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Published on: January 22, 2016
Neurotoxic Methamphetamine Doses Alter CDCel-1 Levels and Its Interaction with Vesicular Monoamine Transporter-2 in
Heli Chauhan1, Nick Carruthers2, Paul Stemmer2
1Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave, Detroit, MI, USA 48201.
Abstract:
In recent years, methamphetamine METH misuse in the US has been rapidly increasing and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). In addition to being dependent on the drug, people with MUD develop a variety of neurological problems related to the toxicity of this drug. A variety of molecular mechanisms underlying METH neurotoxicity has been identified, including dysfunction of the neuroprotective protein parkin. However, it is not known whether parkin loss of function within striatal dopaminergic (DAergic) terminals translates into a decrease in DA storage capacity. This study examined the relationship between parkin, its substrate cell division cycle related-1 (CDCrel-1), and vesicular monoamine transporter-2 (VMAT2) in METH neurotoxicity in male Sprague Dawley rats. To also assess individual differences in response to METH's neurotoxic effects, a large group of rats was treated with binge METH or saline and sacrificed 1h or 24h later. This study is the first to show that binge METH alters the levels and subcellular localization of CDCrel-1 and that CDCrel-1 interacts with VMAT2 and increases its levels at the plasma membrane. Furthermore, we found wide individual differences in the responses of measured indices to METH. Proteomic analysis of VMAT-2-associated proteins revealed upregulation of several proteins involved in the exocytosis/endocytosis cycle. The results suggest that at 1h after METH binge, DAergic neurons are engaged in counteracting METH-induced toxic effects, including oxidative stress- and hyperthermia-induced inhibition of synaptic vesicle cycling, with the responses varying between individual rats. Studying CDCrel-1, VMAT2, and other proteins in large groups of outbred rats can help define individual genetic and molecular differences in responses to METH neurotoxicity which, in turn, will aid treating humans suffering from METH use disorder and its neurological consequences.
Insights
Methamphetamine (METH) use disorder causes neurotoxicity, impacting dopamine storage. This study reveals METH alters CDCrel-1 and VMAT2 interactions in rat brains, highlighting individual differences in response and potential therapeutic targets.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Methamphetamine (METH) misuse is rising in the US, with no approved treatments for METH use disorder (MUD).
- METH neurotoxicity causes neurological issues, potentially linked to the dysfunction of the neuroprotective protein parkin.
- The impact of parkin dysfunction on dopamine storage capacity in striatal dopaminergic terminals remains unclear.
Purpose of the Study:
- To investigate the relationship between parkin, CDCrel-1, and VMAT2 in the context of METH neurotoxicity.
- To assess individual variations in neurotoxic responses to METH exposure.
- To explore the molecular mechanisms underlying METH-induced alterations in dopaminergic neurons.
Main Methods:
- Male Sprague Dawley rats were administered binge METH or saline and sacrificed at 1h or 24h intervals.
- Levels and subcellular localization of CDCrel-1 and VMAT2 were analyzed.
- Proteomic analysis was performed on VMAT2-associated proteins.
Main Results:
- Binge METH exposure altered CDCrel-1 levels and subcellular localization, promoting its interaction with VMAT2.
- CDCrel-1 was found to increase VMAT2 levels at the plasma membrane.
- Significant individual differences in responses to METH were observed across measured indices.
- Proteomic analysis revealed upregulation of proteins involved in the exocytosis/endocytosis cycle in VMAT2-associated fractions.
Conclusions:
- DAergic neurons attempt to counteract METH-induced toxicity, including oxidative stress and hyperthermia, at 1h post-binge.
- Individual variability in METH neurotoxicity responses is substantial.
- Studying CDCrel-1, VMAT2, and associated proteins in diverse rat populations can elucidate genetic and molecular differences, aiding MUD treatment.
