Use of in vitro superfusion to assess the dynamics of striatal dopamine clearance: influence of estrogen

Brain Research 842 Ž1999. 399–407 www.elsevier.comrlocaterbres

Research report

Use of in vitro superfusion to assess the dynamics of striatal dopamine clearance: influence of estrogen Kimberly A. Disshon, Dean E. Dluzen

)

Department of Anatomy, Northeastern Ohio UniÕersities College of Medicine, 4209 State Route 44, P.O. Box 95, Rootstown, OH, 44272-0095 USA Accepted 13 July 1999

Abstract To determine the feasibility of assessing dopamine uptake using in vitro superfusion, striatal tissue from ovariectomized female rats was infused with dopamine Ž1 mM., nomifensine Ž1 mM., or a combination of dopamine and nomifensine. Treatment with nomifensine or dopaminernomifensine increased the recovery of dopamine in the effluent samples as compared to treatment with dopamine alone. In Experiment 2, the striatal tissue was treated with varying concentrations Ž0, 3, 30 or 300 nM. estradiol throughout the superfusion and subsequently given a dopamine Ž1 mM. challenge. The recovery of dopamine was enhanced in the presence of 3 and 30 nM estradiol. These results show that Ž1. in vitro superfusion can be used to dynamically evaluate dopamine recovery, and Ž2. estradiol, like nomifensine, increases the recovery of exogenously applied dopamine from the striata of ovariectomized female rats. Such increases in dopamine recovery with estrogen and similarities to that obtained with nomifensine suggest that estrogen may be inhibiting dopamine uptake from these striatal tissue fragments. Moreover, the doses at which estrogen can exert these effects insinuates a physiological role for this process. Our data provide a clear functional demonstration for one of the mechanisms by which estradiol can modulate striatal dopamine neurons, that of an uptake inhibitor. Such a mechanism has important implications with regard to estradiol’s capacity to function as a neuroprotectant of the nigrostriatal dopaminergic system through inhibition of uptake of neurotoxins which can produce neurodegeneration of striatal dopamine neurons. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Nigrostriatal; Parkinson’s disease; Uptake; Nomifensine

1. Introduction It has been well established that gonadal steroid hormones have a substantial effect on striatal dopaminergic function. Animal studies using rodents show that as hormone levels fluctuate throughout the estrous cycle, changes can be seen in neurochemical w10,22x and behavioral w3,35x parameters of nigrostriatal function. Estradiol in particular has been shown to have an effect on the striatum, independent of the presence of other hormones w4,38x. The effects of estradiol on the striatum are critically dependent upon a number of factors including time of exposure to estrogen ŽEST., dose, and administration route w38x. Of particular interest to our group are results from several studies which suggest an enhancement of dopaminAbbreÕiations: DA, Dopamine; EST, Estrogen; NSDA, Nigrostriatal dopaminergic; NMF, Nomifensine ) Corresponding author. Fax: q1-330-325-5913; E-mail: [email protected]

ergic transmission as a result of acute EST treatment. Within 30 min of an injection of estradiol to an ovariectomized rat, there is an increase in dopamine ŽDA. turnover, revealed by increases in tyrosine hydroxylase activity w28x and in the DA metabolites homovanillic acid and dihydroxyphenylacetic acid w11x. In addition, there is a potentiation of both amphetamine-induced rotational behavior w2x and striatal DA release w2,8x. The rapidity of these responses suggest a non-genomic mechanism of action, since it is generally accepted that it takes at least 1 h to see the effects mediated by the classical steroid receptor mechanism of action w6x. In further support of this idea that EST is working through a non-genomic mechanism, are studies that demonstrate a potentiation in the activity of the nigrostriatal dopaminergic ŽNSDA. system as a result of administration of estradiol directly to the striatum. Estradiol, when applied directly to striatal tissue fragments superfused in vitro, potentiates DA release w1x. Moreover, estradiol implanted into the striatum enhances the beam walking ability of ovariectomized female rats as compared to

