Jones H.B. , Kerns W.D.
Published: April 2009

Drugs that inhibit the low-Km, cGMP-inhibitable form of phosphodiesterase III (PDE III) are associated with arterial lesions in the extramural coronary arteries of dogs following oral and intravenous administration at high doses. Acute coronary arterial lesions have been investigated following administration to the dog of SK&F 95654, a potent PDE III inhibitor, and the progression of the lesion defined. Groups of 3 male beagle dogs received a single 2-hr infusion of SK&F 95654 at 8 mg/kg/hr and the characteristics of the coronary arterial lesions were evaluated at 1, 3, 10, and 34 days postdosing by light, scanning, and transmission electron microscopy. At 24 hr postdosing, the arterial lesion was characterized by segmental or circumferential necrosis of medial smooth muscle cells and hemorrhage; adventitial hemorrhage was also noted, particularly in the right atrial artery. Ultrastructural evaluation showed extensive medial necrosis, characterized by loss of smooth muscle cells and their replacement by cellular debris with ingress of erythrocytes, platelets, and inflammatory cells into the media. Associated with medial changes, significant endothelial effects were observed consisting of widening of intercellular boundaries, loss of normal elongated cellular appearance, and the attachment of numerous leukocytes and platelets. During the 10-34-day postdosing period, substantial repair of the arterial lesions occurred such that by day 34 all sections of extramural coronary artery were normal. The lesions induced in the dog are consistent with a hemodynamic effect induced by the pharmacological action of SK&F 95654.
Comparative Evaluation of Ultrastructural Changes in Articular Cartilage of Ofioxacin-Treated and Magnesium-Deficient Immature Rats
Authors: Shakibaei Mehdi , Kociok Katja , Förster Christian , Vormann Jürgen , Günther Theodor , Stahlmann Ralf , Merker Hans-Joachim
Published: April 2009

Ultrastructural changes in immature articular cartilage were studied after treatment of 5-wk-old rats with ofloxacin—a fluoroquinolone—and in magnesium deficiency. Magnesium deficiency was induced by feeding a magnesium-deficient diet for 9 days; the condition was confirmed by measuring the concentrations of the mineral in plasma, bone, and cartilage samples of the animals by atomic absorption spectrophotometry. Oral administration of single doses of 600 or 1,200 mg ofloxacin/kg body weight and magnesium deficiency were sufficient to induce gross structural cartilage defects. Alterations observed on the ultrastructural level showed striking similarities in magnesium-deficient rats and in rats treated with single doses of 600 mg ofloxacin/kg body weight. Typical observations were (a) bundle-shaped, electron-dense aggregates on the surface and in the cytoplasm of chondrocytes, (b) detachment of the cell membrane from the matrix and necrotic chondrocytes, (c) reduction of the extracellular matrix, and (d) swelling of cell organelles such as mitochondria. These findings further substantiate the histological finding that quinolone treatment and a dietarily induced magnesium-deficiency induce indistinguishable pathological conditions in immature joint cartilage, and they suggest that quinolone-induced arthropathy is probably caused by a reduction of functionally available magnesium (ionized Mg2+) in cartilage (42). Furthermore, they provide a basis for aimed studies with human cartilage samples from quinolone-treated patients that might be available postmortally or after hip replacement surgery.
Neoplastic Response in Japanese Medaka and Channel Catfish Exposed to N-Methyl-N'-Nitro-N-Nitrosoguanidine*1
Authors: Chen Hans C. , Pan In J. , Tu Wen J. , Lin Wen H. , Hong Chou C. , Brittelli Mavis R.
Published: April 2009

Japanese medaka (Oryzias latipes) and channel catfish (Ictalurus punctatus) were investigated for carcinogenic response following a 28-day, 3X/wk pulse exposure to N-methyl- N'-nitro- N-nitrosoguanidine (MNNG). Five-wk-old medaka were exposed at concentrations of 0, 0.5, and 1.0 mg/L, and 5-mo-old catfish at concentrations of 0, 0.1, and 0.5 mg/L. In medaka, a total of 19 tumors including 2 branchioblastomas, 6 thyroid follicular adenomas and 1 adenocarcinoma, and 11 subcutaneous fibrosarcomas were observed in 16 of 96 MNNG-exposed fish. In catfish, a total of 37 tumors including 4 squamous cell carcinomas and 16 papillomas, 3 lipomas, 1 fibroma, 1 osteosarcoma, 4 branchioblastomas, 6 thymic epithelial tumors, and 2 generalized lymphosarcomas were observed in 34 of 172 MNNG-exposed fish. The induction of neoplasms in medaka was primarily in the gill, thyroid, and subcutis of the cervical and trunk regions, whereas in catfish skin, thymus, oro-pharynx, and hemopoietic tissues were also commonly affected. In both species, the neoplastic response was considered to be related to direct exposure of the tissues to MNNG. Some of these tumors have not been reported in the literature in either natural or experimental fish. The results also suggest species-specific differences in carcinogenic response following MNNG exposure.
The Retardation of Aging by Caloric Restriction: Studies in Rodents and Primates
Authors: Weindruch Richard
Published: April 2009

