Development of divergence in dopamine responsiveness in genetically selected rat lines is preceded by changes in pituitary-adrenal activity

Abstract

Two pharmacogenetically selected Wistar rat lines have been used as a model for individual variability in behavioral and neuroendocrine responses. As a selection criterion the behavioral responsiveness for the dopamine agonist apomorphine was used, giving rise to the apomorphine-susceptible (apo-sus) and apomorphine-unsusceptible (apo-unsus) rat lines. This selection has been maintained over 16 generations. Recent studies have shown that adult rats of these selection lines also show pronounced differences in responsiveness of the hypothalamic-pituitary-adrenal (HPA) system. In this study we analyzed to what extent the divergence in dopamine phenotype and HPA resposiveness, as ibserved in adult rats, are linked to possible differences, within both systems, during early postnatal development. Therefore, we measured in neonatal female rats of 10 and 18 days of age several parameters of the dopamine and HPA system which show significant differences in adult rats. These include tyrosine hydroxylase (TH) and dopamine D1 and D2 receptor mRNA levels, which were determined within the nigrostriatal system since this system shows the most pronounced differences between adult rats of both selection lines. As indices of HPA activity we measured CRH mRNA, ACTH and total and free corticosterone plasma concentrations under basal conditions in the morning. Transcripts of the two types of corticosteroid receptors, mineralocorticoid (MR) and glucocorticoid (GR) receptor were measured in hippocampus and paraventricular nucleus. In 10-day-old rats all dopamine and HPA parameters were similar in rats of the two selection lines, except for GR mRNA in the parvocellular neurons of the paraventricular nucleus of the hypothalamus (PVN) of apo-sus rats, which was significantly higher than in apo-sus rats. Eighteen-day-old apo-sus rats, however, showed significantly higher ACTH, comparable total corticosterone and a trend towards lower free corticosterone plasma levels. This HPA profile resembles the situation in adult apo-sus rats as compared with adult apo-sus rats. Hippocampal GR mRNA expression and thymus weight were also higher in apo-sus rats. In addition, these rats showed an age-related increase in hippocampal MR and mRNA expression, while in apo-sus rats MR and mRNA levels did not change between pnd 10 and 18. The measures of the nigrostriatal dopamine system at day 18 were still similar in rats of both lines. In conclusion, divergence in the dopamine systems of the two pharmacogenetically selected rat lines emerges subsequent to divergence in pituitary-adrenal activity