0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 1 8 6 3 - 6

400

K.A. Disshon, D.E. Dluzenr Brain Research 842 (1999) 399–407

non-treated controls w3x. These direct effects of estradiol support the idea of a non-genomic mechanism of action since EST specific steroid receptors are notably absent in the striatum w29x. From this brief review it seems reasonable to suggest that EST can work within the striatum through a non-genomic mechanism to increase extracellular DA levels. Possible explanations for the increased extracellular DA suggested in the above studies include an increase in the release of DA, andror an inhibition of DA uptake as a result of EST treatment. It had been suggested that estradiol may function as an uptake blocker in the striatum w30x, and we have recently reported that estradiol rapidly and competitively inhibits the uptake of w3 HxDA into striatal synaptosomes by decreasing the affinity of the transporter for DA w13x. Because the uptake of DA through the DA transporter is the primary mechanism for removing DA from the synapse w19x, this effect of estradiol represents an important mechanism by which this gonadal steroid may modulate NSDA function. While the use of a synaptosomal preparation enabled us to qualitatively and quantitatively assess the effects of estradiol on the DA transporter, it does not allow for easy interpretation of the physiological relevance or function of this effect. In an attempt to achieve a more physiological and dynamic evaluation of EST upon the fate of extracellular DA, we evaluated the effects of EST at the tissue level using in vitro superfusion. Specifically, we used a modified superfusion technique which involved the administration of a pulse of exogenous DA in the presence or absence of EST, and subsequent collection and quantification of DA in the superfusion effluent. Infusion of a fixed amount of exogenous DA and measurement of the resultant output allows us to compare the extent to which DA was recovered from the neurons and therefore provided an indication of the DA clearance capacity of the tissue as a result of drug treatment. The goal of this study was to use this modified superfusion protocol to determine whether EST has a detectable effect on clearance of extracellular DA at the tissue level. To accomplish this goal, striatal tissue from ovariectomized female rats was superfused with medium containing EST or not. An infusion of exogenous DA was administered to each group and the DA in the effluent was collected and quantified to determine DA recovery.

2. Materials and methods 2.1. Animals Adult female Sprague–Dawley rats ŽZivic Miller Laboratories. were housed in the NEOUCOM vivarium under a 12 h lightr12 h dark cycle, with lights on at 0600 h. Water and Lab chow were available ad libitum. Female rats were ovariectomized more than 10 days prior to use. Ovariectomies were performed while the rats were under ketamine:acepromazine Ž10:1 at 100 mgrkg. anesthesia. All efforts were made to minimize animal suffering and to limit the number of animals used. All treatments adhere to the NIH guidelines and were approved by the animal care committee at NEOUCOM. 2.2. Superfusion Recovery rate determinations of DA were conducted using an in vitro superfusion system. The superfusion medium was a modified Kreb’s Ringer Phosphate ŽKRP. buffer: 120 mM NaCl, 4.8 mM KCl, 0.8 mM CaCl 2 , 1.2 mM MgSO4 , 10.2 mM Na 2 HPO4 , 1.8 mM NaH 2 PO4 , and 0.18% glucose at a pH of 7.4. The specifics of the superfusion apparatus have been described elsewhere w12x. On the day of the experiment, one rat was killed by decapitation, the bilateral striata were minced together into small tissue fragments Ž0.5 = 0.5 = 0.5 mm. and divided equally among eight superfusion chambers with an average Ž"S.E.M.. of 10.18 " 0.29 mg of tissue per chamber. Each of these chambers was then subjected to one of the differing treatment conditions described below. Following a 30-min equilibration, samples were collected on ice at 10 min intervals for nine intervals and analyzed using HPLC with electrochemical detection. 2.3. Experimental conditions 2.3.1. Experiment 1 — nomifensine The purpose of Experiment 1 is to demonstrate the effect of a known uptake blocker, nomifensine ŽNMF., on DA recovery using this modified superfusion protocol. To accomplish this goal, Experiment 1 consisted of three treatment groups involving direct in vitro infusions of Ž1. DA Ž1 mM, dopamine hydrochloride, Sigma. Ž2. DA and

