Postretrieval Extinction Attenuates Alcohol Cue Reactivity in Rats

Abstract

Background: Conditioned responses to alcohol-associated cues can hinder recovery from alcohol use disorder (AUD). Cue exposure (extinction) therapy (CET) can reduce reactivity to alcohol cues, but its efficacy is limited by phenomena such as spontaneous recovery and reinstatement that can cause a return of conditioned responding after extinction. Using a preclinical model of alcohol cue reactivity in rats, we evaluated whether the efficacy of alcohol CET could be improved by conducting CET during the memory reconsolidation window after retrieval of cue-alcohol associations.

Methods: Rats were provided with intermittent access to unsweetened alcohol. Rats were then trained to predict alcohol access based on a visual cue. Next, rats were treated with either standard extinction (n = 14) or postretrieval extinction (n = 13). Rats were then tested for long-term memory of extinction and susceptibility to spontaneous recovery and reinstatement.

Results: Despite equivalent extinction, rats treated with postretrieval extinction exhibited reduced spontaneous recovery and reinstatement relative to rats treated with standard extinction.

Conclusions: Postretrieval CET shows promise for persistently attenuating the risk to relapse posed by alcohol cues in individuals with AUD.

Keywords: Alcohol Cue; Exposure Therapy; Reconsolidation; Relapse; Retrieval.

Figure 1. Experiment timelines

Panel A: Singly housed, adult male Long-Evans rats were induced to drink unsweetened alcohol in the homecage using an intermittent 24hr access schedule: alcohol available on MWF for 5 weeks. Water and standard chow were always available (ad libitum). Panel B: Following habituation to conditioning chamber and stimuli, rats had 12 consecutive days of cue conditioning followed by 14 consecutive days of cue extinction treatment. A test of long-term memory (LTMT) for extinction was conducted 48hr after the last day of extinction. A test of reinstatement (RT) was conducted 48hr after LTMT. Panel C: Cue conditioning sessions consisted of 8-trial blocks. Panel D: Cue extinction treatment days involved 12 extinction trials in either “no retrieval-extinction” or “retrieval-extinction” arrangement. Panel E: LTMT and RT consisted of 4-trial blocks. Panels C-E: The same variable inter-trial interval (vITI) was used (mean=280s; sd=68s; min=160s; max=360s). Panel F: Conditioning trials involved 20s chamber houselight illumination with co-terminating 10s access to alcohol (10% or 15% ethanol v/v in tap water; 10E/15E) sipper starting 10s after light onset. Panel G: Extinction trials for both Extinction and LTMT consisted of 20s houselight illumination with co-terminating 10s access to dry sipper starting 10s after light onset. Panel H: For RT, extinction trials were given, but an open vial of 10E/15E (20mL) was hidden in the cubicle housing the conditioning chamber.

Figure 2. Treatment groups were matched on drinking in the homecage

Group mean ± SEM shown for ingested doses per day. Open circles represent group NoRet-Ext (n=14). Filled circles represent group Ret-Ext (n=13). Horizontal line indicates a priori study inclusion criterion: mean across last 3 days >=1.00 g/kg.

Figure 3. Treatment groups were matched on cue-conditioned response acquisition and drinking during conditioning

Panels A-C: Group mean ± SEM shown for sipper site approach level (max level = 4). Open circles represent group NoRet-Ext (n=14). Filled circles represent group Ret-Ext (n=13). Panels D-E: Group mean ± SEM shown for sipper contact level (max level = 4). Open circles represent group NoRet-Ext (n=14). Filled circles represent group Ret-Ext (n=13). Panel F: Group mean ± SEM shown for ingested doses per session. Open circles represent group NoRet-Ext (n=14). Filled circles represent group Ret-Ext (n=13). Horizontal line indicates a priori study inclusion criterion: mean across last 3 sessions >= 0.30 g/kg.

Figure 4. Isolated cue plus context or context only exposure 1 hr before massed cue exposure similarly extinguished cue-conditioned responses across treatment

Panels A-C: Group mean ± SEM shown for sipper site approach level (max level = 4). Open circles represent group NoRet-Ext (n=14). Filled circles represent group Ret-Ext (n=13). Panels D-E: Group mean ± SEM shown for sipper contact level (max level = 4). Open circles represent group NoRet-Ext (n=14). Filled circles represent group Ret-Ext (n=13). Panels F-G: Group mean ± SEM shown for sipper site approach and sipper contact levels (max level = 4) across the last 4 trials on the last day of treatment. Open bars represent group NoRet-Ext (n=14). Filled bars represent group Ret-Ext (n=13).

Figure 5. Similar daily recovery of cue-conditioned responses between groups across treatment

Panels A-C: Group mean ± SEM shown for sipper site approach level (max level = 4) on trial 1 across extinction days (retrieval trial for Ret-Ext group). Open circles represent group NoRet-Ext (n=14). Filled circles represent group Ret-Ext (n=13). Panels D-E: Group mean ± SEM shown for sipper contact level (max level = 4) on trial 1 across extinction days (trial 1 = retrieval trial for Ret-Ext group). Open circles represent group NoRet-Ext (n=14). Filled circles represent group Ret-Ext (n=13).

Figure 6. Retrieval-extinction treatment protects against early spontaneous recovery of cue-conditioned responses relative to two different baselines

Group mean ± SEM shown for sipper site approach and sipper contact levels (max level = 4) (Panels A, B, C, F, G, H and D, E, I, J respectively). Open circles represent group NoRet-Ext (n=14). Filled circles represent group Ret-Ext (n=13). Panels A-E: Baseline refers to average across E14 trials 9-12. Panels F-J: Baseline refers to E14 trial 1 (retrieval trial for Ret-Ext group). All Panels: Test refers to long-term memory test trial 1. Asterisk (*) signifies one-tailed p<0.05 for directional comparison on response level change (Test – Baseline for NoRet-Ext > Ret-Ext).

Figure 7. Retrieval-extinction treatment protects against alcohol odor-induced reinstatement of cue-conditioned responses relative to two different baselines

Group mean ± SEM shown for sipper site approach and sipper contact levels (max level = 4) (Panels A, B, C, F, G, H and D, E, I, J respectively). Open circles represent group NoRet-Ext (n=14). Filled circles represent group Ret-Ext (n=13). Panels A-E: Baseline refers to long-term memory test trial 4. Panels F-J: Baseline refers to E14 trial 1 (retrieval trial for Ret-Ext group). All Panels: Test refers to reinstatement test trial 1. Asterisk (*) and pound sign (#) signify one-tailed p<0.05 and p<0.07, respectively, for directional comparison on response level change (Test – Baseline for NoRet-Ext > Ret-Ext).