Inhibition of striatal dopamine transporter activity by 17beta-estradiol.
Female; Animals; Rats; Dopamine/metabolism; Neostriatum/*drug effects/metabolism; Dopamine Plasma Membrane Transport Proteins; *Membrane Glycoproteins; *Nerve Tissue Proteins; Estradiol/*pharmacology; *Membrane Transport Proteins; Carrier Proteins/*antagonists & inhibitors; Synaptosomes/*drug effects/metabolism; Sprague-Dawley
Striatal synaptosomes from ovariectomized rats were prepared to examine the effect of 17beta-estradiol on [3H]dopamine uptake. Estradiol inhibited [3H]dopamine uptake in a dose-dependent manner, with an IC50 of 7.2 microM. Use of identical concentrations of progesterone had no effect on [3H]dopamine uptake. The effects of estradiol were exerted by decreasing the affinity of the transporter for dopamine, as revealed by a dose-dependent increase in the Km. The Km values for 0 (control), 10, and 100 microM estradiol were 108+/-11 258+/-44 and 415+/-40 nM, respectively, with each of the three concentrations tested being significantly different among each other. No statistically significant differences were obtained for the Vmax, with values for the three increasing doses being 9.2+/-0.8, 8.3+/-0.5 and 7.3+/-0.8 pmol/min per mg protein. These results demonstrate that estradiol, but not progesterone, inhibits striatal dopamine uptake by decreasing the affinity of the transporter for dopamine. Such a mechanism may serve as one of the bases for the modulatory effects of estradiol upon the nigrostriatal dopaminergic system.
Disshon K A; Boja J W; Dluzen D E
European journal of pharmacology
1998
1998-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Modulation of olfactory bulb tyrosine hydroxylase and catecholamine transporter mRNA by estrogen.
*Membrane Glycoproteins; *Nerve Tissue Proteins; Animals; Delayed-Action Preparations; Dopamine Plasma Membrane Transport Proteins; Drug Combinations; Estrogen Antagonists/administration & dosage; Estrogens/administration & dosage/*pharmacology; Female; Inbred Strains; Membrane Transport Proteins/*genetics/metabolism; Messenger/*metabolism; Mice; Molecular Sequence Data; Norepinephrine Plasma Membrane Transport Proteins; Olfactory Bulb/*drug effects/enzymology/*physiology; Ovariectomy; Rats; RNA; Symporters/*genetics/metabolism; Tyrosine 3-Monooxygenase/*genetics/metabolism
Since estrogen exerts wide ranging effects within the central nervous system, it is important to investigate the sites and actions of this gonadal steroid hormone at extra-hypothalamic locations. In the present report, the effects of estrogen upon catecholaminergic function within the olfactory bulb were examined. To assess the role of estrogen at this site, ovariectomized mice received either no further hormonal treatment or were treated with estrogen, the anti-estrogen, tamoxifen, or a combination of estrogen and tamoxifen as administered in a 21-day release pellet. At 14 days post-hormonal treatment, the olfactory bulbs were assayed for mRNA levels of tyrosine hydroxylase, dopamine transporter and norepinephrine transporter using competitive-PCR. Tyrosine hydroxylase mRNA levels in either estrogen or estrogen+tamoxifen treated females were significantly decreased compared with non-hormonally treated controls. In addition, tyrosine hydroxylase mRNA levels of tamoxifen-treated mice were significantly greater than that of estrogen-treated mice. Dopamine transporter mRNA levels of tamoxifen-treated females were significantly greater than that of non-hormonally treated controls and estrogen treated mice. The combination of estrogen+tamoxifen significantly increased dopamine transporter mRNA levels compared to that of estrogen treated mice. No overall statistically significant differences in norepinephrine transporter mRNA levels were obtained among the four treatment groups. The data demonstrate that estrogen can exert significant modulatory effects upon olfactory bulb catecholaminergic function. Therefore, events which alter estrogen levels (menstrual/estrogen cycle, pregnancy/lactation, menopause, tamoxifen treatment) can modulate olfactory bulb catecholaminergic functions which may be involved with the detection and processing of olfactory stimuli.
Dluzen Dean E; Park June-Hee; Kim Kyungjin
Brain research. Molecular brain research
2002
2002-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0169-328x(02)00520-x" target="_blank" rel="noreferrer noopener">10.1016/s0169-328x(02)00520-x</a>
Dopamine transporter function differences between male and female CD-1 mice.
