Rapamycin prevents drug seeking via disrupting reconsolidation of reward memory in rats

Abstract

The maladaptive drug memory developed between the drug-rewarding effect and environmental cues contributes to difficulty in preventing drug relapse. Established reward memories can be disrupted by pharmacologic interventions following their reactivation. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) kinase, has been proved to be involved in various memory consolidation. However, it is less well characterized in drug memory reconsolidation. Using a conditioned place preference (CPP) procedure, we examined the effects of systemically administered rapamycin on reconsolidation of drug memory in rats. We found that systemically administered rapamycin (0.1 or 10 mg/kg, i.p.) after re-exposure to drug-paired environment, dose dependently decreased the expression of CPP 1 d later, and the effect lasted for up to 14 d and could not be reversed by a priming injection of morphine. The effect of rapamycin on morphine-associated memory was specific to drug-paired context, and rapamycin had no effect on subsequent CPP expression when rats were exposed to saline-paired context or homecage. These results indicated that systemic administration of rapamycin after memory reactivation can persistently inhibit the drug seeking behaviour via disruption of morphine memory reconsolidation in rats. Additionally, the effect of rapamycin on memory reconsolidation was reproduced in cocaine CPP and alcohol CPP. Furthermore, rapamycin did not induce conditioned place aversion and had no effect on locomotor activity and anxiety behaviour. These findings suggest that rapamycin could erase the acquired drug CPP in rats, and that mTOR activity plays an important role in drug reconsolidation and is required for drug relapse.

Mammalian target of rapamycin complex 1 and its downstream effector collapsin response mediator protein‐2 drive reinstatement of alcohol reward seeking

“…) and others (Lin et al . ) demonstrated that rapamycin administration immediately following memory reactivation disrupts the alcohol consolidated memories. Interestingly, the retrieval of alcohol‐associated memories during the reconsolidation window is not driven by mTORC1 pathway in the NAc (Barak et al .…”

Essential role of D1R in the regulation of mTOR complex1 signaling induced by cocaine

“…Rapamycin treatment has also been shown to attenuate the expression of locomotor sensitization and CPP to alcohol (Neasta et al, 2010). Additionally, rapamycin has been shown to affect cocaine and morphine reconsolidation of reward memory in rats, a process thought to be required for drug relapse (Lin et al, 2014; Shi et al, 2014). Clinically, acute rapamycin has been shown to significantly reduce craving in heroin addicts (Shi et al, 2009).…”

mTORC1 Inhibition in the Nucleus Accumbens ‘Protects’ Against the Expression of Drug Seeking and ‘Relapse’ and Is Associated with Reductions in GluA1 AMPAR and CAMKIIα Levels

“…Cocaine-motivated behaviors have been shown to require proteins that enhance glutamate signaling in NAC MSNs (Anderson et al, 2008;Conrad et al, 2008;Wolf, 2010), so we assessed GluA1 AMPAR subunit and CAMKIIa levels in these brain regions after rapamycin treatment. Importantly, given the potential for mTORC1 inhibition to prevent neuroadaptations that promote synaptic plasticity and memory (Barak et al, 2013;Lin et al, 2014), we also tested whether rapamycin delivered to the NACsh during the cocaine-taking phase might have protracted effects on the expression of addictionrelevant behaviors including relapse-like behavior. We then assessed changes in NAC mTORC1 signaling pathway and GluA1 and CAMKIIa proteins, as they have recently been found to also play a role in cocaine relapse (Anderson et al, 2008).…”