Caloric restriction (CR), which has been investigated by gerontologists for more than 60 yr, provides the only intervention tested to date in mammals (typically mice and rats) that repeatedly and strongly increases maximum life span while retarding the appearance of age-associated pathologic and biologic changes. Although the large majority of rodent studies have initiated CR early in life (1-3 mo of age), CR started in midadulthood (at 12 mo) also extends maximum life span in mice. Two main questions now face gerontologists investigating CR. By what mechanisms does CR retard aging and disease processes in rodents? There is evidence to suggest that age-associated increases in oxidative damage may represent a primary aging process that is attenuated by CR. Will CR exert similar actions in primates? Studies in rhesus monkeys subjected to CR and limited human epidemiological data support the notion of human translatability. However, no matter what the answers are to these questions, the prolongation of the health span and life span of rodents by CR has major implications for many disciplines, including toxicologic pathology, and raises important questions about the desirability of ad libitum feeding.
The Need for Policy and Risk Analysis— The Department of Energy Experience
Authors: Henry Carol J. , Moses Marina S. , Henderson Rogene
Published: April 2009

Reduction of major risks to the public and workers is a top priority of all federal agencies. Given current and future budget realities, agencies cannot attempt to address all risks simultaneously nor to address certain relatively lower risk activities as rapidly as some would like. The assumptions and judgments inherent in using risk analysis in the absence of data, however, have to be clearly stated. What is needed is an integrated risk assessment and management process that meets the current and future needs of the government, as well as of stakeholders. Yet there have been many questions raised regarding risk assessment: our ability to define the risks on a specific substance or site basis and in a systematic way; methodology questions about identifying and assessing diverse hazards and risks as well as uncertainties in the estimates, data gaps, and concern over the quality of information; and the fact that "who" performs the risk assessment matters. Knowing these controversies surrounding risk and the use of risk-based approach, the Department of Energy (DOE) requested the National Academy of Sciences-National Research Council to determine whether and how risk and risk-based decisions could be incorporated into a major federal program, the DOE's Office of Environmental Management. The report identified the major obstacles, issues, and barriers to implementing a risk-based management approach. The report concluded that the use of risk-based approach could help compare outcomes, build consensus, and gain early public involvement to include cultural, socioeconomic, historical, and religious values, if its purposes and limitations are well defined. A status of the DOE's ability to implement the recommendations presented in the report on the use of risk assessment in a major federal program and the adoption of principles for using risk analysis will be given.
Selected Lesions of Dioxin in Laboratory Rodents
Authors: Mann Peter C.
Published: April 2009

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) has been the subject of intensive investigations in laboratory animals during the last 2 decades. Toxicity studies have been conducted in several species of rodents and include several carcinogenicity studies as well as numerous mechanistic studies initiated to elucidate dioxin's mode of action, as both a carcinogen and a toxicant. Hepatotoxicity is a primary effect of dioxin. There has been an increase in hepatocellular tumors reported in both rats and mice exposed to dioxin. In addition to neoplastic changes, dioxin causes a spectrum of toxic changes in the liver. Additional neoplastic changes include subcutaneous fibrosarcomas and thyroid follicular cell tumors in both rats and mice and histiocytic sarcomas in mice. Dioxin causes devlopmental effects in the palate and kidney of mice. Changes in the female reproductive tract include ovarian atrophy, sertoliform hyperplasia, and Sertoli cell tumors. Dosing in utero results in gross malformations of the external genetalia. The effects of dioxin on the rodent model of endometriosis are described. In males, there are lowered sperm counts in the epididymis and minor testicular effects following gestational administration of dioxin. Both estrogenic and antiestrogenic-like effects have been ascribed to dioxin in laboratory animals; these activities are the result of dioxin-specific pathways resulting in the same end points as classic reproductive toxicants.
An Ultrastructural Histochemistry and Light Microscopy Study of the Early Development of Renal Proximal Tubular Vacuolation after a Single Administration of the Contrast Enhancement Medium "Iotrolan"
Authors: Rees Jeremy A. , Old Sally L. , Rowlands Phil C.
Published: April 2009

The time course of contrast media (CM)-induced renal proximal tubular vacuolation was investigated in rats by light microscopy, transmission electron microscopy (TEM), and ultrastructural histochemistry for acid phosphatase activity. Young adult male rats were treated with a single dose of 3.0 g I/kg Iotrolan (Isovist® 300 mg I/ml) and sacrificed at 0 min, 5-min, 15-min, 2-hr, and 24-hr intervals. Light microscopy of vibratome sections of freshly excised tissue and of cryostat and paraffin sections was also performed to allow comparison of the appearance of the vacuoles in the fresh state with light and electron microscopy. The sequence of events seen to occur can be summarized as follows.