Fig. 1. ŽA. In vitro DA recovery rate profiles from superfused striatal tissue fragments of ovariectomized rats. The N is equal to the number of animals used, replicated treatment groups within an animal were averaged for the analysis and presentation of the data. The KRP medium was replaced during interval 4 with one of the following treatments: DA Ž1 mM., NMF Ž1 mM., or DA combined with NMF. Infusion resumed with KRP at interval 5. Values represent mean DA recovery rates as expressed in pg of DArmg of tissuerminute. The S.E.M. bars are omitted for purposes of clarity in the presentation of the profiles but are contained within the data summary histograms. Data analyses summaries of critical intervals of the superfusion are contained in ŽB.. The black bar on the X axis denotes the period of DA infusion. ŽB. Summary of the analyses of the DA recovery rate profiles for the treatment groups of ŽA.. The N is equal to the number of animals used, replicated treatment groups within an animal were averaged for the analysis and presentation of the data. Values represent the mean " S.E.M. DA recovery as expressed in pg DArmg of tissuerminute for critical intervals of the superfusion. Interval 3 represents basal release, and intervals 4, 5, 6 and 7 represent DA recovery after the infusion of exogenous DA at interval 4. U Denotes a difference from the DA group.

K.A. Disshon, D.E. Dluzenr Brain Research 842 (1999) 399–407

NMF ŽDA: 1 mM, NMF: 1 mM ŽHoechst–Roussel Pharmaceuticals.., or Ž3. or NMF alone Ž1 mM. during interval 4 into superfusion chambers containing striatal tissue from ovariectomized female rats. Following treatment, superfu-

401

sions resumed with KRP medium. A 1 mM concentration of NMF was used as we have observed this to serve as an effective dose capable of increasing DA output under our conditions of in vitro superfusion. Wet tissue weight was

402

K.A. Disshon, D.E. Dluzenr Brain Research 842 (1999) 399–407

determined after the superfusion and DA output was then expressed as the pg DArmg tissue weightrminute since this provided an index of recovery as related to the specific amount of tissue within each chamber.

2.3.2. Experiment 2 — estradiol The purpose of this experiment was to determine whether the presence of estradiol in the superfusion medium had an effect on the recovery of exogenously applied DA.

K.A. Disshon, D.E. Dluzenr Brain Research 842 (1999) 399–407

In effect, the estradiol was substituted for the NMF to examine whether estradiol would exert a similar effect upon DA recovery. In this experiment, striatal tissue from ovariectomized female rats was subjected to one of four treatments. Each group received a 10-min infusion of DA during interval 4. Three of the groups had either 3, 30 or 300 nM 17b-estradiol ŽSigma. included in the superfusion medium throughout the entire superfusion while the fourth Žcontrol. group received a DA infusion in the absence of estradiol. Estradiol was initially dissolved in ethanol before diluting to experimental concentrations with KRP. Final ethanol concentrations in the KRP medium were - 1.0%. Previous work has indicated no effect of this ethanol concentration and the effect was confirmed from the results of Experiment 3. 2.3.3. Experiment 3 — estradiol alone To verify that the effects of estradiol could not be attributed to an estradiol-evoked increase in DA release under the present superfusion conditions, striatal tissue from ovariectomized female rats was infused with 3 nM estradiol throughout the entire superfusion or KRP, with no subsequent DA infusion during interval 4. 2.4. Statistical analysis In order to compare differences in DA recovery rates among the treatment groups, specific critical collection intervals of the superfusion were compared directly among the groups within an experiment. The N is equal to the number of animals used, replicated treatment groups within an animal were averaged for the analysis and presentation of the data. Collection interval 3 was used to compare DA output among the groups before DA infusion Žbasal release.. Collection intervals 4, 5, 6 and 7 were used to compare the output following DA infusion for all groups. These four intervals were isolated for analyses since this represented the period of maximal responsiveness and physiological significance for the assessment of DA recovery. The effects of the treatments were compared among the groups within an experiment using one-way analysis of variance, and subsequent pairwise comparisons between treatments were made using the Fisher’s least significant difference test. A p-value of 0.05 was required for results to be considered statistically significant.

