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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    157—Drugs of Abuse: Toxicity and Structural Plasticity

    Sunday, November 10, 2013, 8:00 am - 12:00 noon

    157.17: Methamphetamine-induced impairment in phasic dopamine signaling, Arc, and basal ganglia-mediated learning and memory functions

    Location: Halls B-H

    *E. D. PASTUZYN1,2, C. D. HOWARD3, P. A. GARRIS3, K. A. KEEFE1,2;
    1Dept. of Pharmacol. and Toxicology, 2Interdepartmental Program in Neurosci., Univ. of Utah, Salt Lake City, UT; 3Sch. of Biol. Sci., Illinois State Univ., Normal, IL

    Abstract Body: Methamphetamine (METH) causes partial loss of dopamine (DA) in the caudate/putamen in humans and rodents, and this loss 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 DM striatum of saline (SAL)-pretreated rats is infused with either the NMDA receptor antagonist AP5 or Arc antisense oligonucleotide to knock down Arc expression, reversal learning and retention of learning are impaired. However, METH-pretreated rats are unaffected by either treatment. These data provide evidence that METH-pretreated rats no longer use DM striatum to perform this task. The logical next step was to determine which brain region/circuitry now mediates response reversal learning in these rats. Analysis of 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 particular reversal task, we next 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 predictive 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 seen in SAL-pretreated rats. These results suggest that METH-induced neurotoxicity results in altered circuitry use in the brain during a reversal learning task, but that restoration of phasic DA signaling may be able to rescue striatal function.

    Lay Language Summary: Methamphetamine is a highly addictive psychostimulant drug of abuse, and methamphetamine addiction remains a serious societal problem. Research has shown that chronic methamphetamine use can have multiple long-lasting effects, including brain damage, problems with memory, and difficulty in learning new tasks, severely impacting the daily lives of addicts. One of the ways brain damage manifests itself in methamphetamine abusers is in a partial loss of neurons that release the neurotransmitter dopamine. These neurons are lost from a brain region called the striatum. Both dopamine and the striatum are important for learning and movement. We can model this partial loss of dopamine in the striatum in rats, and in doing so, have discovered a novel way in which we might therapeutically treat methamphetamine-induced brain damage.
    Our data suggest that the methamphetamine-induced damage disrupts a particular type of dopamine signaling; namely, “phasic” dopamine signaling. Phasic dopamine signaling is thought to be necessary for learning in the striatum to occur, and so loss of phasic signaling may underlie the memory deficits in methamphetamine abusers. We therefore hypothesized that restoring phasic dopamine signaling should restore function of the striatum.
    To test this hypothesis, we electrically stimulated dopamine neurons in rats with methamphetamine-induced brain damage in a way that mimics phasic dopamine signaling. A gene called Arc, critical for learning and memory, is highly active in healthy striatum, but its activation is impaired in the methamphetamine rat model. We found that electric stimulation could activate Arc to normal levels. This result suggests that restoration of phasic dopamine signaling might help alleviate learning and memory deficits seen in methamphetamine abusers.
    Drug treatments may also recover dopamine signaling. For example, L-DOPA alleviates symptoms of Parkinson’s disease by providing the brain with more dopamine. We tested whether L-DOPA could also restore phasic dopamine signaling and brain function in the methamphetamine rat model. We measured dopamine release in the striatum of normal and methamphetamine-treated rats and found that L-DOPA completely restored the impairment in phasic dopamine signaling. Our findings suggest that L-DOPA, as well as other medications that increase phasic dopamine signaling, may potentially be of therapeutic use in recovering methamphetamine addicts. Future studies will examine the impact L-DOPA and other such drugs have on behavior in the methamphetamine rat model and see whether they can restore cognition.