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

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.