CORTICOSTEROID FEEDBACK RESISTANCE IN RATS GENETICALLY SELECTED FOR INCREASED DOPAMINE RESPONSIVENESS

Pharmacogenetically selected Wistar rat lines were used to investigate the implication of either high or low responsiveness of the dopamine system for the activity of the hypothalamus-pituitary-adrenal (HPA) axis. As selection criterion the gnawing response induced by the dopamine agonist apomorphine was used. This criterion allows to distinguish apomorphine susceptible (apo-sus) rats which show a Vigorous gnawing response from apomorphine unsusceptible (apo-unsus) rats. The present study, using male animals of the 9-12th generation of the two rat lines, revealed the following characteristics of the stress response system: (i) in apo-sus rats under basal conditions corticotrophin-releasing hormone (CRH) mRNA level in the paraventricular nucleus (PVN) and plasma adrenocorticotropin (ACTH) concentration were significantly higher; total corticosterone (B) plasma level was similar but free B level was lower; (ii) exposure to a novel environment resulted in a higher and prolonged plasma ACTH and total B response in the apo-sus rats. Moreover, the elevated free B level was also prolonged; (iii) apo-sus rats had increased CRH-induced pituitary ACTH release and B secretion was also increased, but not as prolonged as during novelty. (iv) In dexamethasone-pretreated rats an intravenous ACTH(1-24) injection resulted in a similar plasma B response in rats of both lines; (v) In vitro, ACTH(1-24) produced a significantly higher B secretion by adrenocortical cells of apo-sus rats reflecting the higher in vivo ACTH priming of the adrenal glands in these animals. (vi) apo-sus rats had higher body and thymic weight. In conclusion, rats genetically selected for increased susceptibility of the dopamine system to apomorphine display subtle adrenocortical hyporesponsiveness and show resistance to corticosteroid hormone feedback action.