Nicotine-seeking reinstatement is reduced by inhibition of instrumental memory reconsolidation

Abstract

The reinforcing properties of nicotine play a major role in instrumental conditioning to nicotine taking in smokers. Retrieval of nicotine-related memories may promote relapse to nicotine seeking after prolonged abstinence. Once consolidated, memories are stable, but they return to a labile phase, called reconsolidation, after their retrieval. The aim of our study was to investigate whether it was possible to interfere with the reconsolidation of instrumental nicotine-related memories by acting at glutamatergic receptors [N-methyl-D-aspartate receptors (NMDARs)] to prevent relapse to nicotine-seeking behaviour in the rat. We assessed whether the NMDAR antagonist MK-801, administered before or after nicotine-related instrumental memory retrieval, can reduce reinstatement of nicotine-seeking behaviour in rats previously trained to nicotine self-administration. Following a period of forced abstinence, MK-801 (0.1 mg/kg intraperitoneally) was administered 30 min before or 1 h after the re-exposure to 20 lever presses without any contingency in the training context to retrieve instrumental memory. MK-801 administered after, but not before, retrieval inhibited reinstatement compared with vehicle controls and groups without retrieval of instrumental memory. Interestingly, a retrieval factor effect was observed as an increase of reinstatement in vehicle-treated groups, suggesting a behavioural outcome of the occurrence of instrumental memory reconsolidation. Our findings suggest that, by acting on NMDARs, it is possible to reduce the reinstatement of nicotine-seeking behaviour through inhibition of instrumental nicotine-related memory reconsolidation.

Updating memories—The role of prediction errors in memory reconsolidation

“…A notable exception to these negative findings is a recent paper by Tedesco et al [126] in which they purport to demonstrate successful destabilisation of an instrumental memory using a non-reinforced reactivation session, and disruption of reconsolidation with the NMDAR antagonist MK-801. Interestingly, they observed enhancement of performance in saline controls, rather than a deficit in the MK-801-treated group [126].…”

“…Interestingly, they observed enhancement of performance in saline controls, rather than a deficit in the MK-801-treated group [126]. This raises an important question as to whether reconsolidationmediated updating, or the consolidation of new learning, was disrupted; the existence of a reconsolidation process is inferred through the absence of behaviour following its disruption and, in the case of enhancement of memory, cannot be easily distinguished from consolidation of new learning on a purely behavioural basis.…”

“…Moreover, given the aforementioned proposed role for reconsolidation in memory modification, this also enables memory content and strength to be modulated during a window of plasticity. Indeed, the simple retrieval of a memory may lead to memory strengthening through reconsolidation processes [51,126].…”

The metaplastic effects of NMDA receptors blockade on reactivation of instrumental memories in rats

“…4 mg/kg/mL, is the same dose that Buck and colleagues showed to induce facilitation of LTP in ex-vivo CA1-subiculum synapses of rats hippocampus 24 hours after dosing (Buck et al, 2006). Twenty-four hours after acute treatment, rats were re-exposed to a short instrumental memory reactivation session (Retrieval; Piva et al, under revision;Tedesco, Mutti, Auber, & Chiamulera, 2014).…”

Inhibition of protein synthesis but not β-adrenergic receptors blocks reconsolidation of a cocaine-associated cue memory

“…Reconsolidation blockade, conversely, is thought to directly alter and/or update the original memory, leading to a long-lasting, context-independent change and, thus, to provide potentially superior relapse prevention (Lee et al 2005;Milekic et al 2006;Sanchez et al 2010). Interfering with memory reconsolidation in rodents has been shown to block memories related to a number of drugs, including morphine (Valjent et al 2006;Taubenfeld et al 2010), ethanol (Wouda et al 2010;Schramm et al 2015), nicotine (Fang et al 2011;Tedesco et al 2014), methamphetamine (Zhao et al 2011b;Yu et al 2013), amphetamine (Sadler et al 2007;Contreras et al 2012), heroin (Hellemans et al 2006;Jian et al 2014), and cocaine (Milton et al 2008;Sanchez et al 2010). Notably, manipulations of memory reconsolidation have also been reported to decrease the strength of drug-related memories in humans (Zhao et al 2011a;Saladin et al 2013).…”