CM-induced vacuolation occurred at a low level as soon as 5 min after compound administration. The vacuolation was observed by TEM but could not be detected by light microscopy. This was followed by an increase in size and numbers of vacuoles up to the 24-hr timepoint with a sequential increase in the staining for acid phosphatase activity of the vacuoles, most marked at the 24-hr timepoint. At timepoints less than 24 hr there appeared to be no marked increase in the normal complement of lysosomes or in the components of the Golgi-endoplasmic reticulum-lysosome pathway. At 24 hr, the vast majority, but not all, of the CM-induced vacuoles were positive for acid phosphatase activity. The intensity of staining varied, and there was evidence of fusion of small lysosomes with CM-induced vacuoles. These results suggest that formation of CM-induced vacuoles is a 2-stage process, following a normal pathway for the handling of endogenous and exogenous substances.
Hypersegmented Megakaryocytes and Megakaryocytes with Multiple Separate Nuclei in Dogs Treated with PNU-100592, an Oxazolidinone Antibiotic
Authors: Lund John E. , Brown Patricia K.
Published: April 2009

Megakaryocytes in normal dogs have a variety of nuclear forms. The most common variations are a single large multilobed nucleus or a segmented nucleus consisting of irregular nuclear lobes joined by strands of chromatin. Exaggerated segmentation (hypersegmentation) of the nucleus occurs in a small number of megakaryocytes. Megakaryocytes with multiple separate nuclei are infrequently observed. In a 1-mo toxicology study in young adult beagle dogs with PNU-100592, a new oxazolidinone antibacterial agent, a large increase in the number of megakaryocytes with hypersegmented nuclei and multiple separate nuclei was observed. The group mean platelet count was slightly decreased for most PNU-100592-treated groups. Siderocytes were observed on peripheral blood smears, and ring sideroblasts were present on bone marrow smears. Minimal to mild toxicologic lesions were observed in the large intestine, rectum, kidneys, liver, and testes, primarily in the high-dose group. PNU-100592 may be useful in the study of the regulation of endomitosis during megakaryocytopoiesis in the dog.
Toxicity of Subacute Intravenous Manganese Chloride Administration in Beagle Dogs
Authors: Khan K. Nasir , Andress James M. , Smith Peter F.
Published: April 2009

Manganese (Mn), a naturally occurring essential trace element, is currently being used as a metal complex for pharmaceutical and magnetic resonance imaging agents. Despite its popularity in these practices, minimal attention has focused on possible toxicity of released free Mn ions, which could occur if these agents decomplexed. There is especially limited information available regarding acute toxicity of Mn in dogs. In this study, we performed an in-depth evaluation of acute toxicologic potential of manganese chloride (MnCl2) when administered as a 4-hr/day intravenous infusion to male beagle dogs. The dose of MnCl2 used (16 mg/kg/day) was equivalent to approximately 3-5 times the daily dose of Mn typically administered in some of the Mn-complexed agents. All routine toxicologic endpoints were evaluated, including cardiovascular parameters. This dosing regimen resulted in the death or moribund sacrifice of all the animals within 4 days of initiation of treatment. Clinical evidence of toxicity included loss of appetite, reduction in blood pressure with reflex tachycardia, and a marked increase in liver enzymes, beginning with the first dose and increasing in severity with successive doses. Gross and histopathologic evaluations confirmed severe hepatotoxicity, which was characterized by massive hepatocellular necrosis, periportal hemorrhages, and mild biliary epithelial hyperplasia. These results indicate that acute treatment of beagle dogs with MnCl2 causes severe hepatotoxicity and hypotension with reflex tachycardia and suggest that dogs are very sensitive to toxic effects of Mn.
Histologic Lesions Associated with Intravenous Infusions of Large Volumes of Isotonic Saline Solution in Rats for 30 Days
Authors: Morton Daniel , Safron Joseph A. , Glosson Jill , Rice Deborah W. , Wilson Daniel M. , White Randy D.
Published: April 2009

The objective of this study was to characterize the changes associated with intravenous infusions of large volumes of isotonic saline solution in rats so that effects of the infusion process could be more easily distinguished from effects of test articles. Male Sprague-Dawley rats weighing approximately 225-275 g at the beginning of the study were given intravenous infusions of isotonic saline solution once daily for 30 consecutive days at dosages of 40 or 80 ml/kg body weight. Saline solution was administered through catheters placed in the caudal veins of the tail according to one of the following regimens: 80 ml/kg at 0.25 ml/min; 80 ml/kg at 0.5 ml/min; 80 ml/kg at 1.0 ml/min; and 40 ml/kg at 1.0 ml/min. Control rats were catheterized but not administered intravenous fluids. One day following the last treatment, all rats were necropsied and major organs were collected in 10% formalin. Histologic lesions associated with treatment included increased incidence and severity of pulmonary periarterial infiltrates of eosinophils, multifocal pulmonary inflammation, pulmonary granulomas that often contained hairshaft fragments, endothelial hypertrophy and hyperplasia within pulmonary arterial vessels, and pulmonary arterial medial thickening. Infiltrates of eosinophils around small pulmonary arteries were more severe in rats given intravenous infusions than in untreated rats and were more severe in rats given isotonic saline at the 80-ml/kg dosage than at the 40-ml/kg dosage. The severity of periarterial infiltrates of eosinophils increased with increasing infusion rates in rats that received 80 ml/kg isotonic saline. Pulmonary granulomas and multifocal pulmonary inflammation were observed in more rats that received intravenous saline than in control rats, but their incidences did not appear to vary with the volume or rate of infusion. Multifocal endothelial hypertrophy and hyperplasia occurred in most rats given isotonic saline solution at all volumes and rates, but not in untreated control rats. Inflammatory lesions in the tail near the injection site were considered sequellae of catheter insertion that, in some instances, may have been exacerbated by intravenous saline infusion. There were no lesions in other organs that were attributable to intravenous infusions of isotonic saline solution.
Relevant Exposure to Environmental Tobacco Smoke Surrogate Does Not Produce or Modify Secretory Otitis Media in the Rat
Authors: Coggins Christopher R.E. , Lovejoy Hugh M. , Mcguirt W. Frederick , Sagartz John W. , Hayes A. Wallace , Ayres Paul H.
Published: April 2009

