STRAIN-SELECTIVE EFFECTS OF CORTICOSTERONE ON LOCOMOTOR SENSITIZATIONTO COCAINE AND ON LEVELS OF TYROSINE-HYDROXYLASE AND GLUCOCORTICOID RECEPTOR IN THE VENTRAL TEGMENTAL AREA

We have studied biochemical and behavioral effects of chronic corticos terone administration in two inbred rat stains (Fischer 344 and Lewis) , known to differ in their hypothalamic-pituitary-adrenal axis and in their behavioral responses to drugs of abuse. First, we studied cortic osterone regulation of phosphoproteins in the ventral tegmental area o f sham- and corticosterone-treated Fischer and Lewis rats, by means of back-phosphorylation and two-dimensional gel electrophoresis and West ern blotting analysis. Corticosterone administration upregulated tyros ine hydroxylase immunoreactivity and decreased glial-fibrillary acidic protein phosphorylation state in the ventral tegmental area of Fische r rats only, with no changes seen in Lewis rats. We also studied corti costerone effects on locomotor sensitization to cocaine, a behavior kn own to be regulated by the ventral tegmental area. In Fischer rats, ch ronic corticosterone pretreatment resulted in development of cocaine s ensitization, which was absent in sham-pretreated Fischer rats. In con trast, Lewis rats developed cocaine sensitization either with or witho ut corticosterone pretreatment. Thus, both biochemical and behavioral effects of corticosterone observed in Fischer rats were absent in Lewi s rats. We next studied the possibility that certain transcription fac tors, thought to play a role in tyrosine hydroxylase expression, could be involved in these strain-selective effects of corticosterone. Cort icosterone treatment decreased levels of glucocorticoid receptor immun oreactivity in the ventral tegmental area of Lewis rats, but not of Fi scher rats. In addition, drug-naive Fischer rats showed higher ventral tegmental area levels of immunoreactivity of cyclic AMP response elem ent binding protein than Lewis rats, with no effect of corticosterone observed in either strain. These findings suggest that hypothalamic-pi tuitary-adrenal axis modulation of responses to drugs of abuse is a ge netically determined characteristic seen in Fischer rats, but absent i n Lewis rats. We propose that corticosterone administration down-regul ates the glucocorticoid receptor in the ventral tegmental area of Lewi s rats, and thereby prevents other adaptations to corticosterone treat ment, while in the ventral tegmental area of Fischer rats the lack of glucocorticoid receptor down-regulation and the high basal levels of c yclic AMP response element binding protein could facilitate the transc riptional, biochemical and behavioral actions of glucocorticoids.