*Sex Characteristics; 3; 4-Dihydroxyphenylacetic Acid/metabolism; Animals; Corpus Striatum/physiology; Dopamine Plasma Membrane Transport Proteins; Dopamine/physiology; Female; Male; Membrane Glycoproteins/*physiology; Membrane Transport Proteins/*physiology; Mice; Nerve Tissue Proteins/*physiology
It has been reported that male mice are more susceptible to the neurotoxic effects of methamphetamine (MA) upon the nigrostriatal dopaminergic (NSDA) system. Since MA utilizes the dopamine transporter (DAT) to exert its effects, in the present study, we tested for differences in the dynamics of DAT function between male and female mice as an approach to understand some of the bases for this sex difference in MA-induced NSDA neurotoxicity. To accomplish this goal, in Experiment 1, the amount of dopamine (DA) obtained following DA infusion into the superfused striatal tissue fragments of male and female mice was measured while in Experiment 2 responses to the DA uptake blocker, nomifensine (NMF), were assessed in these preparations. The differences obtained to these treatments demonstrate that marked differences in DA transporter activity exist between male and female mice. When combining the DA and DOPAC measures from these two experiments, the data suggest that the female mice show a more active and efficient recovery and vesicular packaging of extracellular DA. These findings have important implications for sex differences in NSDA functions and responses to neurotoxins which enter the neurons via the DAT.
Bhatt Sandeep D; Dluzen Dean E
Brain research
2005
2005-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.brainres.2004.12.013" target="_blank" rel="noreferrer noopener">10.1016/j.brainres.2004.12.013</a>
Tamoxifen increases methamphetamine-evoked dopamine output from superfused striatal tissue fragments of male mice.
Animals; Corpus Striatum/*drug effects/*metabolism; Dopamine Agents/*pharmacology; Dopamine Plasma Membrane Transport Proteins; Dopamine/*metabolism; Drug Synergism; Estrogen Antagonists/*pharmacology; Inbred Strains; Male; Membrane Glycoproteins/metabolism; Membrane Transport Proteins/metabolism; Methamphetamine/*pharmacology; Mice; Nerve Tissue Proteins/metabolism; Tamoxifen/*pharmacology
The antiestrogen, tamoxifen (TMX), has been shown to function as a neuroprotectant against the nigrostriatal dopaminergic (NSDA) neurotoxin, methamphetamine (MA), within male mice. In the present report, we examined the effects of a combined infusion of TMX and MA within superfused striatal tissue fragments of male mice as an approach to understand some of the bases for TMX to function as a NSDA neuroprotectant within male mice. In Experiment 1, a coinfusion of TMX at 1, 10, or 100 pg/ml were all equally effective in increasing
Willett Matthew C; Dluzen Dean E
Brain research
2004
2004-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.brainres.2004.09.043" target="_blank" rel="noreferrer noopener">10.1016/j.brainres.2004.09.043</a>
Multiple binding sites for [125I]RTI-121 and other cocaine analogs in rat frontal cerebral cortex.
*Membrane Transport Proteins; *Nerve Tissue Proteins; *Symporters; Animals; Binding; Binding Sites; Carrier Proteins/*metabolism; Cocaine/*analogs & derivatives/pharmacokinetics; Competitive; Corpus Striatum/*metabolism; Dopamine Plasma Membrane Transport Proteins; Dopamine/metabolism; Frontal Lobe/*metabolism; Iodine Radioisotopes/*pharmacokinetics; Kinetics; Male; Membrane Glycoproteins/*metabolism; Norepinephrine Plasma Membrane Transport Proteins; Norepinephrine/metabolism; Rats; Regression Analysis; Serotonin Plasma Membrane Transport Proteins; Serotonin/metabolism; Sprague-Dawley
In an effort to identify novel binding sites for cocaine and its analogs, we carried out binding studies with the high-affinity and selective ligand [125I]RTI-121 in rat frontal cortical tissue. Very low densities of binding sites were found. Saturation analysis revealed that the binding was to both high- and low-affinity sites. Pharmacological competition studies were carried out with inhibitors of the dopamine, norepinephrine, and serotonin transporters. The various transporter inhibitors inhibited the binding of 15 pM [125I]RTI-121 in a biphasic fashion following a two-site binding model. The resultant data were complex and did not suggest a simple association with any single transporter. Correlational analysis supported the following hypothesis: [125I] RTI-121 binds to known transporters and not to novel sites; these include dopamine, norepinephrine, and serotonin transporters. Immunoprecipitation of transporters photoaffinity labeled with [125]RTI-82 and subsequent analysis of SDS-page gels revealed the presence of authentic dopamine transporters in these samples; displacement of the photoaffinity label occurred with a typical dopamine transporter pharmacology. These data are compatible with the binding properties of RTI-121 and the presence of several known transporters in the tissue studied.
Boja J W; Carroll F I; Vaughan R A; Kopajtic T; Kuhar M J
Synapse (New York, N.Y.)
1998
1998-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/(SICI)1098-2396(199809)30:1%3C9::AID-SYN2%3E3.0.CO;2-7" target="_blank" rel="noreferrer noopener">10.1002/(SICI)1098-2396(199809)30:1%3C9::AID-SYN2%3E3.0.CO;2-7</a>