Parental smoking is a possible risk factor in the development of secretory otitis media (SOM) in children. This experiment was designed to determine, using rats as an experimental model, whether exposures to environmental tobacco smoke (ETS) produce SOM and whether ETS exposure affects the rate of clearance of an experimentally induced effusion. Male Sprague-Dawley rats were exposed to 3 different concentrations of aged and diluted sidestream smoke, a surrogate for ETS, from 1R4F research cigarettes for 6 hr per day for 5 days. Experimental SOM was induced bilaterally in subgroups of animals from each group, by cold air exposure to the external auditory canals. Ears of rats were examined during the in-life portion of the study. Histopathologic examination of the middle ear was conducted at the termination of the 5-day period. The production of SOM was not induced by ETS exposure, nor were there differences noted between the groups in the rates of clearance of the experimentally induced SOM. Short-term exposure to ETS did not affect the acquisition or clearance of SOM in the rat.
Dissimilar Characteristics of N-Methyl-N-Nitrosourea-Initiated Foci and Tumors Promoted by Dichloroacetic Acid or Trichloroacetic Acid in the Liver of Female B6C3F1 Mice
Authors: Latendresse John R. , Pereira Michael A.
Published: April 2009

Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are metabolites of the industrial solvent and environmental contaminant trichloroethylene (TCE), as well as contaminants of chlorinated drinking water. Human exposure to these chemicals is of concern as all three have been shown to increase liver tumor incidence in mice. Differences in dose-response curves, progression to cancer, and postexposure regression of lesions suggest that TCA and DCA work through different mechanisms. The purpose of this study was to further characterize the proliferative hepatocellular lesions promoted by TCA and DCA using biomarkers of cell growth, differentiation, and metabolism in liver sections to better delineate the distinctions in the mechanism of the two chloroacetates. Fifteen-day-old female mice were initiated with 25 mg/kg N-methyl- N-nitrosourea. The initiated mice were administered DCA or TCA (20.0 mmol/L) in drinking water from age 49 days until euthanasia at age 413 days. The pathologic assessment showed that the foci of altered hepatocytes and tumors occurring in the animals promoted with DCA were eosinophilic and positive immunohistochemically for TGF-α, c- jun, c- myc, CYP 2E1, CYP 4A1, and glutathione S-transferase-π (GST-π). The DCA lesions also were essentially negative for c- fos and TGF-β, but nontumor hepatocytes were consistently TGF-β-positive. In contrast, tumors promoted by TCA were predominantly basophilic, lacked GST-π, and stained variably; usually, more than 50% of the tumor hepatocytes were essentially negative for the other biomarkers. This study demonstrates some striking differences in certain molecular biomarkers of cell growth, differentiation, and metabolism between DCA and TCA. The results also suggest some potential growth signal transduction pathways that may contribute to the DCA promotion of tumors, further support the premise that these two chloroacetates promote hepatocarcinogenesis in different ways, and provide a rational basis for a similar comparison with TCE. Such a comparison should give some insight as to whether DCA, TCA, or both are playing a significant role in the murine liver carcinogenesis of the parent compound, TCE.
Promotion by Helicobacter hepaticus-Induced Hepatitis of Hepatic Tumors Initiated by N-Nitrosodimethylamine in Male A/JCr Mice
Authors: Diwan Bhalchandra A. , Ward Jerrold M. , Ramljak Danica , Anderson Lucy M.
Published: April 2009

A new murine Helicobacter species, Helicobacter hepaticus, infects the livers of mice, causing a progressive chronic active hepatitis culminating in hepatocellular tumors. To examine the role of chronic H. hepaticus infection in carcinogenesis, H. hepaticus-infected male infant mice of A/JCr strain were given a single ip dose of N-nitrosodimethylamine (NDMA). Noninfected A/J mice similarly treated with NDMA served as controls. The effect of hepatitis induced by H. hepaticus was studied for 64 wk. At 31-36 wk, the incidence of hepatocellular adenomas in infected mice was significantly higher than in noninfected mice (82 vs 52%; p = 0.05). The multiplicity of hepatocellular tumors was also significantly higher in infected mice compared to noninfected mice (3.2 ± 0.09 vs 0.09 ± 0.2; p = 0.03). At 51-64 wk, many (10/18) infected mice developed hepatocellular carcinomas while only 2 of 19 control mice developed such tumors ( p = 0.005). Overexpression of cyclin D was observed in hepatocytes as well as adenomas induced by NDMA in H. hepaticus-infected mice, suggesting its role in inflammation, abnormal cell growth, and early neoplasia. High molecular weight keratins were highly expressed in hyperplastic oval cells in hepatitis and in liver tumors in mice with hepatitis, establishing a reliable marker for oval cells in formalin-fixed, paraffin-embedded tissue. Thus, chronic H. hepaticus infection significantly stimulated cyclin D expression, accelerated the development of liver tumors, increased the multiplicity of such lesions, and enhanced the progression of benign to malignant tumors.
The Proliferation in Uterine Compartments of Intact Rats of Two Different Strains Exposed to High Doses of Tamoxifen or Toremifene
Authors: Karlsson Stefan , Iatropoulos Michael J. , Williams Gary M. , Kangas Lauri , Nieminen L.
Published: April 2009

