[Abstract Title]. - Society for Neuroscience

NINDS Grant NS48141
Title: Using microdialysis coupled on-line to capillary electrophoresis to study the rapid effects
of estradiol on GABA release in the striatum
Authors: *K. N. SCHULTZ 1 , M. HU 2 , S. MUSATOV 3 , M. G. KAPLITT 4 , R. T. KENNEDY 1 ,
J. B. BECKER 2 ;
1 Chem., Univ. Michigan, Ann Arbor, MI; 2 Mol. & Behavioral Neurosci. Inst., Univ. of
Michigan, Ann Arbor, MI; 3 Neurobio. Behavior, Rockefeller Univ., New York, NY;
4 Neurosurg., Weill-Cornel Med. Col., New York, NY
Abstract: Sex differences exist across all stages of addiction from initiation to relapse with
females being more susceptible to the addictive effects of drugs. Work in our lab has shown that
estradiol has a profound effect on drug taking behavior and potentiates stimulated dopamine
release in the striatum. A potential mechanism for this effect is that estradiol modulates GABA
release which in turn modulates release of dopamine. To test the hypothesis that estradiol
regulates GABA release, we have investigated the effect of manipulation of estrogen signaling
on GABA release in the striatum measured using microdialysis coupled on-line to capillary
electrophoresis. We have found that estradiol benzoate (EB) injected subcutaneously into
ovariectomized (OVX) female rats decreases K+-evoked GABA release by 50% (n = 7). To
determine if this effect is mediated by the alpha estrogen receptor (ERα), we overexpressed this
receptor by microinjection of an adeno-associated viral vector containing DNA for human ERα
into the striatum. To control for effects associated with the viral vector implant, half of the OVX
animals received a vector containing DNA for alkaline phosphatase (ALP). We found that with
ERα overexpressed, estradiol was even more potent in inhibiting K+-evoked GABA release with
a two fold greater reduction seen in EB+ERα animals compared to EB+ALP animals (53% [n=8]
vs. 23% [n=9] compared to vehicle+ALP animals). This result supports the hypothesis that
estradiol inhibits GABA function through ERα. We next began to evaluate the mechanism of
estradiol signaling. Our hypothesis is that estradiol exerts its effect through a mitogen activated
protein kinase (MAPK) pathway. To test this hypothesis, PD 98059, an inhibitor of mitogenactivated
protein kinase kinase (MEK), was microinjected into the striatum of OVX rats
pretreated with EB. Compared to vehicle treated controls PD 98059 (0.1 mM, n=3) increased
K+-evoked GABA release 30% suggesting that estradiol binding to ERα activates the MAPK
pathway to inhibit GABA release from the medium spiny neurons. Our results suggest that
estradiol inhibits GABA function through ERα and MAPK pathways. These results suggest that
previously observed enhancing effects of estradiol on dopamine may be mediated by suppression
of GABA release with subsequent disinhibition of DA. This estradiol dependent GABA release
may contribute to sex differences in drug addiction and further investigation into the signaling
mechanisms may identify new therapeutic targets.
Disclosures: K.N. Schultz, None; M. Hu, None; S. Musatov, None; M.G. Kaplitt, None; J.B.
Becker, None; R.T. Kennedy, None.