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Estrogen receptors and lesion-induced response of striatal dopamine receptors

S Al Sweidi1, M Morissette, C Rouillard

  • 1Faculty of Pharmacy, Laval University, Quebec City, QC, Canada G1K 7P4.

Neuroscience
|January 30, 2013
PubMed

Insights

Estrogen receptors (ERs) influence dopamine (DA) receptor responses to MPTP neurotoxicity. ER subtypes differentially affect striatal DA receptors and signaling pathways, impacting neuroprotection strategies.

Area of Science:

  • Neuroscience
  • Endocrinology
  • Pharmacology

Background:

  • 17β-estradiol and estrogen receptor (ER) agonists show neuroprotective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity.
  • The involvement of protein kinase B (Akt) signaling pathways in this neuroprotection is suggested.
  • Understanding the specific roles of ER subtypes (ERα and ERβ) is crucial for elucidating these mechanisms.

Purpose of the Study:

  • To compare the effects of MPTP and 17β-estradiol on dopamine (DA) receptors and signaling pathways in mice with intact or knockout estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ).
  • To evaluate the differential roles of ERα and ERβ in MPTP-induced neurotoxicity and estrogen-mediated neuroprotection.

Main Methods:

  • Utilized wild-type (WT), ERα knockout (ERKOα), and ERβ knockout (ERKOβ) C57Bl/6 male mice.
  • Administered MPTP at varying doses (7, 9, 11 mg/kg) and/or 17β-estradiol.
  • Quantified striatal D1 and D2 dopamine receptors using autoradiography and measured signaling proteins (Akt, GSK3β, ERK1/2) via Western blot.

Main Results:

  • ERKOβ mice exhibited lower baseline striatal D1 receptor binding compared to WT and ERKOα mice.
  • MPTP treatment dose-dependently decreased striatal D1 receptors in ERKOα mice and D2 receptors in WT and ERKOα mice, correlating with dopamine levels.
  • 17β-estradiol increased D1 receptors in ERKOα and ERKOβ mice, and D2 receptors in WT and ERKOβ mice; MPTP modulated Akt and ERK signaling differently across genotypes, notably activating them in ERKOβ mice.

Conclusions:

  • Estrogen receptors significantly modulate the striatal dopamine receptor response to MPTP-induced neurotoxicity.
  • ERα and ERβ play distinct roles in regulating dopamine receptor expression and downstream signaling pathways.
  • Findings highlight the complex interplay between ERs, dopamine system, and neuroprotection mechanisms relevant to neurodegenerative diseases.

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