Effects of Estrogen and Related Agents upon Methamphetamine-Induced Neurotoxicity within an Impaired Nigrostriatal Dopaminergic System of Ovariectomized Mice

Abstract

Estrogen increases methamphetamine (MA)-induced neurotoxicity within the impaired nigrostriatal dopaminergic (NSDA) system of ovariectomized female mice, as defined by enhanced striatal dopamine (DA) depletion. In this study we compared the effects of a lower dose of estradiol benzoate (EB, 1 µg) with related agents – tamoxifen (TMX, 12.5 µg), testosterone (5 µg) and dehydroepiandrosterone (DHEA, 3 mg) in this paradigm. In experiment 1, ovariectomized mice received an initial treatment with MA. At 1 week after MA, mice were treated with EB, TMX, testosterone, DHEA or oil vehicle and 24 h later a second MA treatment. Striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations in the MA-treated groups were decreased compared to the non-MA-treated control. Neither EB nor any of the other agents tested showed enhanced neurodegenerative or neuroprotective effects against a second MA invasion. To verify that estrogen was capable of showing a neuroprotective effect under a condition of two administrations of MA, in experiment 2, EB was administered either once or twice prior to each of the two MA treatments. EB treatment prior to the first MA invasion or first and second MA protected the NSDA system against DA and DOPAC depletion. These results imply that a lower dose of EB, TMX, testosterone and DHEA cannot exert neurodegenerative or neuroprotective effects in the impaired NSDA model. However, EB administered prior to the introduction of neurotoxicity can protect the NSDA system. This study may provide an understanding of the variations in results on the effects of estrogen upon the NSDA neurodegenerative disorder, Parkinson’s disease.

The possible role of estrogen and selective estrogen receptor modulators in a rat model of Parkinson's disease

“…Other reports have shown that estrogens increase dopamine synthesis in the SN (presynaptic effects), and also increases release of dopamine from nigral axon terminates within the striatum (postsynaptic effects). In rodents and in neuronal cell culture studies, estrogens have been shown to protect dopaminergic neurons from injury (Liu and Dluzen, 2006;Arvin et al, 2000).…”

Are Parkinson disease patients protected from some but not all cancers?

“…In ovarectomized mice, studies show that estrogen partly blocks metamphetamine-induced striatal dopaminergic depletion. [37][38][39] Tamoxifen, a selective estrogen receptor modulator, presents a neuroprotective effect against methamphetamine and methoxy-phenyltetrahydropyridine-induced toxicity when used alone but abolishes estrogen's positive effects when combined with this hormone. 40 We have observed PD patients whose initial symptom of metastatic carcinoma was marked exacerbation of parkinsonian symptoms, which became non-levodopa responsive (J. Jankovic, personal observation).…”

Aripiprazole-Induced Tardive Dyskinesia: The Role of Tamoxifen

“…Tamoxifen, a selective estrogen receptor modulator with mixed agonist/antagonist action, is used in the prevention and treatment of breast cancer (4). Animal studies have shown a neuroprotective role of estrogen and tamoxifen at the nigrostriatal dopamine pathway; however, this finding has not been ubiquitous (5,6). Increased dopamine release (directly or indirectly through modulating dopamine receptor function) and modulation of membrane dopamine transporter activity have been postulated as some of the neuroprotective mechanisms of estrogen (5,6).…”