Dopamine Transporter as a Marker of Neuroprotection in Methamphetamine-Lesioned Mice Treated Acutely with Estradiol

Abstract

Our laboratories have shown the positive effect of estradiol on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- and methamphetamine (MA)-induced striatal dopamine (DA) depletion. Most studies on E neuroprotection use chronic administration of the steroid to evaluate its beneficial effect. In the present report, we investigated the neuroprotective potential of 17β-estradiol-3-benzoate (E) under acute conditions when administered 24, 12 or 0.5 h before MA. The effects of E on striatal DA and dihydroxyphenylacetic acid (DOPAC) contents, and DA transporter (DAT) protein and mRNA were measured using high-performance liquid chromatography, autoradiography and in situ hybridization, respectively. We observed neuroprotection with an acute dose of E, and also that protection presents a different time course for each dopaminergic marker. DAT mRNA responded more quickly to E than its protein (at 0.5 h vs. 24 h). Also, E treatment 12 h prior to MA resulted in ‘normal’ (equal to control) DA content, while DAT protein was still decreased as compared to control values. These different responses for each marker may represent different mechanisms of action of E (genomic versus nongenomic). Since most experimental studies use DA content as the sole indicator of nigrostriatal toxicity and examine a single time point following chronic E administration, the present results demonstrate the importance of evaluating differences in temporally dependent responses of DA, DAT protein and mRNA, to achieve a more comprehensive indication of the nigrostriatal state and the means by which E can function as a neuroprotectant in this system.

Sex Differences in Methamphetamine-Evoked Striatal Dopamine Output Are Abolished following Gonadectomy: Comparisons with Potassium-Evoked Output and Responses in Prepubertal Mice

“…Such findings highlight an additional characteristic of MA-induced NSDA neurotoxicity as they suggest the potential for a combination of effects exerted by estrogen and testosterone as contributing to the sex differences obtained. In support of this possibility are data which demonstrate that estrogen can act to diminish striatal DA depletions [14, 15,39,40,41,42] while testosterone either has no effect or displays a tendency to increase striatal DA depletions [43, 44] to MA.…”

“…Moreover, the dissimilarities in gonadal steroid hormones may result in bidirectional effects upon MA-induced neurotoxicity within the NSDA system. This follows from data which show that estrogen can function as a neuroprotectant against MA-induced NSDA neurodegeneration [14, 15,39,40,41,42], while testosterone has no such neuroprotective effects [43], and may exacerbate MA-induced NSDA neurodegeneration [44]. …”

Differential Protective Properties of Estradiol and Tamoxifen against Methamphetamine-Induced Nigrostriatal Dopaminergic Toxicity in Mice

“…This gender difference may, in part, be attributable to estrogen since epidemiological studies have demonstrated a beneficial role of estrogens in PD [3, 4]. Laboratory studies have also shown the protective potential of estrogens on brain against methamphetamine (MA) [5,6,7,8,9] and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [10, 11], two substances that induce damages similar to those encountered in PD [12]. Although these positive effects are well documented, concerns have been raised regarding the clinical use of estrogens.…”

“…Included in this assessment were measures of DA concentrations and transporters, as well as preproenkephalin (PPE) expression. Striatal DA concentration is extensively used as a marker of DA neurodegeneration [5,6,7,8,9,10,11]. In the striatum the DA transporter (DAT)-specific binding is on presynaptic DA terminals of substantia nigra DA neurons whereas in the substantia nigra DAT binding is on DA neurons thus giving anatomical information on degeneration of these neurons [23].…”

The sex difference of plasma homovanillic acid is unaffected by cross-sex hormone administration in transsexual subjects

“…Sex steroids have been found to affect neurotransmitters and neurotransmitter receptors of the dopaminergic systems in complex ways, at least in cell and animal studies (Becker 1999, Eaton et al 1999, Andersen et al 2002, Landry et al 2002, Halbreich & Kahn 2003, D'Astous et al 2004. In humans, the potential effects of sex hormone administration on dopaminergic activity have not yet been studied extensively (Lobo et al 1984, Hannan et al 1991, Paoletti et al 2001.…”