Changes in Neural Circuitry Regulating Response-Reversal Learning and Arc-Mediated Consolidation of Learning in Rats with Methamphetamine-Induced Partial Monoamine Loss

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2014-03, Vol.39 (4), p.963-972
• Main Authors: PASTUZYN, Elissa D, KEEFE, Kristen A
• Format: Article
• Language: English
• Subjects: Animals; Biogenic Monoamines - metabolism; Biological and medical sciences; Brain; Brain - drug effects; Brain - metabolism; Central Nervous System Stimulants - pharmacology; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Dopamine; Dopamine Plasma Membrane Transport Proteins - metabolism; Drug Administration Schedule; Gene Expression Regulation - drug effects; Hypotheses; Laboratory animals; Male; Medical sciences; Memory; Methamphetamine; Methamphetamine - pharmacology; Nerve Net - drug effects; Nerve Net - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neuropharmacology; Neurotoxicity; Oligodeoxyribonucleotides, Antisense - pharmacology; Original; Parkinson's disease; Pharmacology. Drug treatments; Protein Binding - drug effects; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Radioligand Assay; Rats; Rats, Sprague-Dawley; Retention (Psychology) - drug effects; Reversal Learning - drug effects; Serotonin Plasma Membrane Transport Proteins - metabolism; Toxicology
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2013.296

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.