GlycineB antagonists as potential therapeutic agents. Previous hopes and present reality.

It is not clear what therapeutic application is most likely for agents blocking glycine site of the NMDA receptors (glycineB). Majority of the studies to date used either glycineB antagonists with doubtful brain penetration or partial agonists. Following systemic administration to rats of our newly developed glycineB antagonists (MRZ 2/570; 2/571 and 2/576) and L-701,324 (MSD) as a reference agent the following behavioural effects were observed: weak (if any) antiparkinsonian-like effects, lack of anxiolytic activity, inhibition of physical and motivational aspects of morphine dependence and neuroprotective activity in global ischaemia. The side effects include: sedation, ataxia, and myorelaxation. We detected neither vacuolisation in the cingulate cortex nor impairment of pre-pulse inhibition indicating lack of psychotomimetic potential.

Strain and species differences in the induction of ATPase-deficient hepatic foci by diethylnitrosamine.

Diethylnitrosamine (5 mg/kg) was intraperitoneally administered to rats, mice, guinea pigs and tupaias daily for 3 weeks. After 12 weeks of cessation, focal areas of ATPase-deficiency of hepatocytes appeared only in rats and, to a much lesser extent, in guinea pigs. Female rats were more sensitive than males and Wistar rats were less sensitive than Sprague-Dawley rats. These data show that quantitation of ATPase-deficient foci as a determinant of hepatocarcinogenicity is mainly restricted to the rat species.

Spontaneous malignomas in Tupaia (tree shrew).

Nine spontaneous malignomas of the tree shrew were detected and analysed during an observation period of nine years. The tumours were histopathologically examined and classified. All malignomas developed in imported Tupaia only. From the tumour cells of two different animals new Tupaia herpesviruses were isolated. This is the first. report on spontaneous malignomas of Tupaia in captivity.

Experimental infection and the state of viral latency of adult tupaia with herpes simplex virus type 1 and 2 and infection of juvenile Tupaia with temperature-sensitive mutants of HSV Type 2.

The susceptibility of adult Tupaia Belangeri to infection with herpes simplex virus (HVS) was investigated. Adult animals were inoculated intraperitoneally with HSV type 1 or 2. With the exception of HSV-2, strain HG-52, 10(5)--10(6) PFU of all HSV strains caused lethal infection irrespective of the age of the animals. Infections HSV was recovered from the spinal cord of those animals which had survived infection with a low dose of virus. The DNA of the recovered viruses was compared to the DNA of the inoculated HSV. The viral genome of the recovered HSV was unchanged as judged by analysis of the fragment pattern of the viral DNA's using restriction endonucleases. Animals which had survived the first HSV infection were protected against a second infection even at highly lethal doses of HSV-1 or 2. Juvenile Tupaia survived infection with temperature-sensitive mutants of HSV-2, strain HG-52, which induced protection against a second infection with lethal doses of HSV-1 or 2.

Tupaias (tree shrews)--a new animal model for gallstone research. II. Influence of fat, sugar, and cholesterol on bile composition.

The lipid composition of bile obtained from the gallbladder and from the liver of tupaias was determined. Compared to the gallbladder bile of man, the gallbladder bile of tupaias contains the same percentage of phospholipids (PL), one third of the cholesterol (CH), and 50% more total bile acids (TBA). The lithogenic index (LI) of the bile is about 0.2--0.3. No significant sex differences or diurnal variations are found in the composition of bile. The concentration of PL, CH, and TBA is found 5 to 8 times higher in the gallbladder bile than in the liver bile. The bile acid spectrum in tupaias equals that in man qualitatively and is similar quantitatively. In a feeding experiment, the influences of butter, cholesterol, butter plus cholesterol and sucrose on bile composition, clinicochemical serum values, and liver and gallbladder histology were studied. Groups of six animals each were fed the different diets over a 10-week period. In group A: 20% butter added to the standard diet, PL content was higher, the LI was unchanged. In group B: 2% cholesterol added to the standard diet, the CH value and the LI were elevated, CH crystals but no stones were found. In group C: 2% cholesterol and 20% butter in the standard diet, stone formation was observed. PL and CH values were higher than in group A and B, TBA values were lower. In group D: 50% sucrose added to the standard diet very low PL and TBA values were determined in the liver bile, resulting in elevated LIs. It is concluded that all three components of a diet, which had proven lithogenic in a preceding experiment (Schwaier, 1979a), contribute to gallstone formation.

Tupaias (tree shrews)--a new animal model for gallstone research; first observations of gallstones.

In tupaias, rat-sized mammals with phylogenetic affinities to insectivores and primates, gallstones can be induced by diet. Twenty per cent butter, 20% sucrose, and 1% cholesterol, added to the standard diet, caused massive stone formation in 11 of 16 male tupaias. In the other five animals the bile contained cholesterol crystals or few stones, liquid crystals, and fat droplets. The stones were composed almost totally of cholesterol and closely resembled those described in squirrel monkeys, which had been fed a similar diet. The diet caused neither a change in body weight nor serious diarrhea or any other conceivable illness of the experimental animals. Only liver weight and liver fat content increased. No spontaneous gallstones were found in 200 healthy animals, which had been fed standard diet. In sick animals cystine stones or a soft concrement of undefined organic material were observed. Tupaia, thus, represents a suitable and convenient animal model for gallstone research.

Experimental infection of Tupaia belangeri (tree shrews) with herpes simplex virus types 1 and 2.

The susceptibility of Tupaia belangeri (tree shrews, which are primitive prosimian primates) to infection with herpes simplex virus (HSV) and the pathogenesis of HSV in these animals were investigated. Juvenile (28--45 days old) and adult (150 days old) animals were inoculated intravenously, intraperitoneally, or subcutaneously with HSV type 1 or 2 (25--10(5) plaque-forming units per animal). Clinical illness usually appeared in juvenile animals on the second day after inoculation, and the animals died between two and 14 days after inoculation. High titers of infectious HSV were recovered from liver and spleen. The histopathologic examination always showed severe liver changes with numerous necrotic areas. The morphologic events in the liver were designated as herpetic hepatitis. The next most common morphologic findings were encephalitis and fibrosis in the spleen. These results demonstrate the high pathogenicity of HSV types 1 and 2 in juvenile T. belangeri. In contrast, adult animals did not develop acute clinical disease and survived the HSV infection.