Neurotoxic regimens of methamphetamine induce persistent expression of phospho-c-Jun in somatosensory cortex and substantia nigra

Abstract

Repeated systemic administration of moderate doses of methamphetamine (mAMPH) can result in neuronal damage. In addition to the prominent damage of forebrain dopamine and serotonin terminals, mAMPH also injures certain non-monoaminergic neuronal somata in the cerebral cortex. In previous studies, we have localized the damaged neurons to the "whisker barrels" in primary somatosensory cortex, reported the time course of their appearance, and found that sensory inputs from the mystacial vibrissae appear to play a crucial role in the mechanism of their injury by mAMPH. One common feature of these studies is that they used a single marker for neuronal injury, the fluorochrome dye Fluoro-Jade, which stains neurons injured by disparate mechanisms. Here we compare mAMPH-induced damage to somatosensory cortical neurons as assessed by Fluoro-Jade and immunohistochemical staining for phospho-c-Jun. A neurotoxic regimen of mAMPH induced phospho-c-Jun-positive neurons in both cortical whisker barrels and the substantia nigra. Neurons in the barrel cortex can be sufficiently damaged by mAMPH that they become Fluoro-Jade-positive within 2 hr after the final mAMPH injection. By contrast, phospho-c-Jun immunoreactivity does not appear until 12-24 hr after mAMPH. As reported in an earlier study, unilateral removal of vibrissae prior to mAMPH treatment affords partial protection from injury in the hemisphere contralateral to the vibrissotomy. The vibrissotomized animals show similar decreases in Fluoro-Jade staining and phospho-c-Jun immunoreactivity in the protected hemisphere. Since phospho-c-Jun indicates activation of Jun N-terminal kinase pathways, which have been implicated in apoptosis, we conclude that phospho-c-Jun provides a useful new marker for mAMPH-induced damage to cortical neurons.