Striatal learning and memory after methamphetamine-induced neurotoxicity and subsequent restoration of striatal function

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Title Striatal learning and memory after methamphetamine-induced neurotoxicity and subsequent restoration of striatal function
Publication Type dissertation
School or College School of Medicine
Department Neurology
Author Pastuzyn, Elissa D.
Date 2014
Description Methamphetamine (METH) causes partial dopamine (DA) loss in the caudate/putamen and has long-term detrimental effects on cognitive function. We have previously shown that the positive correlation between expression of the immediate-early gene Arc in dorsomedial (DM) striatum and learning on a motor response reversal task is lost in rats with METH-induced striatal DA loss, despite normal behavioral performance. This discrepancy suggests that METH-pretreated rats no longer use DM striatum in this task. When function of or Arc expression in DM striatum of saline (SAL)-pretreated rats is disrupted, reversal learning and retention of learning, respectively, are impaired. However, METH-pretreated rats are unaffected by either treatment, suggesting that METH-pretreated rats no longer use DM striatum to perform this task. In situ hybridization histochemical staining for Arc mRNA expression in various brain regions of rats revealed a correlation between Arc and response reversal learning in nucleus accumbens (NAc) shell of METH-pretreated rats that did not exist in SAL-pretreated rats. When Arc was knocked down in the NAc shell, memory consolidation on the reversal task in METH-pretreated rats was impaired, whereas it was unaffected in SAL-pretreated rats, suggesting that METH-pretreated rats are relying on the NAc shell instead of DM striatum to consolidate reversal memories. Since the above evidence strongly suggests that METH-induced damage to the striatum forces rats to rely on a different brain region to complete this reversal task, we attempted to restore striatal function in METH-pretreated rats by manipulating extracellular DA levels. METH-pretreated rats are selectively deficient in phasic DA signaling, which generates transient DA changes in response to rewards and their cues. We stimulated the brains of METH- and SAL-pretreated rats in a phasic-like manner and found that the reduced striatal preprotachykinin gene expression in METH-pretreated rats was restored to control levels. Furthermore, we found that L-DOPA, the biochemical precursor to DA, restored phasic DA signals in METH-pretreated rats back to the baseline levels in SAL-pretreated rats. These results suggest that METH-induced neurotoxicity results in altered circuitry used in the brain during a reversal learning task, but that restoration of phasic DA signaling may be able to rescue striatal function.
Type Text
Publisher University of Utah
Subject Neurosciences; Pharmacology; Physiological psychology
Dissertation Name Doctor of Philosophy
Language eng
Rights Management (c) Elissa D. Pastuzyn
Format application/pdf
Format Medium application/pdf
ARK ark:/87278/s6s22gj2
Setname ir_etd
ID 1418754
Reference URL https://collections.lib.utah.edu/ark:/87278/s6s22gj2
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