Dopaminergic activity in transgenic mice underexpressing glucocorticoid receptors: Effect of antidepressants

Transgenic mice bearing a transgene coding for a glucocorticoid receptor an tisense mRNA, which partially blocks glucocorticoid receptor expression, we re used to investigate the long-term effect of hypothalamic-pituitary-adren al axis dysfunction on brain dopamine transmission. Compared to control mic e, the transgenic animals showed increased amphetamine-induced locomotor ac tivity and increased concentrations of striatal dopamine and its metabolite s dihydroxyphenylacetic acid and homovanillic acid. Binding of [H-3]SCH 233 90 and [H-3]spiperone to, respectively, D1 and D2 dopamine receptors was in creased in transgenic mice. In contrast, autoradiography of striatal [H-3]G BR 12935 binding to the dopamine transporter was decreased and the mRNA lev els of this transporter, measured by in situ hybridization, remained unchan ged in the substantia nigra pars compacta. The effect of chronic treatment for two weeks with amitriptyline or fluoxetine was compared in control and transgenic mice. No significant changes were observed in control mice follo wing antidepressant treatment, whereas in transgenic mice both antidepressa nts reduced striatal [H-3]SCH 23390 and [H-3]raclopride specific binding to D1 and D2 receptors. Amitriptyline, but not fluoxetine, increased striatal [H-3]GBR 12935 binding to the dopamine transporter, whereas its mRNA level in the substantia nigra pars compacta was decreased in fluoxetine, compare d to vehicle- or amitriptyline-treated transgenic mice. From these results we suggest that hyperactive dopaminergic activity of the nigrostriatal pathway controls motor activity in the transgenic mice. Furt hermore, antidepressant treatment corrected the increased striatal D1 and D 2 receptors and decreased dopamine transporter levels in the transgenic mic e. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.