The basolateral amygdala and nucleus accumbens core mediate dissociable aspects of drug memory reconsolidation

Abstract

A distributed limbic-corticostriatal circuitry is implicated in cue-induced drug craving and relapse. Exposure to drug-paired cues not only precipitates relapse, but also triggers the reactivation and reconsolidation of the cue-drug memory. However, the limbic cortical-striatal circuitry underlying drug memory reconsolidation is unclear. The aim of this study was to investigate the involvement of the nucleus accumbens core and the basolateral amygdala in the reconsolidation of a cocaine-conditioned stimulus-evoked memory. Antisense oligodeoxynucleotides (ASO) were infused into each structure to knock down the expression of the immediate-early gene zif268, which is known to be required for memory reconsolidation. Control infusions used missense oligodeoxynucleotides (MSO). The effects of zif268 knockdown were measured in two complementary paradigms widely used to assess the impact of drug-paired CSs upon drug seeking: the acquisition of a new instrumental response with conditioned reinforcement and conditioned place preference. The results show that both intranucleus accumbens core and intrabasolateral amygdala zif268 ASO infusions at memory reactivation impaired the reconsolidation of the memory underlying a cocaine-conditioned place preference. However, knockdown of zif268 in the nucleus accumbens at memory reactivation had no effect on the memory underlying the conditioned reinforcing properties of the cocaine-paired CS measured subsequently, and this is in contrast to the marked impairment observed previously following intrabasolateral amygdala zif268 ASO infusions. These results suggest that both the basolateral amygdala and nucleus accumbens core are key structures within limbic cortical-striatal circuitry where reconsolidation of a cue-drug memory occurs. However reconsolidation of memory representations formed during Pavlovian conditioning are differentially localized in each site.

Figure 1.

Location of the injector tips within the AcbC for both reactivated (A) and nonreactivated (B) groups. (Black circles) zif268 ASO-infused rats; (white circles) zif268 MSO-infused rats.

Figure 2.

Cocaine-induced CPP is disrupted in a reactivation-dependent manner following intra-AcbC zif268 ASO prior to memory reactivation. Time spent on the cocaine- (black bars) and saline-paired (white bars) sides are shown for the reactivated (C–E; MSO = 10, ASO = 7) and nonreactivated (F,G; MSO = 12, ASO = 11) groups. The timeline of the experimental procedures for the reactivated and nonreactivated memory conditions are shown in A and B, respectively. (C) There was no difference between the groups during the preconditioning test. (D) Both groups acquired a significant preference for the cocaine-paired side as assessed in the memory-reactivation test. (E) The ASO group had a significantly impaired preference for the cocaine-paired side during the post-reactivation test. (F) The nonreactivated groups also did not differ during the preconditioning test. (G) Both groups showed a significant preference for the cocaine-paired side during the post-treatment preference test. Data are presented as mean ± SEM.

Figure 3.

Location of the injector tips within the BLA for both reactivated (A) and nonreactivated (B) groups. (Black circles) zif268 ASO-infused rats; (white circles) zif268 MSO-infused rats.

Figure 4.

Intra-BLA zif268 ASO, prior to memory reactivation, impaired cocaine-induced CPP in a reactivation-dependent manner. Time spent on the cocaine- (black bars) and saline-paired (white bars) sides are shown for the reactivated (C–E; MSO = 4, ASO = 11) and nonreactivated (F,G; MSO = 8, ASO = 11) groups. The timeline of the experimental procedures for the reactivated and nonreactivated memory conditions are shown in A and B, respectively. (C) There was no difference between the groups during the preconditioning test. (D) Both groups acquired a significant preference for the cocaine-paired side as assessed in the memory-reactivation test. (E) The ASO group had a significantly impaired preference for the cocaine-paired side during the post-reactivation test. (F) The nonreactivated groups also did not differ during the preconditioning test. (G) Both groups showed a significant preference for the cocaine-paired side during the post-treatment preference test. Data are presented as mean ± SEM.

Figure 5.

Location of the injector tips within the AcbC for both contingent (A) and noncontingent (B) reactivated groups. (Black circles) zif268 ASO-infused rats; (white circles) zif268 MSO-infused rats.

Figure 6.

Prereactivation intra-AcbC zif268 ASO had no effect on subsequent acquisition of a new instrumental response with conditioned reinforcement. (A) Timeline of the experimental procedures. (B) The number of active (reinforced by CS presentations) and inactive (nonreinforced) lever presses was compared over four testing sessions after treatment given to rats submitted to a response contingent memory reactivation (n = 7–9 per group). (C) The number of active (reinforced by CS presentations) and inactive (nonreinforced) lever presses was compared over four testing sessions after treatment given to rats submitted to a response noncontingent memory reactivation (n = 11 per group). Data are presented as mean ± SEM.

Figure 7.

The knockdown of zif268 in the AcbC prior to both response contingent (A) and noncontingent (B) memory reactivation did not affect the performance of the previously drug-reinforced instrumental behavior, nosepoke responding (n = 7–9 per group in contingent reactivation; 11 per group in noncontingent reactivation). Data are presented as mean ± SEM.