Disruption of relapse to alcohol seeking by aversive counterconditioning following memory retrieval

Abstract

Relapse to alcohol abuse is often caused by exposure to potent alcohol-associated cues. Therefore, disruption of the cue-alcohol memory can prevent relapse. It is believed that memories destabilize and become prone for updating upon their reactivation through retrieval, and then re-stabilize within 6 h during a "reconsolidation" process. We recently showed that relapse to cocaine seeking could be prevented by counterconditioning the cocaine-cues with aversive outcomes following cocaine-memory retrieval, in a place conditioning paradigm. However, to better model addictionrelated behaviors, self-administration models are necessary. Here, we demonstrate that relapse to alcohol seeking can be prevented by aversive counterconditioning conducted during alcoholmemory reconsolidation, in conditioned place preference (CPP) and operant self-administration paradigms, in mice and rats, respectively. We found that the reinstatement of alcohol-CPP was abolished only when aversive counterconditioning with water-flooding was given shortly after alcohol-memory retrieval. Furthermore, rats trained to lever-press for alcohol showed decreased context-induced renewal of alcohol-seeking responding when the lever-pressing was counterconditioned with foot-shocks, shortly, but not 6 h, after memory retrieval. These results 0suggest that aversive counterconditioning can prevent relapse to alcohol seeking only when performed during alcohol-memory reconsolidation, presumably by updating, or replacing, the alcohol memory with aversive information. Also, we found that aversive counterconditioning preceded by alcohol-memory retrieval was characterized by upregulation of brain-derived neurotrophic factor (Bdnf) mRNA expression in the medial prefrontal cortex, suggesting that Bdnf plays a role in the memory updating process. Operant self-administration, Conditioned place preference, BDNFAlcohol place conditioning (days 2-9): Training started 24 h after the Baseline test with one session per day over 8 days, with the sliding door closed. On days 3, 5, 7, and 9, mice were administered with alcohol (1.8 g/kg; i.p.) and immediately confined to the paired compartment for 5 min. On the alternate days (days 2, 4, 6, and 8), mice were administered with saline and were confined to the unpaired compartment for the same duration as on the alcohol-conditioning day.Paired compartments were counterbalanced.Place preference test 1 (day 10): Place preference test was identical to the Baseline stage, and served to index alcohol-CPP (Cunningham et al., 2003). Preference was defined as an increase in the percent of time spent in the alcohol-paired compartment during the Place preference test 1 compared to the Baseline test. Mice that did not show CPP (minimum of 5% change) were excluded from the experiment (3 from Experiment 1; 4 from Experiment 2).Memory retrieval and aversive counterconditioning (days 11-14). Prior to this stage, mice were assigned to different experimental conditions, Retrieval and No Retrieval (matched for CPP scores and sex). Training began 2...

FGF2 is an endogenous regulator of alcohol reward and consumption

“…The alcohol-conditioned place preference (CPP) procedure was performed as we previously described. [33][34][35] Mice were habituated to daily i.p. saline injections for 5 days.…”

Alcohol-specific transcriptional dynamics of memory reconsolidation

“…and immediately confined to the paired compartment for 5 min. This dose and conditioning duration were previously shown to produce alcohol-induced CPP 32,69 . On the alternate days (i.e., days 2, 4, 6, and 8), the mice received saline solution and were confined to the unpaired compartment for the same duration as on the alcohol-conditioning day.…”

“…To assess the role of hippocampal gene transcription in alcohol memory reconsolidation, we formed alcohol-associated memories in the alcohol-CPP procedure, by conditioning one compartment of the CPP-box to alcohol (Figure 1A, experimental design). A day after confirming the strong preference for the alcohol-paired compartment in a CPP test, the mice were re-exposed to the alcohol-paired compartment for 3 min to retrieve alcohol-associated memories, as we previously demonstrated 34, 35 . Immediately after memory retrieval, actinomycin (4 µg/µl; 0.5 µl per side) or vehicle were infused into the DH 18 .…”

“…Thus, the lack of change in Bdnf expression in our study could suggest that our memory retrieval procedure did not initiate extinction learning in parallel with memory retrieval. Moreover, we recently reported that although the mRNA levels of Bdnf in the DH are not increased by alcohol memory retrieval per se , the expression of the growth factor were elevated when the retrieval is followed by aversive counterconditioning that prevented relapse 34 , suggesting a complex role of Bdnf in alcohol memory dynamics.…”