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Updated: May 18, 2026
A Plate-Based Assay for the Measurement of Endogenous Monoamine Release in Acute Brain Slices
Published on: August 11, 2021
Disruption of subcellular Arc/Arg 3.1 mRNA expression in striatal efferent neurons following partial monoamine loss
Melissa L Barker-Haliski1, Katharina Oldenburger, Kristen A Keefe
1Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, USA.
Abstract:
The immediate-early gene Arc (activity-regulated cytoskeleton-associated protein) is provocative in the context of neuroplasticity because of its experience-dependent regulation and mRNA transport to and translation at activated synapses. Normal rats have more preproenkephalin-negative (ppe-neg; presumed striatonigral) neurons with cytoplasmic Arc mRNA than ppe-positive (ppe-pos; striatopallidal) neurons, despite equivalent numbers of these neurons showing novelty-induced transcriptional activation of Arc. Furthermore, rats with partial monoamine loss induced by methamphetamine (METH) show impaired Arc mRNA expression in both ppe-neg and ppe-pos neurons relative to normal animals following response-reversal learning. In this study, Arc expression induced by exposure to a novel environment was used to assess transcriptional activation and cytoplasmic localization of Arc mRNA in striatal efferent neuron subpopulations subsequent to METH-induced neurotoxicity. Partial monoamine depletion significantly altered Arc expression. Specifically, basal Arc expression was elevated, but novelty-induced transcriptional activation was abolished. Without novelty-induced Arc transcription, METH-pre-treated rats also had fewer neurons with cytoplasmic Arc mRNA expression, with the effect being greater for ppe-neg neurons. Thus, METH-induced neurotoxicity substantially alters striatal efferent neuron function at the level of Arc transcription, suggesting a long-term shift in basal ganglia neuroplasticity processes subsequent to METH-induced neurotoxicity. Such changes potentially underlie striatally based learning deficits associated with METH-induced neurotoxicity.
Insights
Methamphetamine (METH) neurotoxicity impairs activity-regulated cytoskeleton-associated protein (Arc) gene expression in rat striatal neurons. This disruption affects Arc mRNA transport and translation, potentially causing long-term changes in neuroplasticity and learning.
Area of Science:
- Neuroscience
- Molecular Biology
- Neuropharmacology
Background:
- Activity-regulated cytoskeleton-associated protein (Arc) is crucial for synaptic plasticity and is regulated by experience.
- Striatal neurons, including preproenkephalin-negative (ppe-neg) and preproenkephalin-positive (ppe-pos) subtypes, show differential Arc mRNA localization.
- Methamphetamine (METH)-induced neurotoxicity is known to affect monoamine systems and potentially alter neuronal function.
Purpose of the Study:
- To investigate the impact of METH-induced neurotoxicity on Arc gene expression in distinct striatal efferent neuron populations.
- To assess how METH affects novelty-induced transcriptional activation and cytoplasmic localization of Arc mRNA.
- To understand the long-term consequences of METH neurotoxicity on basal ganglia neuroplasticity and learning.
Main Methods:
- Rats were subjected to METH treatment to induce partial monoamine loss.
- Novelty exposure was used to trigger Arc expression.
- Arc mRNA levels and localization in ppe-neg and ppe-pos striatal neurons were analyzed using molecular techniques.
Main Results:
- METH-induced neurotoxicity led to elevated basal Arc expression but abolished novelty-induced Arc transcriptional activation.
- Rats pre-treated with METH exhibited significantly fewer neurons with cytoplasmic Arc mRNA following novelty exposure, particularly in ppe-neg neurons.
- These alterations in Arc expression were observed in both striatonigral and striatopallidal pathways.
Conclusions:
- METH-induced neurotoxicity profoundly disrupts the regulation of Arc transcription in striatal efferent neurons.
- The impaired Arc expression suggests a long-term alteration in neuroplasticity mechanisms within the basal ganglia.
- These molecular changes may contribute to the learning deficits associated with METH neurotoxicity.
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