Uterine cell proliferation was studied in intact Sprague-Dawley (SD) and Fischer 344 (F344) rats exposed to the antiestrogens tamoxifen (TAM; 5, 10,20, or 40 mg/kg) and toremifene (TOR; 21.2 or 42.4 mg/kg). The antiestrogens were administered to animals via gavage daily for 2 or 12 wk. Uterine proliferation was assessed using markers for the proliferating cell nuclear antigen (PCNA) and by the bromodeoxyuridine (BrdU) method. Diethylstilbestrol (DES) was used as an estrogenic reference compound. The antiestrogens either reduced or prevented changes of myometrial and stromal proliferation indices (PI). TAM and TOR caused a time-dependent reduction of endometrial glands without an associated decrease in cell proliferation. In the luminal columnar epithelium, the antiestrogens depressed PCNA PI but enhanced BrdU PI, indicating a low continuous DNA synthesis in otherwise quiescent cells. The antiestrogens induced focal hyperplastic multilayered epithelia with PCNA-positive basal cells along segments of the luminal uterine epithelium. We suggest that this hyperplastic epithelium represents remnants from the glandular epithelium. DES was less efficient in inducing these changes but induced squamous metaplasias in the F344 rats. Uterine effects of the 2 antiestrogens were comparable with the exception of 1 TAM-exposed (40 mg/kg) SD rat that showed squamous metaplasia. F344 rats were more sensitive to the estrogenic action of DES than were the SD rats.
An evaluation of the abuse potential of modafinil using methylphenidate as a reference
Authors: Jasinski Donald R.
Published: April 2009

Modafinil is a unique wake-promoting agent. Preclinical studies indicate a mechanism of action which is distinct from that of amphetamine or methylphenidate. To compare the pharmacodynamic profiles of modafinil, methylphenidate, and placebo in humans, a double-blind Latin square crossover study was conducted in 24 male volunteers with a history of polysubstance abuse that included the stimulant cocaine. Each subject was given single oral doses of methylphenidate (45 mg or 90 mg), modafinil (200 mg, 400 mg or 800 mg) and placebo. Measures of subjective, behavioural, and physiological responses were evaluated at fixed intervals during 72 h after each dosing occasion. Subjects discriminated both modafinil and methylphenidate from placebo. Subjects liked the effects of both drugs. However, modafinil differed from methylphenidate in its lack of a significant response on the Amphetamine Scale of the Addiction Research Center Inventory. The profile of physiological effects for modafinil differed from methylphenidate in that it showed greater inhibition of observed and reported sleep, less facilitation of orthostatic tachycardia and less reduction of caloric intake. These findings are consistent with preclinical pharmacological data suggesting that modafinil is not an amphetamine-like agent.
Regulation of serotonin release by GABA and excitatory amino acids
Authors: Tao Rui , Auerbach Sidney B.
Published: April 2009

Regulation of serotonin release by γ-aminobutyric acid (GABA) and glutamate was examined by microdialysis in unanaesthetized rats. The GABAAreceptor agonist muscimol, or the glutamate receptor agonists kainate, γ-amino-3-hydroxy-5-methyl-4-isoxazolaproprionate or N-methyl-D-aspartate were infused into the dorsal raphe nucleus (DRN) while extracellular serotonin was measured in the DRN and nucleus accumbens. Muscimol produced decreases, and the glutamate receptor agonists produced increases in serotonin. To determine if these receptors have a tonic influence on serotonergic neurons, glutamate or GABAAreceptor antagonists were infused into the DRN. Kynurenate, a nonselective glutamate receptor blocker, produced a small, 30% decrease in serotonin. A similar decrease was obtained with combined infusion of AP-5 and DNQX into the DRN. The GABAAreceptor blocker bicuculline produced an approximately three-fold increase in DRN serotonin. In conclusion, glutamate neurotransmitters have a weak tonic excitatory influence on serotonergic neurons in the rat DRN. However, the predominate influence is mediated by GABAAreceptors.
Dopaminergic sensitivity and prediction of antidepressant response
Authors: Healy Elaine , McKeon Patrick
Published: April 2009

