title: Viral vector-mediated overexpression of estrogen receptor-alpha in striatum enhances the estradiol-induced motor activity in female rats and estradiol-modulated GABA release.
abstract: Classical estrogen receptor-signaling mechanisms involve estradiol binding to intracellular nuclear receptors [estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta)] to promote changes in protein expression. Estradiol can also exert effects within seconds to minutes, however, a timescale incongruent with genomic signaling. In the brain, estradiol rapidly potentiates stimulated dopamine release in the striatum of female rats and enhances spontaneous rotational behavior. Furthermore, estradiol rapidly attenuates the K(+)-evoked increase of GABA in dialysate. We hypothesize that these rapid effects of estradiol in the striatum are mediated by ERalpha located on the membrane of medium spiny GABAergic neurons. This experiment examined whether overexpression of ERalpha in the striatum would enhance the effect of estradiol on rotational behavior and the K(+)-evoked increase in GABA in dialysate. Ovariectomized female rats were tested for rotational behavior or underwent microdialysis experiments after unilateral intrastriatal injections of a recombinant adeno-associated virus (AAV) containing the human ERalpha cDNA (AAV.ERalpha) into the striatum; controls received either the same vector into areas outside the striatum or an AAV containing the human alkaline phosphatase gene into the striatum (AAV.ALP). Animals that received AAV.ERalpha in the striatum exhibited significantly greater estradiol-induced contralateral rotations compared with controls and exhibited behavioral sensitization of contralateral rotations induced by a low-dose of amphetamine. ERalpha overexpression also enhanced the inhibitory effect of estradiol on K(+)-evoked GABA release suggesting that disinhibition of dopamine release from terminals in the striatum resulted in the enhanced rotational behavior.
authors.affiliation: Molecular and Behavioral Neuroscience Institute and Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Kristin N
authors.initials: KN
authors.lastname: Schultz
authors.forename: Silke A
authors.initials: SA
authors.lastname: von Esenwein
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.forename: Amy L
authors.initials: AL
authors.lastname: Bennett
authors.forename: Robert T
authors.initials: RT
authors.lastname: Kennedy
authors.forename: Sergei
authors.initials: S
authors.lastname: Musatov
authors.forename: C Dominique
authors.initials: CD
authors.lastname: Toran-Allerand
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kaplitt
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Young
authors.forename: Jill B
authors.initials: JB
authors.lastname: Becker
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000502:physiology / Q000821:virology*; D000229:Dependovirus / Q000235:genetics; D004958:Estradiol / Q000235:genetics / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D009043:Motor Activity / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012725:Sexual Behavior / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D004958:Estradiol; D005680:gamma-Aminobutyric Acid