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In an effort to generate a genome-wide set of high-quality polymorphic markers for the rat, we used the marker-selection method, which has already been proven useful for the development of markers, especially for the human genome. Small-insert (300-900 bp) rat genomic libraries were constructed with an estimated complexity of three genome equivalents and enriched for short tandem repeat sequences (STRs). The enriched libraries were found to contain 45% (CA)n and 27% (GATA)n, representing at least a 50-fold enrichment over unselected small insert genomic libraries. A subset of 2160 STR-containing clones, primarily of the (GATA)n class of repeats, were sequenced. PCR primers flanking the repeats were synthesized from some of the sequences from the (CA)n and (GATA)n classes of STRs and tested for polymorphism in a panel of eight inbred rat strains. This strategy yielded 147 polymorphic markers, which mapped with high odds to all chromosomes by linkage in three F2 populations. The integration of these STR markers with other rat genetic markers and mapping reagents will facilitate the mapping of disease genes in the rat and the identification of loci associated with complex mammalian phenotypes.

11 beta-hydroxylase (Cyp11b1) mutations were previously linked to altered steroid biosynthesis and blood pressure in Dahl salt-resistant (R) and Dahl salt-sensitive (S) rats. In the present work, interval mapping identified a putative blood pressure quantitative trait locus (QTL) near Cyp11b1 in an F1(SxR)xS population (LOD = 2.0). Congenic rats (Designated S.R-Cyp11b) were constructed by introgressing the R-rat Cyp11b1 allele into the S strain. S.R-Cyp11b rats had significantly lower blood pressure and heart weight compared with S rats, proving the existence of a blood pressure QTL on Chromosome (Chr) 7 despite the fact that QTL linkage analysis of blood pressure never achieved stringent statistical criteria for significance. To test the effects of the introgressed region on blood pressure and survival, S.R.-Cyp11b and S rats were maintained on a 4% NaCl diet until they died or became moribund. Analysis of variance (ANOVA) indicated significant strain differences in blood pressure and days survived (P < 0.0001 for both) as well as gender differences in days survived (P = 0.0003). Kaplan-Meier survival analysis also found significant strain (P < 0.0001) and gender (P = 0.007) differences in days survived. However, when the effects of blood pressure were removed, significant strain differences in survival essentially disappeared. This suggests that the increased survival of S.R-Cyp11b rats was largely due to their decreased blood pressure and thus strongly corroborates the existence of a blood pressure QTL on Chr 7 near or at Cyp11b1.

In order to evaluate central serotonergic function during viral encephalitis biochemical, behavioural and immunohistofluorescence studies were carried out. Mice were inoculated with the moderate virulent strain of venezuelan equine encephalomyelitis virus, Pixuna. Signs of encephalitis were observed in 50-60% of infected animals. Levels of serotonin and 5-hydroxyindolacetic acid, and the ratio of the indolamine and its metabolite in raphe and cortex did not change with respect to sham-inoculated mice. A differential decrease in turnover rate by pharmacological methods, such as pargyline, p-chlorophenylalanine and probenecid administration, was observed in raphe and cortex. The ratio serotonin turnover rate/steady state concentration of serotonin was only decreased in the raphe of sick animals. The response to 5-methoxy-N,N-dimethyltryptamine was greater in infected animals. The duration of immobility in the swim test was shorter in the infected group. A greater number of viral antigen particles was localized in raphe and periraphe areas than in cortex, brain stem or striatum. The results suggest a serotonin presynaptic deficit, a postsynaptic hyperreactivity of serotonin system, and a region-selective distribution of the virus.