This study was designed to examine neuroendocrine predictors of antidepressant response to the selective serotonin reuptake inhibitor (SSRI) paroxetine. We assessed the prognostic utility of the apomorphine stimulation test by examining the relationship between pretreatment change in growth hormone (GH) following apomorphine and acute response to paroxetine treatment. We hypothesized that those subjects with most marked pretreatment dopaminergic supersensitivity, as manifested by greatest change in GH, would be most likely to show an early antidepressant response and would also be more likely to develop manic or hypomanic symptoms on paroxetine. Contrary to our hypothesis, greater dopamine postsynaptic sensitivity was associated with greater resistance to paroxetine treatment. In our sample of 13 subjects with a major depressive episode, pretreatment GH response to apomorphine per unit weight was inversely correlated with change in Hamilton depression rating scale following 6 weeks of paroxetine. Within the group of subjects who showed mood elevation on paroxetine, there was a trend towards greater GH response being associated with slower antidepressant response. With regard to the development of manic or hypomanic symptoms on paroxetine, change in GH per unit weight not did distinguish the two subjects who subsequently developed paroxetine-induced hypomania from other subjects. The seven subjects with previous antidepressant-induced hypomania did not differ from the other subjects in change in GH response per unit weight. The finding that subjects who had low dopamine receptor responsivity pretreatment were more likely to have an antidepressant response with paroxetine is consistent with recent suggestions that the therapeutic effect of SSRIs may be mediated through increased dopamine receptor sensitivity in the mesolimbic system. Further work assessing pretreatment and post-treatment GH response to apomorphine will help to test the hypothesis that low dopamine receptor responsivity predicts antidepressant response to SSRIs.
Comparison of donepezil-, tacrine-, rivastigmine-and metrifonateinduced central and peripheral cholinergically mediated responses in the rat
Authors: Dronfield S. , Egan K. , Marsden C. A. , Green A. R.
Published: April 2009

There are now several acetylcholinesterase inhibitors in clinical use for the treatment of Alzheimer's disease, however, no systematic comparative studies of their central and peripheral cholinergic mediated effects in rats appear to have been reported. The present study investigated the dose–response characteristics of donepezil, tacrine, rivastigmine and metrifonate in inducing tremor, lacrimation, salivation and hypothermia and the duration of action of these compounds in Lister hooded rats. Data obtained were compared with the clinical observations on these drugs. Three doses of each compound were given orally to establish a dose–response curve for each behaviour, Tremor and lacrimation were scored, salivation was measured by weighing swabs applied to the mouth area and hypothermia was measured with a rectal probe. ED50 values were calculated for tremor. Using a just sub-maximal tremorigenic dose, the duration of response was examined. All four compounds produced dose–dependent increases in tremor and hypothermia. Only tacrine also produced marked salivation and lacrimation. The order of potency (ED50 value in µmol/kg) was rivastigmine (3.7), donepezil (18.0), tacrine (37.5), metrifonate (470). Tremor following tacrine (150 µmol/kg) and donepezil (20 µmol/kg) was prolonged (> 6 h) with a similar hypothermic response. The duration of these responses following metrifonate (777 µmol/kg) and rivastigmine (12.5 µmol/kg) did not exceed 3 h. Tacrine had poor selectivity for central (tremor) versus peripheral (salivation/lacrimation) effects compared to the other compounds. Donepezil also had a sustained duration of action. The data are consistent with clinical results and indicate that simple in-vivo models may assist in the selection of acetylcholinesterase inhibitors with a suitable response profile for use in the symptomatic treatment of Alzheimer's disease.
Preclinical psychopharmacology of AIDS-associated dementia: lessons to be learned from the cognitive psychopharmacology of other dementias
Authors: Sarter Martin , Podell Michael
Published: April 2009

Following a brief discussion of the epidemiology, underlying neuropathological mechanisms, neuropsychological symptoms and present treatment strategies of AIDS-associated dementia (AAD), parallels are drawn between the longer standing research on drugs for the treatment of other cognitive disorders, particularly senile dementia, and ongoing efforts to develop psychopharmacological approaches for the treatment of the cognitive impairments in AAD. Important aspects of hypotheses designed to guide such a research are indicated with the help of a speculative, paradigmatic hypothesis concerning the role of cortical cholinergic inputs in AAD. Furthermore, aspects of validity of animal models, and cognition as a crucial intervening variable in the effects of potential treatments, are evaluated.
Neurobehavioural consequences of substance abuse and HIV infection
Authors: Basso Michael R. , Bornstein Robert A.
Published: April 2009

Although our understanding of how human immunodefiency virus (HIV)-related neurobehavioural deficits develop is nascent and preliminary, some clues have emerged which may clarify lingering uncertainties. In particular, HIV seems to yield brain dysfunction by mediating pathological changes upon neuronal function. HIV also compromises immunological integrity, thereby resulting in secondary infections that may further increase brain dysfunction. Notably, many individuals with HIV tend to be current or past abusers of drugs, and, in some cases, their drug use may have actually presented a pathway for initial HIV infection. Similar to HIV, many drugs tend to yield pathological changes upon neuronal function. Further paralleling HIV, some drugs seem to compromise immune function, which in turn may yield secondary detrimental effects upon the brain. Yet, despite the relatively high comorbidity rates of HIV infection and substance abuse, few investigations have addressed the potential interaction between these two factors upon neurobehavioural status. Towards this end, the present paper reviews the existing literature concerning neuropsychological effects of HIV and substance use, and suggests potential mechanisms whereby substance use may potentiate and exacerbate the onset and severity of neurobehavioural abnormalities in HIV infection.
Morphine inhibits human microglial cell production of, and migration towards, RANTES
Authors: Hu Shuxian , Chao Chun C. , Hegg Colleen C. , Thayer Stanley , Peterson Phillip K.
Published: April 2009

