Neuroprotective role of estrogen upon methamphetamine and related neurotoxins within the nigrostriatal dopaminergic system

In this report we describe some of the data on the capacity for estrogen to function as a neuroprotectant of the nigrostriatal dopaminergic (NSDA) system. The data show that estrogen (E) can alter two different response characteristics to NSDA neurotoxins. The first being that striatal DA concentrations of ovariectomized rodents treated with E are consistently greater than non-E-treated animals in response to neurotoxins which produce degeneration of the NSDA system. The second being that E significantly reduces the amount of DA output upon initial exposure to the NSDA neurotoxin, 1-methyl-4-phenylpyridium ion (MPP+). At present, it is not known whether these two response characteristics are related. An intriguing possibility is that the E-dependent changes in initial DA output are related to the resultant neurotoxicity ( I attenuations in DA concentration reductions). So far our incipient findings do not seem to support this eventuality. However, additional testing on this topic is required. The present data suggest that one of the mechanisms by which E can exert these effects is through inhibition of DAT activity. This conclusion results from data which show that E produces: I) an inhibition of [H-3]DA uptake, 2) a reduction in DA clearance rates, and 3) an effect upon DA recovery that is similar to that observed to the putative DA uptake blocker, nomifensine. The capacity and significance for steroid hormones to modulate neurotransmitter transporters has been recently reviewed.