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Alterations in reward valuation are thought to have a central role at all stages of the addiction process. We previously reported work aversion in an effortful T-maze task following a binge exposure to methamphetamine, and no such changes in effort following escalating doses. Limitations of the T-maze task include its two available options, with an effort requirement, in the form of increasing barrier height, varying incrementally as a function of time, and reward magnitudes held constant. Reward preferences and choices, however, are likely affected by the number of options available and the manner in which alternatives are presented. In the present experiment, we investigated the long-lasting, off-drug effects of methamphetamine on reward choices in a novel effortful maze task with three possible courses of action, each associated with different effort requirements and reward magnitudes. Neuroinflammatory responses associated with drug exposure, proposed as one of the mechanisms contributing to suboptimal choices on effort-based tasks, were also examined. We investigated region-specific changes in pro- and anti-inflammatory markers in the mesocorticolimbic pathway after methamphetamine, and their relationship with animals' reward choices. We observed long-lasting, increased sensitivity to differences in reward magnitude in the methamphetamine group: animals were more likely to overcome greater effort costs to obtain larger rewards on our novel effortful maze task. These behavioral changes were strongly predicted by pronounced decreases in frontocortical cytokines, but not amygdalar or striatal markers. The present results provide the first evidence that neuroinflammatory processes are associated with alterations in reward valuation during protracted drug withdrawal.

Reductions in Frontocortical Cytokine Levels are Associated with Long-Lasting Alterations in Reward Valuation after Methamphetamine