MTORC1 SIGNALING IN INSTRUMENTAL COCAINE- AND HEROIN- MEMORY RECONSOLIDATION IN RATS

Substance use disorder is a form of maladaptive learning in which drug-related cues evoke persistent memories that drive craving and drug-seeking behaviour, contributing to relapse after abstinence, one of the greatest challenges in addiction treatment. Memory reconsolidation is a process whereby reactivated memories become temporarily labile and require de novo protein synthesis to restabilize, allowing them to be strengthened or updated. Disrupting this process can weaken drug-associated memories and reduce drug seeking. The mechanistic target of rapamycin (mTOR) pathway is a promising candidate, given its central role in regulating the protein synthesis required for memory reconsolidation.
We hypothesize that inhibition of mTOR complex 1 (mTORC1) with rapamycin reduces drug-seeking behaviour by disrupting the reconsolidation of heroin- and cocaine-associated memories. To test this, Sprague–Dawley rats trained in heroin self-administration will undergo a withdrawal period, followed by systemic rapamycin administration prior to memory reactivation. A subsequent drug-seeking test will evaluate the impact of rapamycin on heroin memory reconsolidation. In a second, parallel experiment, rats that have acquired cocaine or heroin self-administration will be analysed for mTORC1 activation following withdrawal and memory reactivation. mTORC1 activity will be assessed by immunofluorescent detection of its downstream effectors, phospho-S6 and phospho-4E-BP1, in the nucleus accumbens, ventromedial prefrontal cortex, orbitofrontal cortex, prelimbic cortex, central amygdala, and ventral hippocampus.
This study aims to elucidate the neurobiological substrates underlying relapse vulnerability and to identify anatomically and mechanistically defined targets for future therapeutic interventions in substance use disorders.
Grant PID2022-142469OA-I00 funded by AEI 10.13039/501100011033.