Nigrostriatal damage is increased in males relative to females. While estrogen is neuroprotective in females, less is known about potential protective effects of testosterone in males. We determined if castration enhances neuronal injury to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Castrates or sham-castrated mice were sacrificed 1 week following injection of MPTP ( ？mg/kg) or saline ( /group). The right striatum was immunostained for tyrosine hydroxylase (TH). The left hemisphere was stained by Golgi Cox to quantify neuronal morphology in medium spiny neurons (MSNs) of the dorsolateral striatum. MPTP reduced TH, but there was no effect of castration and no interaction. For MSN dendritic morphology, MPTP decreased the highest branch order and increased spine density on 2nd-order dendrites. Castrated males had shorter 5th-order dendrites. However, there was no interaction between gonadal status and MPTP. Thus, castration and MPTP exert nonoverlapping effects on MSN morphology with castration acting on distal dendrites and MPTP acting proximally. 1. Introduction Gonadal steroid hormones are potent modulators of neuronal survival and neuronal morphology [1]. In the adult, steroid hormones exert activational effects in steroid-responsive brain regions which include protective effects against neurodegeneration [2, 3]. However, sex differences exist in many neurodegenerative disorders, suggesting that the male and female brains are not equally responsive to gonadal steroids. In this regard, Parkinson’s disease (PD) is a common neurological disorder that demonstrates a substantial sex difference, with a one- to twofold higher incidence in men [4]. PD results from the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNC; [5]). Dopaminergic efferents from SNC project rostrally as part of the nigrostriatal pathway to the dorsolateral striatum, where they synapse onto medium spiny neurons (MSNs). These efferents are reduced in PD, leading to a depletion of striatal dopamine. Gonadal steroids modulate the function of the nigrostriatal system and are thought to contribute, in part, to this sex difference. In females, estrogen promotes the function of the nigrostriatal system by enhancing striatal dopamine release, increasing dopamine metabolism and altering both dopamine receptors and uptake sites [6, 7]. In response to neurotoxic insult, estrogen is also neuroprotective in the nigrostriatal system [7]. This has been well demonstrated using？1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine？(MPTP) and 6-hydroxydopamine (6-OHDA),
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