403

3. Results 3.1. Experiment 1 — nomifensine The DA recovery profiles for the three treatment groups of Experiment 1 are presented in Fig. 1A, while Fig. 1B contains a summary of these data analyses. No significant differences in DA output were seen among the groups during intervals 3, 4 or 5. During interval 6 of the superfusion, there was an overall significant difference in DA recovery Ž F2,9 s 5.468, p s 0.028.. Post hoc comparisons revealed that DA recovery from chambers receiving DArNMF were significantly greater Ž p s 0.0092. compared to the DA alone group. No significant differences in DA output were seen among the groups during interval 7. 3.2. Experiment 2 — estradiol The DA recovery rate profiles for the four treatment groups of Experiment 2 are presented in Fig. 2A, while Fig. 2B contains a summary of the data analyses. No differences were seen in basal DA levels among groups Žinterval 3.. During interval 4 there was an overall significant difference in DA recovery Ž F3,19 s 5.313, p s 0.008. with a significantly greater output of DA from chambers treated with 3 Ž p s 0.040. and 30 Ž p s 0.026. nM estradiol than from those treated with DA alone. During interval 5, the DA recovery after DA infusion was again significantly different Ž F3,19 s 4.458, p s 0.016., with greater output from the groups treated throughout the superfusion with 3 Ž p s 0.050. or 30 nM Ž p s 0.045. estradiol when compared to the DA alone group. No differences were seen among groups during intervals 6 and 7 of the superfusion. The DA recovery from the 300 nM estradiol group failed to differ from that of the DA group at any of the collection intervals analyzed. Significantly more DA was recovered from both the 3 and 30 nM estradiol groups as compared to the 300 nM group at intervals 4 Ž p s 0.0061, p s 0.0039. and 5 Ž p s 0.0093, p s 0.0083.. 3.3. Experiment 3 — estradiol alone The DA recovery rate profiles for the four treatment groups of Experiment 3 are presented in Fig. 3A, while Fig. 3B contains a summary of the data analyses. No

Fig. 2. ŽA. In vitro DA recovery rate profiles from the superfused striatal tissue fragments of ovariectomized rats. The N is equal to the number of animals used, replicated treatment groups within an animal were averaged for the analysis and presentation of the data. Of the four groups in Experiment 2, three were perfused with one of three doses of EST Ž3, 30 and 300 nM. throughout the entire superfusion, while the other received no EST treatment. All four groups were infused with 1 mM DA during interval 4. Infusion resumed with KRP during interval 5. Values represent mean DA recovery expressed in pg DArmg tissuerminute. Data analyses summaries of critical intervals of the superfusion are contained in ŽB.. The black bar on the X axis denotes the period of DA infusion. ŽB. Summary of the analyses of the DA recovery rate profiles for the treatment groups of ŽA.. The N is equal to the number of animals used, replicated treatment groups within an animal were averaged for the analysis and presentation of the data. Values represent the mean " S.E.M. DA recovery for critical intervals of the superfusion. Interval 3 represents basal release, and intervals 4, 5, 6 and 7 represent DA recovery after the infusion of DA at interval 4. U Denotes a difference from the DA group, and a denotes a difference from the 300 nM EST.

404

K.A. Disshon, D.E. Dluzenr Brain Research 842 (1999) 399–407

Fig. 3. ŽA. In vitro DA release rate profiles from superfused striatal tissue fragments of ovariectomized rats. The N is equal to the number of animals used, replicated treatment groups within an animal were averaged for the analysis and presentation of the data. The tissue was treated with 3 nM EST throughout the superfusion or not ŽKRP.. No DA infusion was given. Values represent mean DA recovery rates as expressed in pg of DArmg of tissuerminute. Data analyses summaries of critical intervals of the superfusion are contained in ŽB.. ŽB. Summary of the analyses of the DA recovery rate profiles for the treatment groups of ŽA.. The N is equal to the number of animals used, replicated treatment groups within an animal were averaged for the analysis and presentation of the data. Values represent the mean " S.E.M. DA recovery for critical intervals of the superfusion. No significant differences were obtained at any of the intervals compared.

K.A. Disshon, D.E. Dluzenr Brain Research 842 (1999) 399–407

differences were found between the estradiol treated and the non-treated group during any of the critical intervals analyzed for the two treatment groups of Experiment 3.

