title: Changes in neural circuitry regulating response-reversal learning and Arc-mediated consolidation of learning in rats with methamphetamine-induced partial monoamine loss.
abstract: Methamphetamine (METH)-induced neurotoxicity results in long-lasting depletions of monoamines and changes in basal ganglia function. We previously reported that rats with METH-induced neurotoxicity no longer engage dorsomedial striatum during a response-reversal learning task, as their performance is insensitive to acute disruption of dorsomedial striatal function by local infusion of an N-methyl-D-aspartate receptor antagonist or an antisense oligonucleotide against the activity-regulated cytoskeleton-associated (Arc) gene. However, METH-pretreated rats perform the task as well as controls. Therefore, we hypothesized that the neural circuitry involved in the learning had changed in METH-pretreated rats. To test this hypothesis, rats were pretreated with a neurotoxic regimen of METH or with saline. After 3-5 weeks, rats were trained on the reversal-learning task and in situ hybridization for Arc was performed. A significant correlation between Arc expression and performance on the task was found in nucleus accumbens shell of METH-, but not saline-, pretreated rats. Consistent with the idea that the correlation between Arc expression in a brain region and behavioral performance implicates that brain region in the learning, infusion of an antisense oligonucleotide against Arc into the shell impaired consolidation of reversal learning in METH-, but not saline-, pretreated rats. These findings provide novel evidence suggesting that METH-induced neurotoxicity leads to a shift from dorsal to ventral striatal involvement in the reversal-learning task. Such reorganization of neural circuitry underlying learning and memory processes may contribute to impaired cognitive function in individuals with METH-induced neurotoxicity or others with striatal dopamine loss, such as patients with Parkinson's disease.
authors.affiliation: Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, UT, USA.
authors.forename: Elissa D
authors.initials: ED
authors.lastname: Pastuzyn
authors.affiliation: 1] Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, UT, USA [2] Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Keefe
mesh_terms: D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012153:Retention, Psychology / Q000187:drug effects*; D012193:Reversal Learning / Q000187:drug effects*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
chemical_list: D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D003598:Cytoskeletal Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D050486:Serotonin Plasma Membrane Transport Proteins; C092069:activity regulated cytoskeletal-associated protein; D008694:Methamphetamine