Differential Responses of LINE-1 in the Dentate Gyrus, Striatum and Prefrontal Cortex to Chronic Neurotoxic Methamphetamine: A Study in Rat Brain

Abstract

Methamphetamine (METH) is a widely abused psychostimulant with the potential to cause a broad range of severe cognitive deficits as well as neurobehavioral abnormalities when abused chronically, particularly at high doses. Cognitive deficits are related to METH neurotoxicity in the striatum and hippocampus. The activation of transposable Long INterspersed Nuclear Element 1 (LINE-1) is associated with several neurological diseases and drug abuse, but there are very limited data regarding the effects of high-dose METH on the activity of LINE-1 in the adult brain. Using real-time quantitative PCR, the present study demonstrates that the chronic administration of neurotoxic METH doses results in the increased expression of LINE-1-encoded Open Reading Frame 1 (ORF-1) in rat striatum shortly after the last dose of the drug and decreased ORF-1 expression during METH withdrawal, with dentate gyrus potentially developing “tolerance” to these METH effects. LINE-1 activation may be a new factor mediating the neurotoxic effects of chronic METH in the striatum and, therefore, a new drug target against METH-induced psychomotor impairments in chronic METH users.

Interchromosomal translocation in neural progenitor cells exposed to L1 retrotransposition

“…Virtually any RNA molecule can be subject to in trans retrotransposition if hijacked by L1 machinery (Esnault et al, 2000;Wei et al, 2001;Kajikawa and Okada, 2002;Dewannieux et al, 2003). Thus, each developing neuron can potentially carry several L1-mediated events, and if some of the resulting insertions occur in genes expressed during neuronal development, it is possible that neuronal networks during brain development could be significantly impacted by de novo L1 insertions (Muotri and Gage, 2006;Cao et al, 2006;Baillie et al, 2011;Evrony et al, 2012;Jacob-Hirsch et al, 2018;Shpyleva et al, Short Communication Cellular, Molecular and Developmental Genetics Muotri 2 2018;Moszczynska, 2020;Bundo and Iwamoto, 2023). The characterization of L1 insertions in NPCs reveals if the neural intracellular milieu can interfere with L1 insertion, helping to pave the way for a better understanding of the role of L1 retrotransposition in the nervous system (Thomas et al, 2012;Suarez et al, 2018).…”