4. Discussion Our primary goal was to determine whether EST alters the clearance of extracellular DA as determined by the recovery of exogenously infused DA from striatal tissue of ovariectomized female rats under conditions of in vitro superfusion. To accomplish this goal, the recovery of DA from superfused striatal tissue was compared between estradiol treated and non-treated tissue. In order to examine whether EST could function in this capacity, it was first necessary to establish the feasibility of utilizing superfusion for evaluating DA recovery. Such demonstrations of DA recovery involving uptake was indicated by the experiments using the putative uptake blocker, NMF. This agent has been used previously as a means to assess DA clearance in studies utilizing in vivo voltammetry w36,39x. Under the conditions of this experiment, DA recoveries were significantly increased when NMF was contained within the medium as compared with that of the DA alone group ŽFig. 1B.. The fact that increased recovery responses were revealed with NMF suggests that DA recoveries serve as an index of uptake activity. We then asked whether similar response characteristics would be obtained by substituting estradiol for NMF to assess whether this gonadal steroid hormone may also display this function. The data from Experiment 2 show that the inclusion of 3 and 30 nM estradiol in the superfusion medium resulted in the greatest amount of DA recovery during intervals 4, 5 and 6, and was significantly greater than that obtained in the absence of EST. This increase in extracellular DA concentrations could be due to several factors, but we favor the idea that our results are most likely due to a decrease in uptake for several reasons: Ž1. the increased DA recovery observed when EST was included in the medium was analogous to that obtained with NMF; Ž2. although estradiol has been reported to increase release when administered in a pulsatile fashion w1x, or when estradiol was present during release that was induced by another stimulus w2,8x, there is no evidence that a continuous infusion alone w1,12x as administered in the present experiment was effective in increasing DA release; Ž3. to confirm the absence of any direct effects of continuous EST infusion, chambers containing striatal tissue from ovariectomized rats were infused with either 3 nM estradiol or KRP and no difference in DA recovery was seen during any of the critical intervals in the absence of a DA infusion ŽExperiment 3., suggesting that the increase in DA in the effluent was not due to an increase in DA release ŽFig. 3A and B.; Ž4. our laboratory has recently reported that estradiol inhibits the uptake of DA into striatal synaptosomes by causing an increase in the K m of

405

the DA transporter for DA w13x; Ž5. the reports that estradiol can inhibit the uptake of DA from a number of central nervous system sites including cortex w23x, thalamus w40x and hypothalamus w18x. It should be noted that not all data support this hypothesis that EST inhibits DA uptake since an increase in DA transporter density after acute estradiol treatment as assessed using w3 HxGBR 12935 has also been reported to occur in response to EST w25x. The mechanism by which EST inhibits the uptake of DA is unclear, but several mechanisms can be suggested based on the available evidence from the literature. Estradiol may affect DA transporter function through a non-genomic membrane receptorrsecond messenger system. For example, estradiol has been demonstrated to inhibit neuronal membrane calcium channels through such a mechanism w24x. Estradiol has also been demonstrated to affect several isozymes of protein kinase C, with most studies reporting an increase in protein kinase C activity w5,27,34x. Since protein kinase C has been demonstrated to phosphorylate the DA transporter, thereby inhibiting DA uptake w9,20,41x, this may represent an additional mechanism. When comparing NMFrDA profiles and 3 nM ESTrDA profiles to that of the DA alone group, the estradiol treated group shows a significant increase in DA recovery at intervals 4 and 5, but NMFrDA fails to invoke a significant increase until interval 6. The fact that we observe significant increases in DA recovery at earlier collection intervals with ESTrDA than with that of NMFrDA could suggest some effect upon DA metabolism. Estradiol can alter DA synthesis and metabolism, resulting from its effects on tyrosine hydroxylase w28x andror monoamine oxidase w33x activities to alter recovery rates. However, this difference may also be due to the fact that estradiol is present in the superfusion chamber at a maximal concentration at the time of DA infusion. By contrast, NMF infusion began with the DA infusion, and may not reach a maximum concentration until later. Therefore, the experimental paradigm may contribute to the differences seen in the latency of the maximal effect. It is well known that the effects of estradiol on the striatum are dose-dependent w38x. The observed increases in DA recovery with 3 and 30 nM estradiol treatment as compared to DA alone or 300 nM estradiol is interesting in light of the fact that the concentration of estradiol in the rat striatum has been reported to fluctuate between 1.1 and 4.6 nM throughout the estrous cycle w26x. The 3 nM concentration of estradiol used in our present study is clearly within the range of normal physiological brain concentrations in the rat, suggesting that the observed effect of estradiol on DA clearance can occur under physiological conditions. These effects are lost when a supra-physiological estradiol dose Ž300 nM. is used, providing further evidence for a limited range and physiological response of this gonadal steroid hormone. An enhancement of dopaminergic neurotransmission, via an inhibition of uptake by estradiol, may help explain

