Cue-induced cocaine seeking and relapse are reduced by disruption of drug memory reconsolidation

Abstract

Long-lasting vulnerability to drug cue-induced relapse to a drug-taking habit is a major challenge to the treatment of drug addiction. Here we show that blockade of drug memory reconsolidation, through infusion of Zif268 antisense oligodeoxynucleotides into the basolateral amygdala shortly before reexposure to a cocaine-associated stimulus but not simply to the training context, severely impaired subsequently cue-maintained cocaine seeking under a second-order schedule of reinforcement and abolished cue-induced reinstatement of and relapse to cocaine seeking. This reduction in relapse after disrupted memory reconsolidation was not only seen after several hundred pairings of the stimulus with self-administered cocaine, but older, as well as recent, memories were also disrupted. Reconsolidation blockade may thus provide a potential therapeutic strategy for the prevention of relapse in drug addiction.

Figures

Figure 1.

Location of injectors within the BLA. Schematic representation of the brain at three rostrocaudal levels (−2.30, −2.56, and −2.80 mm from bregma). All rats included in the statistical analyses had injectors placed bilaterally in the BLA (gray shaded area).

Figure 2.

Effect of pre-reactivation intra-BLA Zif268 ASO on subsequent cocaine seeking 6 d into withdrawal. a, The number of active and inactive lever presses during the first and second 30 min bins of the 60 min test for rats infused and reexposed to the cocaine CS 3 d after the end of self-administration training (n = 6–10 per group). b, The number of lever presses for control rats infused and reexposed to the training context alone (n = 6–7 per group). c, Zif268 ASO infusion reduced drug seeking to the same degree as omission of the CS. The discriminated responding (ratio of active/inactive lever presses) of Zif268 ASO and MSO groups relative to same ratio for the no-CS group is shown for the entire test session. d, The number of lever presses for rats with delayed infusions of Zif268 ASO and MSO after reexposure to the cocaine CS (n = 4 per group). Data are presented as mean + SEM.

Figure 3.

Effect of pre-reactivation intra-BLA Zif268 ASO on subsequent cocaine seeking 30 d into withdrawal. The number of active and inactive lever presses during the first and second 30 min bins of the 60 min test are presented for rats infused 27 d after the end of self-administration training (n = 6 and 8 per group). Data presented as mean + SEM.

Figure 4.

Effect of pre-reactivation intra-BLA Zif268 ASO on the subsequent maintenance of cocaine seeking under a second-order schedule of reinforcement. The number of active lever presses during the first, pre-cocaine interval (a) and averaged over the four post-cocaine intervals (b) are presented for representative sessions in the four stages of the experiment (n = 6–10 per group): baseline, CS introduction under a second-order schedule of reinforcement [FI15(FR10:S); session 6 after reactivation], CS omission (FI15; session 13), and CS reintroduction (session 15). Groups were infused with Zif268 ASO or MSO and reexposed to either the training context alone (Non-reactivated) or the cocaine-associated CS in the training context (Reactivated). Infusion and reexposure took place between baseline and CS introduction. Data are presented as mean ± SEM.

Figure 5.

Effect of pre-reactivation intra-BLA Zif268 ASO on the subsequent cue-induced reinstatement of cocaine seeking after extinction of the instrumental response. The number of active and inactive lever presses are presented for the first hour of the last session of instrumental extinction and for the subsequent 1 h reinstatement test (n = 8–9 per group). Data are presented as mean + SEM.