Disrupting reconsolidation by systemic inhibition of Thioredoxin-1 attenuates cocaine and morphine relapse

The enduring nature of drug-associated memories is an essential factor contributing to the relapse. Drug-related cues can activate drug memories, making them enter reconsolidation, during which interventions can effectively disrupt these memories. Interventions targeting memory reconsolidation present a promising therapeutic strategy for addressing substance use disorders (SUDs). Oxidative stress can disrupt neural function and impair memory. Thioredoxin-1 (Trx-1) effectively alleviates oxidative stress and reduces inflammation levels. However, few studies have connected Trx-1 to drug memory or explored its specific role in reconsolidation. This research employed the conditioned place preference (CPP) model to investigate the effects of Trx-1 inhibitors on the reconsolidation of morphine- and cocaine-related memories. Results show that immediate administration of PX-12, a Trx-1 inhibitor, after retrieval significantly attenuated the reinstatement of cocaine and morphine CPP induced by both cues and the drug itself, with the effect lasting for at least 14 days. In contrast, the inhibition of Trx-1, either 6 hours following retrieval or in the absence of retrieval, does not influence drug-seeking behaviors associated with cocaine or morphine. Furthermore, Trx-1 inhibitor itself did not produce any preferences. In summary, our results indicate that Trx-1 activity is crucial for cocaine- and morphine-related memories, and that the Trx-1 inhibitor may serve as a potential treatment for drug abuse.