The B-chemokine RANTES has recently been implicated in the neuropathogenesis of the human immunodefiency virus. Based upon previous studies of the effects of morphine on microglial cell production of cytokines and chemotaxis towards the activated complement component C5a, we tested the hypothesis that this opiate would alter the production of and migration towards RANTES by human microglia. Treatment of highly purified microglial cell cultures with morphine (10–8–10–6M) potently inhibited RANTES production by lipopolysaccharide-and interleukin-1[.beta]-stimulated cells. Using a chemotaxis chamber to assess directed migration towards RANTES, treatment of microglial cells with morphine (10–10–10–6M) was found to suppress chemotaxis. The inhibitory effects of morphine on RANTES production and on chemotaxis were blocked by naloxone and [.beta]-funaltrexamine, indicating that morphine mediated its suppressive effects via activation of microglial µ-opioid receptors. Morphine's inhibitory effect on chemotaxis did not appear to be associated with an alteration in RANTES-induced [Ca2+]i mobilization. While the clinical significance of these in-vitro findings is unknown, they suggest that µ-opioid receptor agonists could alter certain neurodegenerative and inflammatory processes within the brain.
Pharmacological frontiers in the treatment of AIDS dementia
Authors: McGuire Dawn , Marder Karen
Published: April 2009

Even in the era of highly active antiretroviral therapy, AIDS dementia remains an important and devastating complication of human immunodeficiency virus (HIV-1) infection. Based on the 1997 AIDS case rate of 56 per 100 000 population in the USA, a reasonable estimated incidence of AIDS dementia is 3–8 per 100 000, similar to that of multiple sclerosis. The pharmacology of AIDS dementia has been dominated by antiretroviral therapies, the best studied of which is azidothymidine. New and specific therapies are needed to treat and prevent brain injury in the setting of HIV infection. Rational therapy has been limited by the absence of large, adequate and well-controlled clinical trials using neuroprotective agents or those with disease-modifying potential, as well as by an incomplete understanding of the pathophysiology of AIDS dementia. In this review, a summary of evidence-based hypotheses of HIV-associated brain injury is followed by information on current nonantiretroviral therapeutic trials and their scientific rationale.
The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of 3, 4-methylenedioxymethamphetamine (‘Ecstasy’) in healthy volunteers
Authors: Liechti Matthias E. , Vollenweider Franz X.
Published: April 2009

MDMA (3, 4-methylenedioxymethamphetamine) or ‘Ecstasy’ is a widely used recreational drug that produces a state of heightened mood but also cardiovascular and vegetative side-effects. In animals, MDMA releases serotonin and, to a lesser extent, dopamine and norepinephrine. The release of serotonin can be blocked by serotonin uptake inhibitors such as citalopram. It is unknown to what extent this mechanism is also responsible for the physiological side-effects of MDMA seen in humans. We investigated the effect of citalopram pretreatment (40 mg i.v.) on vegetative and cardiovascular effects of MDMA (1.5 mg/kg p.o.) in a double-blind placebo-controlled study in 16 healthy volunteers. MDMA moderately increased blood pressure and heart rate, slightly elevated body temperature and produced a broad range of acute and shortterm side-effects. Citalopram reduced all these MDMA-induced physiological changes except for body temperature. These findings suggest that physiological effects of MDMA in humans are partially due to an interaction of MDMA with the serotonin carrier and a subsequent release of serotonin.
Amelioration of specific working memory deficits by methylphenidate in a case of adult attention deficit/hyperactivity disorder
Authors: Mehta Mitul A. , Calloway Paul , Sahakian Barbara J.
Published: April 2009

Cognitive neuroscience has provided an extensive literature on the neuroanatomy and psychopharmacology of working memory. However, while it has been shown that children with attention deficit/hyperactivity disorder (AD/HD) have deficits in working memory, relatively little is known about working memory functions in adults diagnosed with AD/HD. Furthermore, it remains to be seen whether methylphenidate (Ritalin), which is used in the treatment of childhood AD/HD can improve performance deficits in adult AD/HD patients. We have used three paradigms of spatial working memory validated in cortical lesion patients, and psychopharmacological and neuroimaging studies, in order to examine the effects of methylphenidate administration in a case of an adult diagnosed with AD/HD. In the AD/HD patient at baseline testing, performance on a test of spatial recognition memory and on a task of self-ordered spatial working memory was shown to be impaired. Importantly, the impairments on the self-ordered spatial working memory task were ameliorated by an acute oral dose of methylphenidate (0.5 mg/kg). These findings provide insights into the possible neurochemical and neuroanatomical substrates of the action of methylphenidate in AD/HD and suggest a useful methodology for further research into this potentially debilitating disorder.
Clozapine pharmacokinetics and pharmacodynamics studied with CYP1A2-null mice
Authors: Aitchison Katherine J. , Jann Michael W. , Zhao Jing Hua , Sakai Takafumi , Zaher Hani , Wolff Kim , Collier David A. , Kerwin Robert W. , Gonzalez Frank J.
Published: April 2009

