Spatial discrimination and visual discrimination: two methods evaluating learning and memory in juvenile Göttingen minipigs.

Two methods investigating learning and memory in juvenile Göttingen minipigs were evaluated for potential use in preclinical toxicity testing. Twelve minipigs were tested using a spatial hole-board discrimination test including a learning phase and two memory phases. Five minipigs were tested in a visual discrimination test. The juvenile minipigs were able to learn the spatial hole-board discrimination test and showed improved working and reference memory during the learning phase. Performance in the memory phases was affected by the retention intervals, but the minipigs were able to remember the concept of the test in both memory phases. Working memory and reference memory were significantly improved in the last trials of the memory phases. In the visual discrimination test, the minipigs learned to discriminate between the three figures presented to them within 9-14 sessions. For the memory test, all minipigs performed 9/12 correct choices or better. Juvenile Göttingen minipigs are able to learn to perform in a spatial hole-board discrimination test as well as in a visual discrimination test, showing an increase in performance over time. Both tests have considerable scope to assess learning and memory of pigs, and we seem to have succeeded in establishing two test systems suitable for performing preclinical toxicity testing in juvenile minipigs.

Radiotoxicity of the alpha-emitting bone-seeker 223Ra injected intravenously into mice: histology, clinical chemistry and hematology.

BACKGROUND: The alpha-emitter 223Ra, which localizes in osteoblastic active zones, including on skeletal surfaces and in osteoblastic metastases, has recently been introduced as a potential therapeutic agent against skeletal metastases. Here, the adverse effects of high dosages in animals were investigated. MATERIALS AND METHODS: Balb/c mice received intravenously (i.v.) either 1250, 2500, or 3750 kBq/kg of dissolved 223RaCl2 and were followed in the initial toxicity phase. At the 4-week end-point, the animals were sacrificed and blood samples were collected to study the effects on clinical chemistry and hematological parameters. Selected organs were weighed and tissue samples examined by microscopy. RESULTS: Treatment with 223Ra caused a dose-related minimal to moderate depletion of osteocytes and osteoblasts in the bones. Furthermore, a dose-related minimal to marked depletion of the hematopoietic cells in the bone marrow, and a minimal to slight extramedullary hematopoiesis in the spleen and in the mandibular and mesenteric lymph nodes were observed. The LD50 for acute toxicity, defined as death within 4 weeks of receiving the substance, was not reached. CONCLUSION: This study demonstrated that high doses of the bone-seeker 223Ra did not completely inactivate the blood-producing cells. The relatively high tolerance to skeletal alpha doses was probably caused by the surviving pockets of red bone marrow cells beyond the range of alpha particles from the bone surfaces, and the recruitment of peripheral stems cells.

Increased manganese concentration in the liver after oral intake.

RATIONALE AND OBJECTIVES: Manganese is a well-known liver-specific agent used in magnetic resonance imaging. For this purpose, manganese is now administered intravenously. In theory it should be possible to increase the gastrointestinal uptake of manganese through the use of nutritional products as promoters. Such an agent has now been formulated. As part of a primary pharmacologic investigation, the uptake of manganese in the kidney, heart, and liver was studied. MATERIALS AND METHODS: One hundred two female Sprague Dawley rats fasted for 18 hours before the agent (CMC-001) was given orally by gavage. One hundred micromol/kg BW was given to all rats except six, who served as controls. Various concentrations of the promoters (vitamin D3 and the amino acid alanine) were also given. Three hours after administration the rats were killed and the heart, the liver and kidneys were removed. The manganese content was determined by atomic absorption. RESULTS: No systematic increased concentration of manganese was found in either the kidneys or the heart; whereas the manganese content of the liver (approximately 100%) increased significantly compared with the controls and the group receiving pure manganese. No side effects were observed. CONCLUSION: It is possible to increase the gastrointestinal uptake of manganese in fasting rats and thereby increase the concentration in the liver.