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

Neuroscience. 2001;102(1):151-8. doi: 10.1016/s0306-4522(00)00444-9.

Abstract

Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA, which partially blocks glucocorticoid receptor expression, were used to investigate the long-term effect of hypothalamic-pituitary-adrenal axis dysfunction on brain dopamine transmission. Compared to control mice, the transgenic animals showed increased amphetamine-induced locomotor activity and increased concentrations of striatal dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid. Binding of [3H]SCH 23390 and [3H]spiperone to, respectively, D1 and D2 dopamine receptors was increased in transgenic mice. In contrast, autoradiography of striatal [3H]GBR 12935 binding to the dopamine transporter was decreased and the mRNA levels of this transporter, measured by in situ hybridization, remained unchanged 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 following antidepressant treatment, whereas in transgenic mice both antidepressants reduced striatal [3H]SCH 23390 and [3H]raclopride specific binding to D1 and D2 receptors. Amitriptyline, but not fluoxetine, increased striatal [3H]GBR 12935 binding to the dopamine transporter, whereas its mRNA level in the substantia nigra pars compacta was decreased in fluoxetine, compared 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. Furthermore, antidepressant treatment corrected the increased striatal D1 and D2 receptors and decreased dopamine transporter levels in the transgenic mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amitriptyline / pharmacology
  • Animals
  • Antidepressive Agents / pharmacology*
  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Carrier Proteins / drug effects
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Depression / metabolism
  • Depression / physiopathology
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins
  • Female
  • Fluoxetine / pharmacology
  • Hypothalamo-Hypophyseal System / metabolism*
  • Hypothalamo-Hypophyseal System / physiopathology
  • Male
  • Membrane Glycoproteins*
  • Membrane Transport Proteins*
  • Mice
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Neostriatum / drug effects
  • Neostriatum / metabolism
  • Nerve Tissue Proteins*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Receptors, Dopamine D1 / drug effects
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Glucocorticoid / drug effects
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Stress, Physiological / metabolism
  • Stress, Physiological / physiopathology
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism*
  • Substantia Nigra / physiopathology

Substances

  • Antidepressive Agents
  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Receptors, Glucocorticoid
  • Fluoxetine
  • Amitriptyline
  • Dopamine