The aim of this study was to use the CYP1A2-null mouse to investigate the in-vivo contribution of CYP1A2 to clozapine pharmacokinetics and pharmacodynamics. An intraperitoneal injection of 10 mg/kg clozapine was administered to four male CYP1A2 –/– mice and four male wild-type mice. Clozapine, desmethylclozapine, and clozapine N-oxide concentrations in sequential tail blood samples were measured by HPLC with UV detection. Behavioural parameters were recorded at each time point. The area under the curve (AUC) of clozapine was 2.6 times greater, the clearance of clozapine was 2.6 times slower, and the half-life was 1.2 times longer in the CYP1A2 –/– mice (p=0.0143) as compared to the wild-type mice. Sixty-one percent of the clozapine clearance in wild-type mice was calculated to be mediated by CYP1A2. The AUC of desmethylclozapine was 1.6 times lower in the CYP1A2 –/– mice compared to the wild-type mice (p=0.0286), while there was a trend for the AUC of clozapine N-oxide to be greater in the CYP1A2 –/– mice (p=0.0571). The CYP1A2 –/– mice were significantly more drowsy and showed more motor impairment (p = 0.0145) and myoclonus than the wild-type mice. Our results indicate that, in vivo, CYP1A2 is the major determinant of clozapine clearance, contributes significantly to the demethylation of clozapine, and has a negligible contribution to the N-oxidation. Our data also indicate that CYP1A2 poor metabolizers might be more susceptible than extensive metabolizers to dose-related adverse effects of clozapine, such as sedation, myoclonus and seizures.
Effects of pentagastrin and the cold pressor test on the acoustic startle response and pupillary function in man
Authors: Tavernor S. J. , Abduljawad K. A. J. , Langley R. W. , Bradshaw C. M. , Szabadi E.
Published: April 2009

Pentagastrin, a cholecystokinin2 (CCK2) receptor agonist, evokes autonomic and subjective features of anxiety in healthy volunteers. The present experiments examined the effects of pentagastrin on two responses with known sensitivity to another anxiogenic procedure (threat of electric shock): the acoustic startle response and the pupillary light reflex. The effects of pentagastrin were compared with those of the cold pressor test, a procedure known to elicit sympathetic activation. Twelve healthy males (18–35 years) participated in two experiments each consisting of two sessions in which they received (1) pentagastrin (0.3 µg/kg, i.v.) and a control infusion (saline), and (2) cold pressor test (90 s hand immersion at 4 °C) and a control immersion (37 °C), using a balanced single-blind protocol. Electromyographic responses of the orbicularis oculi to 40 ms, 1 kHz, 115 dB tones (‘startle responses’) [Experiment 1], and miotic responses to 200 ms, 0.43 mW/cm2 light pulses [Experiment 2] were recorded before, during and after the infusions and hand immersions. Heart rate, blood pressure and subjective feelings were also recorded. The amplitude of the startle response was not significantly affected by pentagastrin, but was reduced during the cold pressor test. Resting pupil diameter increased during both pentagastrin infusion and the cold pressor test, but neither procedure altered the amplitude of the light reflex. Tachycardia, increased blood pressure and subjective anxiety were induced by both pentagastrin and the cold pressor test. The cardiovascular and mydriatic effects of pentagastrin and the cold pressor test are consistent with the known ability of these treatments to induce sympathetic activation. The anxiety induced by these treatments, unlike anxiety induced by threat of electric shock, was not accompanied by potentiation of the startle response or reduction of the miotic response. The results indicate that different anxiogenic procedures do not have equivalent effects on these reflexes.
Selective cognitive processing of drug cues in heroin dependence
Authors: Franken Ingmar H. A. , Kroon Linda Y. , Wiers Reinout W. , Jansen Anita
Published: April 2009

Previous studies provide evidence for the selective processing of disorder related stimuli on anxiety, depression, and eating disorders. There exist some preliminary indications that selective processing of drug cues may be involved in drug craving and relapse that deserve further investigation. In order to investigate the role of processing bias in an abnormal motivational system, the attentional bias for drug related stimuli was studied in a heroin dependent population. Heroin dependent participants (n = 21) and control participants (n= 30) performed a supra- and subliminal heroin Stroop task and heroin craving was assessed. Heroin dependent participants showed a considerable attentional bias for supraliminally presented heroin cues. However, there was no evidence for a preattentive bias on the subliminal presented cues. Reaction time on heroin cues was significantly predicted by heroin craving-levels. Results indicate that selective processing may be related to motivational induced states in general. The finding are discussed in the context of selective information processing in general psychopathology and in motivational processes as addiction specifically.