Disruption of Long-Term Alcohol-Related Memory Reconsolidation: Role of β-Adrenoceptors and NMDA Receptors

Abstract

Disrupting reconsolidation of drug-related memories may be effective in reducing the incidence of relapse. In the current study we examine whether alcohol-related memories are prone to disruption by the β-adrenergic receptor antagonist propranolol (10 mg/kg) and the NMDA receptor antagonist MK801 (0.1 mg/kg) following their reactivation. In operant chambers, male Wistar rats were trained to self-administer a 12% alcohol solution. After 3 weeks of abstinence, the animals were placed in the self-administration cages and were re-exposed to the alcohol-associated cues for a 20-min retrieval period, immediately followed by a systemic injection of either propranolol, MK801 or saline. Rats were tested for cue-induced alcohol seeking on the following day. Retrieval session, injection and test were repeated on two further occasions at weekly intervals. Both propranolol and MK801 administration upon reactivation did not reduce alcohol seeking after the first reactivation test. However, a significant reduction of alcohol seeking was observed over three post-training tests in propranolol treated animals, and MK801 treated animals showed a strong tendency toward reduced alcohol seeking (p = 0.06). Our data indicate that reconsolidation of alcohol-related memories can be disrupted after a long post-training interval and that particularly β-adrenergic receptors may represent novel targets for pharmacotherapy of alcoholism, in combination with cue-exposure therapies.

Noradrenergic Regulation of Fear and Drug-Associated Memory Reconsolidation

“…In this model, rodents are trained to lever press or nose poke for rewards, such as food, intravenous drug infusion, or intracranial stimulation (eg, of the lateral hypothalamus). Experiments have revealed that systemic propranolol injections administered after memory retrieval disrupt context-or cue-driven sucrose seeking (Diergaarde et al, 2006;Milton et al, 2008b), cocaine seeking (Milton et al, 2008b), and ethanol seeking (Wouda et al, 2010) within the SA paradigm (but see Milton and Everitt, 2010;Williams and Harding, 2014). However, these convincing experiments have been overshadowed by studies revealing no effect of propranolol when administered before memory retrieval (Lee and Everitt, 2008;Milton and Everitt, 2010).…”

“…Synaptic plasticity is a critical mechanism for reconsolidation (Clem and Huganir, 2010). Moreover, NMDA receptor Impaired Sucrose (CR) Milton et al (2008b) Impaired Cocaine (CR) Milton et al (2008b) No effect Cocaine (reinstatement) Milton and Everitt (2010) Impaired EtOH (extinction) Wouda et al (2010) No effect EtOH (extinction) Williams and Harding (2014) Before No effect Sucrose (PCA) Lee and Everitt (2008) No effect Sucrose (PIT) Lee and Everitt (2008) No effect EtOH (PCA) Milton et al (2012) No effect EtOH (PIT) Milton et al (2012) Abbreviations: CR, conditioned reinforcement; PCA, Pavlovian conditioned approach; PIT, Pavlovian-to-instrumental transfer. Summary of findings for research examining the effectiveness of propranolol for reconsolidation blockade within the SA paradigm.…”

“…For example, inhibition of a 1 -and b-adrenergic receptor (AR) activity during reconsolidation leads to memory disruption within both appetitive and aversive memory paradigms (Bernardi et al, 2006(Bernardi et al, , 2009Do Monte et al, 2013;Gazarini et al, 2013;Milton et al, 2008b;Przybyslawski et al, 1999;Wouda et al, 2010). Furthermore, disruption of noradrenergic signaling during reconsolidation reduces long-term emotional memory in healthy humans (for a recent meta-analysis, see Lonergan et al, 2013), is associated with better quality of life among PTSD patients (Poundja et al, 2012), and is capable of reducing cue-induced cravings among patients with cocaine addiction (Saladin et al, 2013).…”

Inhibition of Hippocampal β-Adrenergic Receptors Impairs Retrieval But Not Reconsolidation of Cocaine-Associated Memory and Prevents Subsequent Reinstatement

“…The short CPP tests were chosen to induce reconsolidation while limiting CPP extinction across the initial tests. This length of test is standard for testing reconsolidation of drugassociated memories, and previous investigations using this length of CPP test have revealed a role for dHipp or b-AR signaling in reconsolidation of CPP memories (eg, Bernardi et al, 2009 andOtis et al, 2013) and self-administration memories (eg, Ramirez et al, 2009;Wells et al, 2011 andWouda et al, 2010). A CPP was determined when rats spent significantly more time within the previously cocainepaired chamber than in the saline-paired chamber.…”

Appetitive Pavlovian goal-tracking memories reconsolidate only under specific conditions

“…This has been demonstrated in a number of experimental paradigms using natural (Diergaarde et al 2006;Lee and Everitt 2008a), alcohol (Wouda et al 2010;Milton et al 2012), and addictive drug rewards (Lee et al 2005(Lee et al , 2006aMilton et al 2008a,b). However, there are two notable failures to observed memory reconsolidation in appetitive settings: instrumental responding (Hernandez and Kelley 2004) and Pavlovian goal-tracking (Blaiss and Janak 2007).…”