406

K.A. Disshon, D.E. Dluzenr Brain Research 842 (1999) 399–407

several of the behavioral and biochemical effects seen after administration of this hormone. Following ovariectomy, amphetamine-induced rotational behavior, electrically induced rotational behavior, and amphetamine-induced stereotyped behaviors are attenuated w7,31,32x. Treating ovariectomized rats with EST enhances amphetamine-induced rotational behavior w2x and amphetamine-stimulated DA concentrations w2,8x. These responses to EST have previously been attributed to EST effects on synthesis, release, and metabolism, but in light of the present data, inhibition of DA uptake must be considered as an additional explanation for the increased dopaminergic transmission. Such a mechanism would have wide-ranging implications. Not only could these effects result in substantial modulation of NSDA function, as DA clearance represents an important mechanism regulating DA effects w19,21x, but may also influence such activities as responses to neurotoxins which utilize the DA transporter to gain access to the neuron. For example, we have demonstrated that striatal DA neurotoxicity to both 6-hydroxydopamine and MPTP is attenuated in EST treated rodents and have speculated that these effects may involve a reduction in the uptake of these neurotoxins by EST w12,14,16,17x. The effect of EST on NSDA function is important in light of the gender differences seen in the pathology of this system, Parkinson’s disease. Parkinson’s disease has been reported to occur more in men than women Žreviewed in Dluzen et al., 1998 w15x. and it has been speculated that the pathogenesis of Parkinson’s disease may be related to DA transporter function w37x. The role that gonadal steroid hormones may play in this gender difference is still unclear. The inhibition of DA uptake by estradiol may alter dopaminergic neurotransmission, or inhibit the uptake of an endogenous or environmental toxin, providing some form of protection for women when compared to men. Accordingly, a better understanding of gonadal steroid hormone effects on nigrostriatal function is needed to determine the role they play in the gender differences in Parkinson’s disease. In summary, these results demonstrate that in vitro superfusion can be used to dynamically evaluate the clearance of extracellular DA and that estradiol affects DA clearance with a maximal effect at a concentration reported to be within physiological ranges.

w5x

w6x

w7x

w8x

w9x

w10x

w11x

w12x

w13x

w14x w15x

w16x

w17x

w18x

w19x

w20x

w21x

References w22x w1x J.B. Becker, Direct effect of 17 beta-estradiol on striatum: sex differences in dopamine release, Synapse 5 Ž1990. 157–164. w2x J.B. Becker, Estrogen rapidly potentiates amphetamine-induced striatal dopamine release and rotational behavior during microdialysis, Neurosci. Lett. 118 Ž1990. 169–171. w3x J.B. Becker, P.J. Snyder, M.M. Miller, S.A. Westgate, M.J. Jenuwine, The influence of estrous cycle and intrastriatal estradiol on sensorimotor performance in the female rat, Pharmacol. Biochem. Behav. 27 Ž1987. 53–59. w4x P.J. Bedard, T. Di Paolo, P. Langelier, P. Poyet, F. Labrie, Behav-

