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Neurotoxic‐related changes in tyrosine hydroxylase, microglia, myelin, and the blood‐brain barrier in the caudate‐putamen from acute methamphetamine exposure

Changes in the histological morphology of the caudate‐putamen (CPu) were determined after a high‐dose methamphetamine (METH) exposure in an effort to elucidate whether BBB disruption plays a role in CPu neurotoxicity. This was accomplished by evaluating the tyrosine hydroxylase immunoreactivity (TH‐IR), isolectin B4 reactivity, Black Gold II (BG‐II) and Fluoro‐Jade C (FJ‐C) staining, and immunoreactivity to mouse immunoglobulin G (IgG‐IR) in adult male mice at 90‐min, 4‐h, 12‐h, 1‐day, and 3‐day post‐METH exposure. The IgG‐IR indicated that the BBB was only modestly altered in the CPu at time points after neurodegeneration occurred and dependent on hyperthermia and status epilepticus. The modest CPu IgG‐IR changes observed in the perivascular areas indicated that immunoglobulins were present on some CPu microglia 1 day or more after METH. The first signs of CPu damage were swellings in the TH‐IR axons, myelin damage, and a few degenerating neurons at 4‐h post‐METH. The loss of TH‐IR was dependent on hyperthermia but not seizures or CPu neurodegeneration, and the TH‐IR was virtually absent throughout the CPu within 12 h. Surprisingly, signs of FJ‐C labeling (degenerating) axons in the CPu were seen only in the regions of pronounced somatic neurodegeneration and independent of TH‐IR loss. Microglial activation did not occur until 1 day or more post‐METH. In summary, a major BBB disruption within the CPu does not directly contribute to neurotoxicity in this single high‐dose METH exposure. However, seizure activity produced or exacerbated by amygdalar BBB disruption can significantly increase CPu somatic neurodegeneration (but not affect dopamine (DA) terminal damage). The time course of microglial activation indicates a response to the neurodegeneration, myelin damage, and/or damaged DA terminals after loss of TH‐IR. Synapse 62:193–204, 2008. © 2007 Wiley‐Liss, Inc.