, Volume 14, Issue 4, pp 307-315

effect of methamphetamine neurotoxicity on learning-inducedarc mRNA expression in identified striatal efferent neurons

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Methamphetamine abuse results in lasting, partial depletions of striatal dopamine and cognitive dysfunction. However, the effect of partial dopamine depletions on the expression of an effector immediate early gene,Arc (activity regulated, cytoskeletal-associated protein), known to be involved in synaptic modifications underlying learning and memory, has heretofore not been examined. Male Sprague-Dawley rats were pre-treated with a neurotoxic regimen of methamphetamine or saline. Seven weeks later, rats were trained in a motor-response task on a T-maze for five days, and then underwent reversal training on day five. Rats were sacrificed 5 min after reaching criterion on the reversal task, and the brains were removed and processed using double-label fluorescentin situ hybridization forArc andpreproenkephalin (PPE) mRNA expression in the dorsomedial striatum. Rats pretreated with methamphetamine had an average (±SEM) 54.4±7.9% loss of dopamine in dorsomedial striatum. Interestingly, there was no difference in reversal trials to criterion in methamphetamine- vs. saline-pretreated rats. However, the expression ofArc mRNA in dorsomedial striatum was attenuated in methamphetamine-pre-treated animals, particularly inPPE-negative neurons. Furthermore, the correlation betweenArc mRNA expression in dorsomedial striatum and learning was abolished in methamphet-amine-pretreated animals. These data suggest that methamphetamine-induced partial mono-amine loss is associated with disrupted induction of the effector immediate early geneArc during a behavioral task, particularly inPPE- negative (presumed striatonigral) neurons, as well as with disruption of the relation betweenArc mRNA expression in dorsomedial striatum and reversal learning.