Effects of sex and hormonal status on astrocytic basic fibroblast growth factor-2 and tyrosine hydroxylase immunoreactivity after medial forebrain bundle 6-hydroxydopamine lesions of the midbrain dopamine neurons.

ABSTRACT

We examined astrocytic basic fibroblast growth factor immunoreactivity (FGF-2-IR) and tyrosine hydroxylase immunoreactivity (TH-IR) in the cell-body region of midbrain dopaminergic neurons after unilateral infusions of the neurotoxin 6-hydroxydopamine into the medial forebrain bundle in male and female rats. In addition, to determine whether neonatal exposure to gonadal hormones has consequences on the expression of astrocytic FGF-2 and cell loss in response to injury in adulthood, we studied the effects of these lesions in adult male and female rats that had been exposed or not to testosterone in the neonatal period. In both males and females there was a progressive loss of TH-expressing cells that peaked 5 weeks after the lesions. Females showed less loss of TH-expressing cells than males, but this effect was not estrogen dependent. Lesions led to an increase in expression of astrocytic FGF-2 that was greater in males than in females. Finally, it was found that, regardless of genetic sex, rats exposed to testosterone neonatally showed greater astrocytic FGF-2 expression after lesions than those not exposed, and that among those not exposed to testosterone, estrogen treatment had a modest protective effect. Analysis of behavior and striatal dopamine content showed that the percent of striatal dopamine depletion 14 days after the lesion correlated with the amount of behavioral asymmetry displayed by animals on all tests conducted after lesioning. In groups killed 2 and 5 weeks after the lesion, the amount of behavioral asymmetry correlated with the percent loss of TH-IR cells and with the percent increase in FGF-2-IR cells in the midbrain. These relationships were not evident in groups killed 3 and 7 days after the lesion, possibly because the changes in the number of FGF-2- and TH-IR cells were not fully manifested. The present findings show that hormonal events early in life can alter the response of midbrain dopamine neurons to insult and injury in adult life and suggest that the slow degeneration of these neurons may release signals triggering a sustained activation of adjacent astrocytes which, in turn, may lead to induction of astrocytic FGF-2.