w23x

w24x

w25x

ioral and biochemical evidence of an effect of estradiol on striatal dopamine receptors, in: K. Fuxe, J.-A. Gustafsson, L. Welterberg ŽEds.., Steroid Hormone Regulation of the Brain, Pergamon, Oxford, 1981, pp. 331–339. E. Bignon, A. Kishimoto, M. Pons, A.C. de Paulet, J. Gilbert, J.-F. Miquel, Y. Nishizuka, Dual action of hydroxylated diphenylethylene estrogens on protein kinase C, Biochem. Biophys. Res. Commun. 166 Ž1990. 1471–1478. D.W. Brann, L.B. Hendry, V.B. Mahesh, Emerging diversities in the mechanism of action of steroid hormones, J. Steroid Biochem. Mol. Biol. 52 Ž1995. 113–133. D.M. Camp, J.B. Becker, T.E. Robinson, Sex differences in the effects of gonadectomy on amphetamine-induced rotational behavior in rats, Behav. Neural Biol. 46 Ž1986. 491–495. S.A. Castner, L. Xiao, J.B. Becker, Sex differences in striatal dopamine: in vivo microdialysis and behavioral studies, Brain Res. 610 Ž1993. 127–134. B.J. Copeland, V. Vogelsberg, N.H. Neff, M. Hadjiconstantinou, Protein kinase C activators decrease dopamine uptake into striatal synaptosomes, J. Pharmacol. Exp. Ther. 277 Ž1996. 1527–1532. C.F. Davis, B.F. Davis, A.E. Halaris, Variations in the uptake of 3 H-dopamine during the estrous cycle, Life Sci. 20 Ž1977. 1319– 1332. T. Di Paolo, C. Rouillard, P. Bedard, 17b-estradiol at a physiological dose acutely increases dopamine turnover in rat brain, Eur. J. Pharmacol. 117 Ž1985. 197–203. K.A. Disshon, D.E. Dluzen, Estrogen as a neuromodulator of MPTP-induced neurotoxicity: effects upon striatal dopamine release, Brain Res. 764 Ž1997. 9–16. K.A. Disshon, J.W. Boja, D.E. Dluzen, Inhibition of striatal dopamine transporter activity by 17b-estradiol, Eur. J. Pharmacol. 345 Ž1998. 207–211. D.E. Dluzen, Estrogen decreases corpus striatal neurotoxicity in response to 6-OHDA, Brain Res. 767 Ž1997. 340–344. D.E. Dluzen, K.A. Disshon, J.L. McDermott, Estrogen as a modulator of striatal dopaminergic neurotoxicity. In: J. Marwah, H. Teitelbaum ŽEds.., Recent Advances in Neurodegenerative Disorders, Prominent Press, Scottsdale, 1998, pp. 149–192 D.E. Dluzen, J.L. McDermott, B. Liu, Estrogen alters MPTP-induced neurotoxicity in female mice: effects on striatal dopamine concentrations and release, J. Neurochem. 66 Ž1996. 658–666. D.E. Dluzen, J.L. McDermott, B. Liu, Estrogen as a neuroprotectant of the nigrostriatal dopaminergic system against MPTP-induced neurotoxicity, Neurotoxicol. Teratol. 18 Ž1996. 603–606. C.A. Endersby, C. Wilson, The effect of ovarian steroids on the accumulation of 3 H-labelled monoamines by hypothalamic tissue in vitro, Brain Res. 73 Ž1974. 321–331. A.S. Horn, in: A.S. Horn, J. Korf, B.H.C. Westerink ŽEds.., The Neurobiology of Dopamine, Academic Press, New York, 1979, pp. 217–235. R.A. Huff, R.A. Vaughan, M.J. Kuhar, G.R. Uhl, Phorbol esters increase dopamine transporter phosphorylation and decrease transport Vma x , J. Neurochem. 68 Ž1997. 225–232. M. Jaber, S. Jones, B. Giros, M.G. Caron, The dopamine transporter: a crucial component regulating dopamine transmission, Mov. Disord. 12 Ž1997. 629–633. A. Jori, F. Colturani, E. Dolfini, M. Rutczynski, Modifications of the striatal dopamine metabolism during the estrus cycle in mice, Neuroendocrinology 21 Ž1976. 262–266. M.C. Michel, A. Rother, C. Hiemke, R. Ghraf, Inhibition of synaptosomal high-affinity uptake of dopamine and serotonin by estrogen agonists and antagonists, Biochem. Pharmacol. 36 Ž1987. 3175– 3180. P.G. Mermelstein, J.B. Becker, D.J. Surmeier, Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor, J. Neurosci. 16 Ž1996. 595–604. M. Morissette, D. Biron, T. Di Paolo, Effect of estradiol and

