Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse

Abstract

Relapse to alcohol abuse is a critical clinical issue, frequently caused by cue-induced drug craving. Therefore, disruption of the memory for the cue-alcohol association is expected to prevent relapse. It is increasingly accepted that memories become labile and erasable soon after their reactivation through retrieval, during a memory reconsolidation process that depends on protein synthesis. Here, we show that reconsolidation of alcohol-related memories triggered by the sensory properties of alcohol itself (odor and taste) activates mammalian target of rapamycin complex 1 (mTORC1) in select amygdalar and cortical regions in rats, resulting in increased levels of several synaptic proteins. Furthermore, systemic or central amygdalar (CeA) inhibition of mTORC1 during reconsolidation disrupts alcohol-cue associated memories, leading to a long-lasting suppression of relapse. Our findings provide evidence that the mTORC1 pathway and its downstream substrates play a crucial role in alcohol-related memory reconsolidation, and highlight this pathway as a therapeutic target to prevent relapse.

Counterconditioning During Reconsolidation Prevents Relapse of Cocaine Memories

“…According to the memory reconsolidation hypothesis, the 'reconsolidation window', during which memories are labile for manipulations, lasts 5-6 h (Nader and Hardt, 2009;Barak et al, 2013). Therefore, applying a manipulation aimed at disrupting memory reconsolidation after the 'reconsolidation window' closes would not affect the target memory and its behavioral expression (Nader and Hardt, 2009;Milton and Everitt, 2012).…”

“…Therefore, applying a manipulation aimed at disrupting memory reconsolidation after the 'reconsolidation window' closes would not affect the target memory and its behavioral expression (Nader and Hardt, 2009;Milton and Everitt, 2012). Thus, we tested whether aversive counterconditioning conducted outside the 'reconsolidation window', that is, 5 h after the retrieval of cocaine-associated memories (Barak et al, 2013), would fail to reinstate cocaine-seeking behavior.…”

“…Therefore, the retrieved memory becomes labile for a short period of time termed the 'reconsolidation window', during which it can be strengthened, updated, or even erased (Nader and Hardt, 2009;Dudai, 2012;Reichelt and Lee, 2013;Tronson and Taylor, 2013). Reconsolidation of drug-associated memories is disrupted by inhibition of protein synthesis in animal models, resulting in a reduced cue-induced reinstatement of drug-seeking behavior (eg, von der Goltz et al, 2009;Barak et al, 2013;Tronson and Taylor, 2013). However, most pharmacological treatments used to disrupt memory reconsolidation may cause serious side effects.…”

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

“…Studies using rapamycin have implicated mTORC1 in late phase (protein synthesis dependent) LTP and LTD (Cammalleri et al, 2003;Stoica et al, 2011), as well as associative learning processes, including inhibitory avoidance memory and fear conditioning (Blundell et al, 2008;Parsons et al, 2006). More recently, experiments using rapamycin have implicated mTORC1 signaling in addiction-relevant behaviors and in alcohol-related memory consolidation (Barak et al, 2013). Both acute systemic and intra-NAC injections of rapamycin attenuated alcohol-drinking behaviors and conditioned place preference (CPP) for alcohol (Neasta et al, 2010).…”

“…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).…”