K.A. Disshon, D.E. Dluzenr Brain Research 842 (1999) 399–407

w26x

w27x

w28x

w29x

w30x

w31x

w32x

w33x

progesterone on rat striatal uptake sites, Brain Res. Bull. 25 Ž1990. 419–422. M. Morissette, L.M. Garcia-Segura, A. Belanger, T. Di Paolo, Changes of rat striatal neuronal membrane morphology and steroid content during the estrous cycle, Neuroscience 49 Ž1992. 893–902. T.M. Morozova, R.L. Mitina, V.A. Rau, O.M. Sidorkina, Mechanisms of the stimulating action of estradiol on Protein Kinase C in the plasma membranes of target cells, Biochemistry ŽUSSR. 54 Ž1989. 475–482. C. Pasqualini, V. Olivier, B. Guibert, O. Frain, V. Leviel, Acute stimulatory effect of estradiol on striatal dopamine synthesis, J. Neurochem. 65 Ž1995. 1651–1657. D. Pfaff, M. Keiner, Atlas of estradiol-concentrating cells in the central nervous system of the female rat, J. Comp. Neurol. 151 Ž1973. 121–158. V.D. Ramirez, Hormones and striatal dopaminergic activity: a novel neuroendocrine model, in: A.S. Bhatnagar ŽEd.., The Anterior Pituitary Gland, Raven Press, New York, 1983, pp. 97–45. T.E. Robinson, D.M. Camp, J.B. Becker, Gonadectomy attenuates turning behavior produced by electrical stimulation of the nigrostriatal dopamine system in female but not male rats, Neurosci. Lett. 23 Ž1981. 203–208. M.M. Savageau, W.W. Beatty, Gonadectomy and sex differences in the behavioral responses to amphetamine and apomorphine of rats, Pharmacol. Biochem. Behav. 14 Ž1980. 17–21. H. Shimizu, G.A. Bray, Effects of castration, estrogen replacement

w34x

w35x

w36x w37x

w38x w39x

w40x

w41x

407

and estrus cycle on monoamine metabolism in the nucleus accumbens, measured by microdialysis, Brain Res. 621 Ž1993. 200–206. O.M. Sidorkina, T.M. Morozova, V.A. Rau, Translocation of protein kinase C under the action of estradiol from the cytosol into the cell membranes and activation of the enzyme in the target cells, Biochemistry ŽUSSR. 53 Ž1988. 347–352. M. Steiner, R.J. Katz, G. Baldrighi, B.J. Carroll, Motivated behavior and the estrous cycle in rats, Psychoneuroendocrinology 6 Ž1981. 81–90. T.L. Thompson, In vivo dopamine transport may be inhibited by estrogen priming, Soc. Neurosci. 23 Ž1997. 693, abstract a 274.10. G.R. Uhl, Hypothesis: the role of dopaminergic transporters in selective vulnerability of cells in Parkinson’s disease, Ann. Neurol. 43 Ž1998. 555–560. C. Van Hartesveldt, J.N. Joyce, Effects of estrogen on the basal ganglia, Neurosci. Biobehav. Rev. 10 Ž1986. 1–14. C. Van Horne, B.J. Hoffer, I. Stomberg, G.A. Gerhardt, Clearance and diffusion of locally applied dopamine in normal and 6-hydroxydopamine-lesioned rat striatum, J. Pharmacol. Exp. Ther. 263 Ž1992. 1285–1292. A. Wirz-Justice, E. Hackmann, M. Lichtsteiner, The effect of oestradiol dipropionate and progesterone on monoamine uptake in rat brain, J. Neurochem. 22 Ž1974. 187–189. L. Zhang, L.L. Coffey, M.E.A. Reith, Regulation of the functional activity of the human dopamine transporter by protein kinase C, Biochem. Pharmacol. 53 Ž1997. 677–688.